1
Author for contact: Claus-Peter Witte 1, Leibniz Universität Hannover, Department of 1
Molecular Nutrition and Biochemistry of Plants, Herrenhäuser Str. 2, 30419 Hannover, 2
Germany 3
Update: Nucleotide Metabolism in Plants 4
Claus-Peter Wittea,2,3 and Marco Herdea 5
a Leibniz Universität Hannover, Department of Molecular Nutrition and Biochemistry of 6
Plants, Herrenhäuser Str. 2, 30419 Hannover, Germany 7
2 Author for contact 8 3 Senior author 9
ORCID ID: 0000-0002-3617-7807 (C.-P.W.) 10
ORCID ID: 0000-0003-2804-0613 (M.H.) 11
One-sentence summary: Nucleotide metabolism is an essential function in plants. 12
13
Author contributions: C.-P.W. conceived the study, C.-P.W. and M.H. wrote the article 14
Funding: The authors acknowledge funding from the Deutsche Forschungsgemeinschaft 15
(WI3411/4-1 to C.-P.W. and HE 5949/3-1 to M.H.) and the Bundesministerium für Bildung 16
und Forschung (Nutzpflanzen der Zukunft - 031B0540). 17
E-mail address of the author for contact: [email protected] 18
19
Nucleotide metabolism in plants 20
Nucleotides are essential for life. It is easy to validate this statement – one just needs to 21
recall that nucleotides are the building blocks of DNA and RNA, and that many molecules 22
which are central for metabolism, for example ATP, NADH, Co-A and UDP-glucose, are 23
nucleotides or contain nucleotide moieties. Generally, a nucleotide is defined as a 24
phosphorylated ribose or deoxyribose linked to a nitrogen-containing heterocyclic group 25
called the nucleobase via a glycosidic bond (Figure 1). Because of the phosphate groups, 26
nucleotides are negatively charged, whereas at neutral pH nucleosides and nucleobases are 27
uncharged. The exception is xanthine, which is partially charged as a free base (pKa = 7.4) 28
but completely charged at the base in xanthosine (pKa = 5.5) or the corresponding 29
nucleotides (Figure 1, Sigel et al., 2009). 30
Many excellent reviews focus on general (Wagner and Backer, 1992; Zrenner et al., 2006; 31
Zrenner and Ashihara, 2011; Stasolla et al., 2003; Moffatt and Ashihara, 2002) or particular 32
Plant Physiology Preview. Published on October 22, 2019, as DOI:10.1104/pp.19.00955
Copyright 2019 by the American Society of Plant Biologists
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2
aspects of (Smith and Atkins, 2002; Ashihara et al., 2018; Kafer et al., 2004) plant nucleotide 33
metabolism. The aim of this review is to provide an update on how nucleotide metabolism is 34
hardwired, mostly focusing on the cellular level, because our understanding of the 35
organization at the tissue and organ level remains very limited. The presented models are 36
mostly based on results from Arabidopsis thaliana. These will often be valid for most plants, 37
but certainly there will be species-dependent variations. We also cover extracellular 38
nucleotide metabolism and review the evidence for overlap between cytokinin metabolism 39
and central nucleotide metabolism. Figure 2 shows a general overview of plant nucleotide 40
metabolism. 41
DE NOVO SYNTHESIS 42
Purine de novo synthesis 43
Plants possess the metabolic pathways for the de novo synthesis of purine nucleotides 44
generating AMP as well as pyrimidine nucleotides yielding UMP. During de novo 45
biosynthesis, nucleotides are newly synthesized from the general metabolites activated 46
ribose (5-phosphoribosyl-1-pyrophosphate, PRPP), glutamine, aspartate, and bicarbonate as 47
well as specifically for the purine nucleotides, glycine and formyl tetrahydrofolate (Figure 2). 48
There is strong evidence that AMP biosynthesis occurs entirely in the plastids, because the 49
11 enzymes (catalyzing 12 reactions; Smith and Atkins, 2002) required for AMP biosynthesis 50
in Arabidopsis all have an N-terminal organelle targeting peptide, and C-terminal yellow 51
fluorescent protein (YFP)-fusion proteins of several of these enzymes were observed 52
exclusively in the plastids when they were transiently expressed in Nicotiana benthamiana 53
in our laboratory (N. Medina Escobar and C.-P. Witte, unpublished data) (Figure 3A). In rice 54
(Oryza sativa), the pathway also seems to reside in plastids (Zhang et al., 2018). However, it 55
has been reported that in nodules of the tropical legume cowpea (Vigna unguiculata), 56
purine biosynthesis is targeted to plastids and mitochondria (Atkins et al., 1997; Smith and 57
Atkins, 2002). It may be worthwhile to reconfirm this special localization in nodules using 58
fluorescent tagged proteins. 59
AMP is exported from the plastids by the adenine nucleotide uniporter brittle1 (BT1, Figure 60
3A, number 1), which can also transport ADP and ATP (Hu et al., 2017; Kirchberger et al., 61
2008; Leroch et al., 2005). Interestingly, BT1 from Arabidopsis and maize (Zea mays) was 62
reported to be dual localized to the chloroplast and mitochondria (Bahaji et al., 2011b) and 63
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a bt1 mutant with a severe dwarf phenotype could be complemented with an N-terminally 64
truncated version of BT1 that is exclusively located in the mitochondria and not in the 65
plastids (Bahaji et al., 2011a). This either indicates that there are certain tissues or 66
developmental stages where purine nucleotide biosynthesis occurs mainly in mitochondria, 67
or that BT1 has an alternative and essential function in this organelle. In the latter case, BT1 68
might still also be involved in exporting adenylates from plastids, but the abrogation of the 69
plastidic variant would not cause the strong dwarf phenotype, indicating that de novo 70
synthesized AMP has an alternative, BT1 independent, way to leave the plastids. 71
GMP biosynthesis requires inosine monophosphate (IMP, Figure 3A), which can either be 72
derived from AMP deamination in the cytosolic compartment catalyzed by AMP deaminase 73
(AMPD, Figure 3A, #2) or from direct export of IMP from the plastids, because IMP is 74
generated there en route to AMP (Figure 3A). Mutation of AMPD is zygote lethal (Xu et al., 75
2005) and coformycin, an AMPD inhibitor, is a potent herbicide after its phosphorylation in 76
vivo (Dancer et al., 1997). These phenotypic effects might be caused by hampered GMP 77
biosynthesis, suggesting that AMPD could be required for this process. Consistent with this, 78
AMPD is strongly activated by ATP (Han et al., 2006) and this regulation might balance 79
cellular ATP and GTP concentrations. However, it has also been reported that AMPD 80
inhibition might be detrimental by severely altering the cellular energy charge and that the 81
GTP pool is not altered upon AMPD inhibition (Sabina et al., 2007), implying that GMP 82
biosynthesis is independent of AMPD and that there is an alternative IMP supply from the 83
plastids. The activity of AMPD likely resides in the cytosol, but the protein has an N-terminal 84
transmembrane domain and is clearly attached to a membrane (Han et al., 2006). 85
The following enzymatic reactions for GMP biosynthesis, (i) the oxidation of IMP to 86
xanthosine monophosphate (XMP, Figure 1) by IMP dehydrogenase (IMPDH, Figure 3A, #3), 87
and (ii) the amination of XMP to GMP by GMP synthetase (GMPS, Figure 3A, #4) probably 88
take place in the cytosol. Both enzymes have no apparent subcellular targeting peptide and 89
were detected in the cytosolic proteome of Arabidopsis (Ito et al., 2011). Also, IMPDH from 90
cowpea nodules was associated with the cytosolic fraction (Shelp and Atkins, 1983). GMP is 91
a quite strong competitive inhibitor of IMPDH (Atkins et al., 1985) maybe resulting in 92
feedback regulation in vivo. 93
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Pyrimidine de novo synthesis 94
The first dedicated reaction of UMP biosynthesis (Figure 3B) is catalyzed by asparate 95
transcarbamoylase (ATCase, Figure 3B, #5). The enzyme is located in the plastids. The next 96
enzyme, dihydroorotatase (DHOase, Figure 3B, #6) was associated to plastids in cell 97
fractionation studies (Doremus and Jagendorf, 1985 and references on the SUBA web 98
server, Hooper et al., 2017) but was located in the cytosol when transiently overexpressed 99
in Arabidopsis protoplasts as a green fluorescent protein (GFP)-tagged fusion protein (Witz 100
et al., 2012). Maybe DHOase is associated with the chloroplast membrane via a protein-101
protein interaction, and the interaction partner is overwhelmed by strong overexpression of 102
DHOase. The following enzyme, dihydroorotate dehydrogenase (DHODH, Figure 3B, #7), is 103
associated with mitochondria (Witz et al., 2012; Doremus and Jagendorf, 1985) and likely 104
located on the outer surface of the inner mitochondrial membrane as observed for the 105
mammalian orthologs (Ullrich et al., 2002). UMP synthase (UMPS, Figure 3B, #8), the final 106
enzyme, was associated with the plastids and the cytosol, as shown by cell fractionation of 107
pea (Pisum sativum) leaves (Doremus and Jagendorf, 1985) and was present in the cytosol 108
after overexpression in Arabidopsis protoplasts (Witz et al., 2012). Thus, UMP is generated 109
in the cytosol, while it appears that the responsible enzyme might have some affinity for the 110
chloroplast. Because ATCase (Figure 3B, #5) is feedback regulated by uridylates, in particular 111
UMP (Doremus and Jagendorf, 1985), the cytosolic uridine nucleotide pool must be tightly 112
connected to the plastidic pool. 113
CTP biosynthesis requires the phosphorylation of UMP to UTP (see below), which is the 114
substrate of CTP synthetase (CTPS, Figure 3B, #9). There are five CTPS isoenzymes in 115
Arabidopsis, and all reside in the cytosol. For one isoform (CTPS3) the activity and 116
stimulatory allosteric regulation by UTP and GTP has been recently shown (Daumann et al., 117
2018). Interestingly, some CTPS isoenzymes form filamentous aggregates, called 118
cytoophidia, inactivating the enzyme. In vitro, these are generated in particular in the 119
presence of CTP, indicating that the enzyme is feed-back regulated by this mechanism 120
(Daumann et al., 2018). Knockout mutants for each CTPS were characterized and except for 121
CTPS2, which showed a complete block of germination, no phenotypes were observed in the 122
single mutants (Daumann et al., 2018), indicating redundancy of the CTPS enzymes in most 123
situations. 124
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The generation of nucleoside triphosphates 125
The final steps of UMP, GMP and CTP biosynthesis occur in the cytosol. With the exception 126
of CTP, which is directly synthesized from UTP, purine and pyrimidine nucleoside 127
triphosphate synthesis is achieved by phosphorylation of the respective monophosphates 128
(Figure 4). 129
The plastids and the mitochondria, which possess their own transcription and translation 130
machineries, must be supplied with ribonucleotides and deoxyribonucleotides from the 131
cytosol. Not much is known about (i) the phosphorylation state in which nucleotides are 132
taken up, (ii) which transporters are involved, (iii) if the concentrations of (desoxy) 133
nucleotides differ in the distinct cellular compartments and how this may be regulated –134
subcellular distributions have been estimated only for the adenylates (Stitt et al., 1982). 135
Describing the subcellular distribution of the enzymes involved in the last two steps of 136
mononucleotide phosphorylation can help in building hypotheses regarding the exact 137
nucleotide species imported into organelles. 138
The pyrimidine nucleotides, UMP and CMP, are phosphorylated by UMP kinases (UMK, 139
Figure 4, A and B, #12) Arabidopsis possess two evolutionarily distinct families of such 140
enzymes (i) UMKs related to adenylate kinases (AMKs) encoded by four genes and (ii) UMKs 141
related to eubacterial UMP kinases encoded by two genes. The AMK-like UMKs have not yet 142
been characterized, except for a biochemical analysis of UMK3 (At5g26667), which was 143
shown to utilize UMP and CMP as the best substrates (Zhou et al., 1998). These enzymes 144
have been predicted to reside in the cytosol and the mitochondria (Lange et al., 2008). From 145
the eubacterial UMP kinase family, one member called ‘plastid UMP kinase’ (PUMKIN, 146
At3g18680) was shown to be located in chloroplasts, and to have UMK activity in vitro. 147
Interestingly, the enzyme binds certain plastidic transcripts and is involved in plastid RNA 148
metabolism, which may not require its enzymatic function. Mutants are small and 149
compromised in plastid translation and photosynthetic performance (Schmid et al., 2019). 150
The orthologous enzyme in rice is localized in chloroplasts, participates in RNA metabolism, 151
and the corresponding loss-of-function mutants are pale green (Chen et al., 2018a; Zhu et 152
al., 2016). Additionally, they contain less UDP and more UMP (Dong et al., 2019) suggesting 153
that UMP phosphorylation in the chloroplast is functionally important. The phosphorylation 154
of TMP is not catalyzed by UMKs, but by a dedicated thymidine monophosphate kinase 155
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6
(TMK, Figure 4B, #16). In Arabidopsis, a mitochondrial and a cytosolic version are generated 156
from a single gene by alternative splicing. Mutation of TMK leads to early seed abortion at 157
the zygote state (Ronceret et al., 2008). 158
The phosphorylation of GMP to GDP and dGMP to dGDP (Kumar et al., 2000) is catalyzed by 159
guanylate kinases (GMK, Figure 4C, #17) of which plants have two different types, a 160
cytosolic type (GKc), and a organelle type, dual targeted to plastids and mitochondria 161
(GKpm) (Figure 4C). The activity of GKpm in rice, pea, and Arabidopsis is regulated by 162
guanosine 3’, 5’-bisdiphosphate (ppGpp), a bacterial and plastid signaling molecule (Nomura 163
et al., 2014). Suppression of Arabidopsis GKpm (At3g06200) transcripts by RNA interference 164
(RNAi) results in a pale green or albino phenotype (Sugimoto et al., 2007) emphasizing the 165
importance of nucleotide monophosphate transport into organelles. Interestingly, the loss-166
of-function mutant of the rice GKpm gene is pale green, but does not exhibit DNA depletion 167
in the organelles, suggesting that deoxynucleotide and ribonucleotide metabolism are not 168
fully linked (Sugimoto et al., 2007). 169
Adenylate monophosphate is converted by adenylate kinase (AMK, Figure 4D, #18) into 170
adenosine diphosphate (ADP). Arabidopsis has seven AMK isoforms. AMK1, AMK2, and 171
AMK5 are located in the plastids, AMK3 and AMK4 reside in the cytosol, and AMK7 is 172
present in the mitochondria. For AMK1 a mitochondrial localization has also been observed 173
(Carrari et al., 2005; Lange et al., 2008). Because the plastids harbor the de novo synthesis 174
for AMP, they will not require net import of adenylates. Consistently, the loss-of-function 175
mutant for AMK2 has a bleached phenotype (Lange et al., 2008) suggesting that there is no 176
net ADP or ATP import to compensate for compromised adenlyate kinase activity in plastids. 177
A strong reduction of plastidic AMK activity in rice also results in an albino phenotype (Wei 178
et al., 2017). In potato (Solanum tuberosum), a reduction of plastidic AMK activity led to an 179
increase of the adenylate pool (AMP, ADP, ATP, and ADP-glucose) and increased starch 180
synthesis in tubers, but it is still not understood how plastidic AMK and adenylate de novo 181
synthesis are connected (Regierer et al., 2002). Interestingly, it was suggested that the 182
AMKs might contribute to protect RNA from random mis-incorporation of methyl-6 A marks. 183
AMKs are highly selective for AMP versus N6-methyl AMP released during the degradation 184
of RNA species carrying this abundant A modification. The selectivity of the AMKs possibly 185
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7
prevents the formation of N6-methyl ATP, which is a substrate of RNA polymerase II (Chen 186
et al., 2018b). 187
Recently, a broad spectrum mononucleotide kinase only distantly related to the AMKs, but 188
with relatively high adenylate kinase activity was described (At5g60340). This enzyme was 189
localized in the nucleus and a knockout mutant was affected in stem elongation (Feng et al., 190
2012). 191
Plastids and mitochondria possess nucleoside monophosphate kinases for all nucleotides. 192
Thus, nucleoside monophosphates are probably imported into these organelles and are 193
phosphorylated to dinucleotides. Enzymes catalyzing the next step to trinucleotides, the 194
nucleoside diphosphate kinases (NDPKs), should therefore be found in plastids and 195
mitochondria as well as in the cytosol. This has been indeed observed (Luzarowski et al., 196
2017). The exact locations of the enzymes have been debated and a detailed phylogenetic 197
analysis suggests the presence of a fourth enzyme type in the endoplasmic reticulum (ER) 198
(Dorion and Rivoal, 2015). The NDPKs are multi-substrate enzymes accepting all nucleoside / 199
deoxynucleoside diphosphates (Zrenner et al., 2006) but there is a preference for generating 200
GTP (Kihara et al., 2011), which in the chloroplast may assist in repairing photosystem II 201
(Spetea and Lundin, 2012). Mutation of the gene for the plastidic NDPK in rice results in a 202
pale green phenotype and a lower photosynthetic rate (Zhou et al., 2017; Ye et al., 2016), 203
but since the chloroplast function is partially retained, there must be also nucleoside 204
triphosphate import into this organelle. Interestingly, NDPKs can also have moonlighting 205
activity as modulators of gene expression (Dorion and Rivoal, 2018). 206
Besides nucleotides, the nucleus and organelles need deoxynucleotides (dNTPs) for DNA 207
synthesis. Deoxynucleotide synthesis requires the reduction of the hydroxyl moiety on the 208
2’ carbon of the ribose by an enzyme complex called ribonucleotide reductase (RNR, Figure 209
4, #10). The RNR complex is comprised of two large regulatory (R1) and two small catalytic 210
(R2) subunits. Mutation of the major R2 subunit gene (tso2) results in lower dNTP 211
concentrations and abnormal plant development, while the additional mutation of a further 212
R2 subunit gene (Arabidopsis has three R2 subunit genes in total) is lethal (Wang and Liu, 213
2006). The substrates of RNR are the ribonucleotide diphosphates, suggesting that for CTP a 214
dedicated phosphatase might exist to support dCDP synthesis (Figure 4A). Alternatively, CDP 215
for dCTP synthesis might be generated from salvage of cytidine (see below). Interestingly, 216
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RNR is subject to a complex allosteric regulation to adjust the correct dNTP pool sizes 217
(Sauge-Merle et al., 1999). In plants, RNR resides exclusively in the cytosol with the potential 218
to relocate to the nucleus upon exposure to UV radiation (Lincker et al., 2004). Especially 219
the plastidic DNA replication seems to rely strongly on sufficient RNR activity, because 220
partially compromising the function of the large RNR subunit by different mutations in the 221
corresponding gene resulted in reduced dNTP levels and impaired chloroplast division in 222
Arabidopsis (Garton et al., 2007). Consistently, chlorophyll biosynthesis in rice is reduced in 223
mutants of the small RNR subunit genes (Chen et al., 2015). All dNDPs can be synthesized 224
directly by RNR, except thymidine diphosphate, because it has no ribonucleotide 225
counterpart. Instead, RNR catalyzes the formation of dUDP from UDP (Figure 4B) and dUMP 226
is methylated at C5 to TMP catalyzed by thymidilate synthase. In Arabidopsis, three 227
enzymes were recently characterized as thymidylate synthases, which are also dihydrofolate 228
reductases (DHFR-TS, Figure 4B, #15) with only two isoforms displaying thymidylate 229
synthase activity (Gorelova et al., 2017). Interestingly, in roots all isoforms can reside either 230
in the cytosol, the nucleus, or the mitochondria depending on the developmental state of 231
the cell, but not in plastids. The two active isoforms seem to be redundant, since only a 232
double mutant of the respective genes is lethal, whereas single gene loss-of-function 233
mutants are phenotypically inconspicuous (Gorelova et al., 2017). The substrate for DHAFR-234
TS is dUMP (Gorelova et al., 2017), but the RNR provides dUDP. It is unknown which enzyme 235
links these two processes in vivo. An alternative dUMP source in mitochondria is the 236
deamination of dCMP as shown recently in rice (Niu et al., 2017; Xu et al., 2014). 237
238
SALVAGE AND DEGRADATION 239
Metabolic sources of nucleosides and nucleobases 240
Nucleosides and nucleobases can be released from nucleotides or nucleic acids in 241
metabolism (Figures 2, 5 and 6) or can be taken up from the environment (Girke et al., 242
2014), where they can occur in substantial amounts (Phillips et al., 1997). 243
The main metabolic source for most nucleosides is probably the turnover of RNA, in 244
particular in the vacuole. Vacuolar RNA degradation, for example of ribosomal RNA after 245
ribophagy (Floyd et al., 2015), generates nucleotides which likely are degraded to 246
nucleosides by vacuolar phosphatases. The details of this process have not been 247
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9
investigated so far. The tonoplast membrane possesses a nucleoside exporter (equilabrative 248
nucleoside transporter 1, ENT1, At1g70330; Bernard et al., 2011) for the release of 249
nucleosides into the cytoplasm. For adenosine, the turnover of S-adenosyl methionine 250
(SAM), used for methylation reactions, is another important source (Figures 2 and 5). After 251
transfer of the methyl group from SAM, the resulting S-adenosyl homocysteine (SAH) is 252
hydrolyzed to homocysteine and adenosine (Sauter et al., 2013). 253
There are no strong sources for nucleobases in plant metabolism, except for adenine, which 254
is released during polyamine, nicotianamine, and ethylene biosynthesis (Sauter et al., 2013). 255
In all three pathways SAM is used and 5’-methylthioadenosine is generated, which is 256
hydrolyzed to 5-methylthioribose and adenine (Siu et al., 2008). Also the degradation of 257
cytokinins produces small amounts of adenine (Schmülling et al., 2003). Purine bases are 258
released from nucleic acids by spontaneous depurination (Barbado et al., 2018) resulting in 259
low amounts of adenine and guanine. The metabolic source of hypoxanthine is likely the 260
spontaneous deamination of adenine in DNA, resulting in a hypoxanthine base, which is 261
removed from the DNA by base excision repair (Karran and Lindahl, 1980). Similarly, the 262
non-enzymatic deamination of cytosine in DNA generates uracil, which is removed by base 263
excision repair (Figure 2). 264
Purine and Pyrimidine Salvage Metabolism 265
Nucleosides and nucleobases can be converted into nucleotides, which is called ‘salvage’ 266
(Figures 2, 5 and 6). In contrast to de novo biosynthesis of nucleotides, which generates 267
nucleotides from basic metabolites (see above), the salvage reactions recycle nucleobases 268
and nucleosides derived from metabolism or uptake (see previous section) to nucleotides. 269
Nucleobases react with activated phosphoribose (5-phosphoribosyl-1-pyrophosphate, PRPP) 270
to the respective nucleotides - a reaction catalyzed by phosphoribosyltransferases (PRTs). 271
Adenine phosphoribosyltransferase (APRT, Figure 5A, #19), hypoxanthine guanine 272
phosphoribosyltransferase (HGPRT, Figure 5A, #21) and uracil phosphoribosyltransferase 273
(UPRT, Figure 6, #39) are the three types of nucleobase-specific enzymes present in plants. 274
Nucleosides are phosphorylated to nucleoside monophosphates by kinases. Adenosine 275
kinase (ADK, Figure 5A, #20), inosine guanosine kinase (IGK, Figure 5A, #22), and uridine 276
cytidine kinase (UCK, Figure 6, #35) salvage ribonucleotides, whereas thymidine kinase (TK, 277
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Figure 4B, #14) and deoxynucleoside kinase (dNK, Figure 4, #11) phosphorylate thymidine 278
and the other three deoxynucleosides, respectively. 279
Several salvage enzymes have a critical function for plant metabolism and their mutation 280
has severe consequences. Mutation of the gene for the main APRT (Figure 5, #19) activity, 281
APT1 (At1g27450), results in male sterility (Gaillard et al., 1998b), whereas a strong 282
downregulation increases the resistance to oxidative stress (Sukrong et al., 2012). Deletion 283
or strong downregulation of the gene for the main ADK (Figure 5, #20) enzyme, ADK1 284
(At3g09820), compromises transmethylation reactions, because the accumulating 285
adenosine inhibits S-adenosylhomocystein (SAH) hydrolase – an enzyme of the SAM cycle. It 286
has been shown that ADK1 and SAH hydrolase interact and partially reside in the nucleus 287
probably mediated by nuclear methyltransferases (Lee et al., 2012). Reduced 288
transmethylation causes a range of developmental abnormalities (Young et al., 2006; 289
Moffatt et al., 2002). Guanine and hypoxanthine salvage seems to be less critical, because 290
HGPRT (Figure 5, #21) mutants are phenotypically normal except for a slight delay in 291
germination (Schroeder et al., 2018; Liu et al., 2007). Mutation of HGPRT leads to guanine 292
but not hypoxanthine accumulation in vivo, probably reflecting that guanine can only be 293
salvaged, whereas hypoxanthine can also be degraded (Baccolini and Witte, 2019). Kinase 294
activity for inosine and guanosine has been measured in plant extracts (Deng and Ashihara, 295
2010; Katahira and Ashihara, 2006) (IGK, Figure 5A, #22) but the corresponding gene is still 296
unknown. Some evidence has been provided that the activity is associated with the 297
intermembrane space of mitochondria (Combes et al., 1989). 298
The only uracil salvage activity in Arabidopsis is located in plastids and encoded by UPP 299
(UPRT, Figure 6, #39). Mutation of UPP leads to growth arrest in the seedling stage and an 300
albino phenotype (Mainguet et al., 2009). Interestingly, it was recently shown that this 301
phenotype is unrelated to the lack of UPRT activity in the mutant, but is caused by the 302
absence of the UPP protein per se, demonstrating that uracil salvage does not play such an 303
essential role for Arabidopsis as previously thought (Ohler et al., 2019). Salvage of uridine is 304
more prominent than salvage of uracil in Arabidopsis. Uridine and cytidine salvage are 305
performed by dual-specific uridine and cytidine kinases (UCK) (Ohler et al., 2019). These 306
enzymes also possess a UPRT-like domain, but do not have UPRT activity (Chen and Thelen, 307
2011). Simultaneous mutation of UCK1 and UCK2 results in dwarf plants that fail to reach 308
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11
maturity (Chen and Thelen, 2011). Previously, UCK1 and UCK2 were found to localize in 309
plastids (Chen and Thelen, 2011), but Ohler et al. (2019) demonstrated that these enzymes 310
reside in the cytosol, which was also confirmed in our laboratory (M. Chen and C.-P. Witte, 311
unpublished data). 312
Interestingly, deoxynucleoside-specific salvage enzymes also exist (Figure 4) and the 313
abrogation of thymidine salvage by thymidine kinase (TK, Figure 4B, #14) is lethal for plants 314
(Clausen et al., 2012). However, it is unclear, why thymidine salvage is of such importance. 315
Thymidine kinase occurs in the cytosol, the mitochondria, and the plastids (Xu et al., 2015) 316
and is of particular importance for chloroplast maintenance when germinating seedlings 317
turn autotrophic (Pedroza-García et al., 2019). The other deoxynucleosides are salvaged by 318
an enzyme with broad deoxynucleoside specificity (Clausen et al., 2012) (dNK, Figure 4, 319
#11), potentially associated with mitochondria (Clausen et al., 2014). 320
Purine Nucleotide Degradation 321
Instead of being salvaged, nucleobases and nucleosides can also be fully degraded by plants, 322
but for guanine, adenine, and adenosine a salvage reaction needs to precede degradation. 323
Adenine and adenosine first must be converted to AMP, which can then be deaminated by 324
AMP deaminase (AMPD, Figure 5A, #2) to IMP as a first step into degradation. This is 325
necessary because Arabidopsis and plants in general lack adenosine deaminase (Chen et al., 326
2018b; Dancer et al., 1997). Interestingly, for N6-methyl AMP, plants as well as many other 327
eukaryotes possess a special deaminase, called N6-methyl-AMP deaminase (MAPDA) (Chen 328
et al., 2018b). N6-methylated adenine is the most frequent modification in mRNA, but is 329
also present in other RNA species (Chen and Witte, 2019). MAPDA is phylogenetically 330
related to adenosine deaminases and hydrolyzes N6-methyl AMP to IMP removing the 331
aminomethyl group. This example shows that modified nucleotides must also have an 332
access route to general nucleotide degradation. 333
From IMP, the purine nucleotide degradation pathway cannot be entered directly in 334
Arabidopsis, but conversion to XMP and apparently even to GMP is required (Baccolini and 335
Witte, 2019). These recent results show that the route for AMP catabolism and the route for 336
GMP biosynthesis (partially) overlap. Therefore, branch points of both routes must be 337
controlled, but it is not yet clear how this is achieved. GMP dephoshorylation by a so far 338
unknown phosphatase (GMPP, Figure 5A, #23) initiates purine nucleotide catabolism. At the 339
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12
stage of guanosine, salvage back to the nucleotide level via IGK (Figure 5A, #22) is still 340
possible, but the GMPP and IGK reactions might be spatially or temporarily separated to 341
avoid a futile cycle. The deamination of guanosine to xanthosine by guanosine deaminase 342
(GSDA, Figure 5A, #24; Dahncke and Witte, 2013) marks the point of no return, because 343
xanthosine cannot be salvaged and is dedicated for degradation (Yin et al., 2014). Although 344
xanthosine appears to be generated mainly by GSDA, there is strong evidence for an 345
alternative route directly from XMP to xanthosine catalyzed by an XMP phosphatase (XMPP, 346
Figure 5A, #25) (Baccolini and Witte, 2019). An XMP-specific phosphatase, which may 347
represent this XMPP, is currently under investigation in our laboratory. In summary, GMP 348
catabolism begins with dephosphorylation and deamination of guanosine, and most AMP is 349
apparently also degraded via GMP, while some might be dephosphorylated already at the 350
stage of XMP. 351
In clear contrast to purine metabolism in many other organisms, guanine is not an 352
intermediate of purine nucleotide catabolism in Arabidopsis and probably most plants. For 353
degradation, guanine must first be salvaged to GMP (Dahncke and Witte, 2013; Baccolini 354
and Witte, 2019). As well in contrast to purine metabolism in many other organisms, inosine 355
and hypoxanthine are not major intermediates of purine nucleotide catabolism in 356
Arabidopsis, because they are not derived from IMP dephosphorylation (Baccolini and 357
Witte, 2019), but possibly from t-RNA turnover and base excision repair of deaminated 358
adenine in DNA (Figure 5A). Because guanine and hypoxanthine do not play an important 359
role in purine nucleotide degradation, HGPRT (Figure 5A, #21) is decoupled from purine 360
catabolism in plants (Baccolini and Witte, 2019), which is in stark contrast to humans, where 361
mutation of HGPRT results in accumulation of purine nucleotide breakdown products and 362
severe phenotypic consequences (Lesch-Nyhan Syndrome) (Torres and Puig, 2007). 363
Purine catabolism can lead to the complete disintegration of the purine ring in plants 364
(Werner and Witte, 2011) (Figure 5B) to recycle nitrogen (Soltabayeva et al., 2018), but is 365
also used to generate the intermediates uric acid and especially allantoin, which counteract 366
stress by reducing reactive oxygen species (Brychkova et al., 2008; Irani and Todd, 2016; 367
Irani and Todd, 2018; Nourimand and Todd, 2019; Lescano et al., 2016; Watanabe et al., 368
2014; Casartelli et al., 2019; Ma et al., 2016). Sometimes also the accumulation of allantoate 369
has been observed (Alamillo et al., 2010). In tropical legumes like soybean (Glycine max) or 370
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13
common bean (Phaseolus vulgaris), the ureides allantoin and allantoate are used as long 371
distance nitrogen transport compounds for the export of fixed nitrogen from the nodules 372
(Carter and Tegeder, 2016; Tegeder, 2014) mediated by the ureide permease (UPS) 373
transporters (Collier and Tegeder, 2012; Desimone et al., 2002; Schmidt et al., 2006). 374
Ureides also function in long distance transport in non-nodulated legumes (Diaz-Leal et al., 375
2012; Quiles et al., 2019) and are probably used in many plants for this purpose (Redillas et 376
al., 2019; Lescano et al., 2016). 377
It has recently been shown that xanthosine hydrolysis to xanthine and ribose is catalyzed by 378
a cytosolic nucleoside hydrolase heteromer consisting of nucleoside hydrolase 1 (NSH1, 379
Figure 5A, #26) and nucleoside hydrolase 2 (NSH2, Figure 5A, #27) in vivo (Baccolini and 380
Witte, 2019). NSH1 has only weak xanthosine and inosine but strong uridine hydrolase 381
activity (Jung et al., 2009; Jung et al., 2011; Baccolini and Witte, 2019; Riegler et al., 2011). 382
However, NSH1 is required to activate NSH2, which is the stronger xanthosine and inosine 383
hydrolase in the complex. Nucleoside catabolism is the major metabolic source of ribose, 384
which is recycled to ribose-5-phosphate by ribokinase in the plastids (Riggs et al., 2016; 385
Schroeder et al., 2018). Xanthine and hypoxanthine are catabolized by the same enzyme, 386
xanthine dehydrogenase (XDH, Figure 5A, #28; Urarte et al., 2015) finally to uric acid in the 387
cytosol. Arabidopsis has a second gene encoding XDH (At4g34900) with no apparent 388
xanthine dehydrogenase activity in vivo (Hauck et al., 2014). Interestingly, XDH has been 389
shown to play a dual role during powdery mildew pathogen attack on Arabidopsis (Ma et al., 390
2016). In the epidermis the enzyme is postulated to operate as an NADH oxidase generating 391
superoxide (Zarepour et al., 2010) to prevent fungal entry, whereas in the mesophyll it 392
works as a xanthine dehydrogenase producing urate, which is suggested to function as a 393
reactive oxygen species scavenger. It was proposed that by this mechanism the reactive 394
oxygen species are confined to the infection site. For further degradation, uric acid must be 395
imported into the peroxisomes, but molecular details about this import are still unknown. In 396
the peroxisome, urate is oxidized by urate oxidase (UOX, Figure 5B, #29) as well as 397
hydrolyzed and decarboxylated by allantoin synthase (ALNS, Figure 5B, #30) to (S)-allantoin 398
(Lamberto et al., 2010; Pessoa et al., 2010). Mutation of UOX leads to strong accumulation 399
of uric acid, which is deleterious for peroxisome maintenance in the embryo, leading to a 400
severe suppression of germination and seedling establishment (Hauck et al., 2014) – 401
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14
surprisingly, accumulation of similar amounts of xanthine in Arabidopsis plants lacking XDH 402
does not lead to strong phenotypic alterations under standard growth conditions (Hauck et 403
al., 2014; Schroeder et al., 2018; Soltabayeva et al., 2018). Allantoin must be transported 404
from the peroxisomes to the ER for further degradation, but it is unclear how this is 405
achieved. One may speculate that allantoin accumulation under certain stress conditions 406
may be in part caused by altered peroxisome to ER transport efficiency. However, one 407
apparent reason for allantoin accumulation is an altered catalytic capacity for allantoin 408
generation and degradation under stress (Irani and Todd, 2016; Irani and Todd, 2018; 409
Lescano et al., 2016; Casartelli et al., 2019). 410
In the ER, allantoin is hydrolyzed by four enzymes (Figure 5B, #31 to #34) completely 411
releasing the ring nitrogen as ammonia (Werner et al., 2008; Werner et al., 2010; Serventi et 412
al., 2010; Todd and Polacco, 2006). These enzymes are also responsible for supplying the 413
shoot of tropical legumes with nitrogen exported from the nodules as allantoin and 414
allantoate (Werner et al., 2013; Díaz-Leal et al., 2014). 415
Pyrimidine Nucleotide Degradation 416
Pyrimidine nucleotide catabolism is initiated by UMP / CMP phosphatase(s) (UCPP, Figure 6, 417
#36) which have not yet been identified. Their activity might be temporarily and / or 418
spatially separated from uridine cytidine kinases (UCKs, Figure 6, #35; Ohler et al., 2019) to 419
avoid a futile cycle of pyrimidine nucleotide dephosphorylation and pyrimidine nucleoside 420
salvage. Cytidine is deaminated to uridine by a cytosolic cytidine deaminase (CDA, Figure 6, 421
#37). Interestingly, plants can neither degrade nor salvage the free base cytosine (Katahira 422
and Ashihara, 2002). Arabidopsis contains several copies of cytidine deaminase, but only 423
one copy is functional. The mutation of CDA results in smaller plants probably because 424
cytidine accumulation is toxic (Chen et al., 2016). Generally, the accumulation of nucleosides 425
can reduce plant performance as has been shown for GSDA (Figure 5A, #24) mutants 426
(Schroeder et al., 2018). Consistently, transgenic lines with increased vacuolar nucleoside 427
export (Bernard et al., 2011) are smaller than the wild type. 428
Uridine is hydrolyzed by the cytosolic nucleoside hydrolase 1 (NSH1, Figure 6, #26) to uracil 429
and ribose (Jung et al., 2009). NSH2 is not involved in uridine hydrolysis. NSH1 occurs in two 430
forms in vivo, either as a homomer (probably a homodimer: Kopecná et al., 2013) for uridine 431
hydrolysis, and as a heteromer interacting with NSH2 for xanthosine and inosine hydrolysis 432
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15
(Baccolini and Witte, 2019). One should note that these nucleoside hydrolases usually do 433
not hydrolyze cytidine (Jung et al., 2009) or guanosine in vivo unless these compounds 434
accumulate in catabolic mutants (Chen et al., 2016; Dahncke and Witte, 2013; Baccolini and 435
Witte, 2019). Adenosine is a substrate of NSH1 and also of 5′-methylthioadenosine 436
nucleosidase 2 (MTAN2; Siu et al., 2008) in vitro, but both enzymes hydrolyze adenosine 437
with very low catalytic efficiency. The main adenosine hydrolytic activity of Arabidopsis 438
resides probably in the apoplast (see below). 439
The plastidic nucleobase transporter (PLUTO, Figure 6, #38) reallocates uracil probably in 440
symport with protons from the cytosol into the plastids for further metabolic conversion 441
(Witz et al., 2012). PLUTO belongs to the Nucleobase:Cation Symporter 1 (NCS1) family and 442
transports guanine and adenine as well, albeit with lower efficiency than uracil. There are 443
indications that a thiamine precursor, hydroxymethylpyrimidine, is also a PLUTO substrate 444
(Beaudoin et al., 2018). Interestingly, it was recently reported that PLUTO orthologs from 445
two grasses do not transport uracil, but only adenine and guanine next to a few other 446
substrates (Rapp et al., 2016), indicating that uracil metabolism might be organized 447
differently in these species. However, one should note that definite evidence for a function 448
of PLUTO in uracil transport into plastids in vivo has not yet been presented in any plant. 449
Other transporters capable of uracil transport have been identified, but these are located in 450
the plasma membrane (Niopek-Witz et al., 2014; Schmidt et al., 2004). 451
In the plastid, there is a branch point: uracil can either be salvaged by UPRT (Figure 6, #39, 452
see above) or be degraded. When uracil is applied from outside, strong catabolic activity is 453
usually observed (Ashihara et al., 2001; Katahira and Ashihara, 2002). The first reaction, in 454
which the uracil ring is reduced to dihydrouracil by dihydropyrimidine dehydrogenase (DPYD 455
/ PYD1, Figure 5, #40) residing in plastids, was shown to be rate limiting (Tintemann et al., 456
1985). Compared to mammalian DPYD, the plant enzyme lacks C-terminal domains for 457
cofactor binding, which are involved in electron delivery to the active site. Therefore the 458
plant enzyme is probably incomplete and might require a so far unknown interaction 459
partner for activity. The loss of activity, when the enzyme is expressed in the cytosol instead 460
of the plastid, is in agreement with this hypothesis (Cornelius et al., 2011). Mutants of DPYD 461
/ PYD1 show delayed germination and a misregulation of ABA responsive genes, whereas 462
constitutive overexpression results in an increase in growth and seed number (Cornelius et 463
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16
al., 2011). In the next enzymatic steps, the dihydrouracil ring is opened by 464
dihydropyrimidine hydrolase (DPYH / PYD2, Figure 6, #41) and then the carbamino group is 465
hydrolytically released by -ureidopropionase (-UP / PYD3, Figure 6, #42; Walsh et al., 466
2001) generating -alanine. Not only uracil but also 5-methyluracil (thymine) is degraded in 467
this pathway (Cornelius et al., 2011) resulting in -aminoisobutyrate instead of -alanine. 468
The first reaction (DPYD, Figure 6, #40) is located in the plastids, the second (DPYH, Figure 6, 469
#41) in the ER, and the third (-UP, Figure 6, #42) in the cytosol, but it is unclear why such a 470
distribution is favorable, and how the metabolites are shuttled to these different locations 471
(Zrenner et al., 2009). Recently, the combination of genome-wide association data with 472
correlation networks built from metabolite and transcriptome data identified an 473
aminotransferase correlated with -alanine. The corresponding mutants accumulated -474
alanine, indicating that this might be the missing -alanine aminotransferase (BAAT / PYD4, 475
Figure 6, #43) of pyrimidine catabolism in plants (Wu et al., 2016). 476
Pyrimidine catabolism is induced by nitrogen starvation and in senescence (Cornelius et al., 477
2011; Zrenner et al., 2009) suggesting that similar to purine nitrogen also pyrimidine 478
nitrogen is recycled by plants. When uracil is given as the sole nitrogen source, its 479
degradation can support the growth of Arabidopsis to a limited extent (Zrenner et al., 2009). 480
EXTRACELLUAR ATP 481
Extracellular ATP (eATP) is a signal molecule, which is either actively released upon a 482
stimulus by plant cells via exocytosis or transport, or which is derived from damaged cells 483
(Cao et al., 2014) (Figure 7). A plasma-membrane based nucleotide transporter belonging to 484
the mitochondrial carrier family (pmANT1, Figure 7, #44) is involved in ATP export with 485
physiological relevance at least in pollen (Rieder and Neuhaus, 2011). eATP plays a role in 486
stress responses and is perceived by the receptor-like kinase ‘does not respond to 487
nucleotides 1’ (DORN1, Figure 7, #50), which recognizes ATP, GTP, and ADP but not AMP 488
and adenosine (Choi et al., 2014). Interestingly, CTP and NAD are also sensed by plant cells 489
and a potential receptor for NAD has been identified recently (Wang et al., 2017). 490
The ATP signal might be quenched by an apoplastic apyrase (Riewe et al., 2008a), an enzyme 491
which hydrolyzes NTPs or NDPs to NMPs. Seven apyrases are encoded by the Arabidopsis 492
genome (APY1 to APY7) and APY1 and APY2 were believed to represent these extracellular 493
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17
enzymes (Lim et al., 2014). However, by scanning the substrate spectra of the apyrases, only 494
APY3 (Figure 7, #45) showed strong activity with ATP (and other NTPs) but also APY5 and 495
APY6 were slightly active with NTPs (Chiu et al., 2015). These apyrases are therefore 496
possible candidates for the apolastic enzymes in Arabidopsis. However, other secreted 497
phosphatases might also be involved, for example members of the unspecific purple acid 498
phosphatases (Del Vecchio et al., 2014; Wang et al., 2011). 499
The AMP resulting from ATP dephosphorylation is hydrolyzed in the apoplast to adenosine 500
by a 5’ nucleotidase (Figure 7, #46). An AMP-specific extracellular 5’ nucleotidase associated 501
to the plasma membrane was purified from peanut (Arachis hypogaea) (Sharma et al., 1986; 502
Gupta and Sharma, 1996), but the corresponding gene has not been identified. Adenosine 503
can be either taken up via the adenosine proton symporter ‘equilibrative nucleoside 504
transporter 3’ (ENT3, Figure 7, #47) (Cornelius et al., 2012; Traub et al., 2007) or further 505
hydrolyzed by the apoplastic purine-specific nucleoside hydrolase 3 (NSH3, Figure 7, #48) 506
(Jung et al., 2011) to adenine and ribose. NSH3 hydrolyzes inosine more efficiently than 507
adenosine, whereas a cell wall bound nucleoside hydrolase of potato, probably the ortholog 508
of NSH3 in this plant, was highly specific for adenosine and did not hydrolyze inosine (Riewe 509
et al., 2008b). 510
Simultaneous genetic blockage of nucleoside uptake and hydrolysis leads to an 511
accumulation of adenosine and uridine in the apoplast, a reduction of photosystem II 512
efficiency, and a higher susceptibility to the necrotrophic fungus Botrytis cinerea possibly 513
caused by reduced expression of WRKY33 (Daumann et al., 2015), known to be essential for 514
Botrytis resistance (Liu et al., 2015). Treatment with eATP increases the resistance to 515
Botrytis (Tripathi et al., 2017) and the expression of WRKY33 and other defense related 516
genes is reduced in a dorn1 mutant and boosted in a DORN1 overexpression line upon 517
challenge with eATP (Jewell et al., 2019). Taken together it appears that adenosine 518
accumulation in the apoplast dampens the DORN1 mediated response, indicating that ENT3 519
and NSH3 are required to remove the breakdown products of eATP signaling. Also the 520
adenine resulting from adenosine hydrolysis by NSH3 is taken up by plant cells. It is not 521
entirely clear which transporters mediate this uptake. Possible candidates are azaguanine 522
resistant 1 and 2 (AZG1 and 2; Figure 7, #49), which have been shown to facilitate adenine 523
and guanine uptake into Arabidopsis seedlings (Mansfield et al., 2009), or members of the 524
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18
nucleobase-ascorbate transporter (NAT) family (Niopek-Witz et al., 2014) as well as of the 525
purine permease (PUP) family (Girke et al., 2014). Interestingly, fungi seem to be able to 526
influence the purinergic signaling in the apoplast by interfering with apoplastic nucleotide 527
metabolism via the excretion of nucleotidases to improve colonization (Nizam et al., 2019). 528
CONNECTIONS TO CYTOKININ HOMEOSTASIS 529
The biosynthesis of the cytokinins involves the generation of N6-modified AMP, carrying an 530
isoprenoid group (Sakakibara, 2005). However, cytokinin ribotides or ribosides are inactive – 531
the free modified base is the active hormone binding to the receptors (Romanov et al., 532
2018; Yamada et al., 2001). The question arises whether the enzymes that are employed for 533
cytokinin homeostasis (activation from ribotides and inactivation to ribosides / ribotides) 534
are the same as for the metabolism of adenine nucleotides. 535
It was shown that a cytokinin ribotide-specific enzyme (cytokinin riboside 5′-536
monophosphate phosphoribohydrolase, called lonely guy (LOG)) can release the active 537
cytokinin from the ribotide (Kurakawa et al., 2007; Kuroha et al., 2009). A recent report 538
demonstrated that the mutation of the seven genes coding for functional LOGs in 539
Arabidopsis resulted in a phenotype that cannot be attenuated by exogenous cytokinin 540
ribotides, suggesting that the hydrolysis by LOGs is the main pathway of cytokinin activation 541
(Osugi et al., 2017). Therefore, the cytosolic nucleoside hydrolases do not seem to be 542
involved in cytokinin activation, although it could be shown that cytokinin ribosides are 543
substrates in vitro, catalyzed with comparatively low efficiency (Kopecná et al., 2013; Jung 544
et al., 2009). Consistently, cytokinin-related phenotypes were not observed in nucleoside 545
hydrolase mutants (Riegler et al., 2011). However, long-distance transport of cytokinins may 546
involve an activation of cytokinin ribosides / ribotides in the apoplast prior to uptake or 547
perception (Romanov et al., 2018). In Arabidopsis, a third nucleoside hydrolase (NSH3) that 548
is located in the apoplast (see section on extracellular ATP) has been shown to hydrolyze 549
adenosine, but cytokinin ribosides have not been assessed (Jung et al., 2011). Interestingly, 550
an apoplastic nucleoside phosphorylase was isolated from potato that converted cytokinin 551
ribosides to cytokinins and ribose-1-phosphate in the presence of phosphate, and can also 552
work in the synthesis direction of ribosides (Bromley et al., 2014). The enzyme preferred 553
cytokinins / cytokinin ribosides over adenine / adenosine as substrates and is supposedly 554
involved in cytokinin-mediated tuber endodormancy. Close homologs in Arabidopsis (e.g. 555
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19
At4g28940) are predicted to be located in the apoplast (SUBA web server, Hooper et al., 556
2017), but have not yet been characterized. 557
The inactivation of cytokinins is inter alia achieved by transferring a phosphoribosyl moiety 558
on the active cytokinin resulting in an inactive cytokinin-ribotide. This reaction is at least 559
partially performed by an adenine phosphoribosyltransferase (APRT, Figure 5A, #19) 560
because (i) APT1 mutants convert cytokinins less efficiently to the respective ribotides 561
(Moffatt et al., 1991), (ii) APT1 loss-of-function plants contain more active cytokinins (Zhang 562
et al., 2013), and (iii) APT1 mutants have cytokinin-related phenotypes (Gaillard et al., 563
1998a). APT1 is also clearly involved in the salvage of adenine, which is less efficiently 564
converted to AMP in an APT1 mutant (Moffatt et al., 1991) and is slightly more abundant in 565
a mutant plant with reduced APT1 activity (Sukrong et al., 2012). In conclusion, APT1 566
participates in adenine and cytokinin metabolism and the question arises how one enzyme 567
can serve both distinct metabolic roles adequately. There is also some evidence that 568
adenosine kinase (ADK, Figure 5A, #20) contributes to cytokinin homeostasis, because plants 569
with reduced ADK activity show cytokinin-related phenotypes and contain more cytokinin 570
ribosides (Schoor et al., 2011). However, ADK is also involved in the maintenance of 571
transmethylation activity, therefore an indirect impact of reduced ADK activity on cytokinin 572
homeostasis cannot be fully excluded. 573
Conclusions 574
The synthesis, interconversion, and degradation of nucleotides is intrinsically linked with the 575
propagation and reading of genetic information, with energy metabolism including the 576
metabolic activation of many biomolecules, but also with methylation reactions, signal 577
transduction, the recycling of nitrogen, and the modification of oxidative stress. We are 578
getting closer to completing a full inventory of enzymes involved in plant nucleotide 579
metabolism, but we are far from understanding how these enzymes operate together to 580
achieve nucleotide homeostasis. There is only fragmentary information about regulation on 581
all levels, transport processes are incompletely defined, and the organization of nucleotide 582
metabolism on tissue and organ level is not well understood (see outstanding questions). 583
These issues need to be addressed to allow a better integration of nucleotide metabolism 584
into a molecular model of plant physiology. 585
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20
586
Acknowledgements 587
The authors thank Henryk Straube for critical reading of the manuscript. 588
589
590
Figure Legends 591
Figure 1. Structural composition of nucleobases, nucleosides, and nucleotides. 592
For the nucleobases ‘R’ is simply a proton. For the nucleosides ‘R’ is a sugar moiety which 593
can be ribose or deoxyribose (carrying a proton instead of a hydroxyl group at the 2’ carbon 594
of the ribose). Nucleotides have up to three phosphate groups esterified to the hydroxyl 595
group of the 5’ carbon of the nucleoside sugar determining the prefix mono-, di-, and 596
triphosphate in the name of the molecule. The terminal phosphate always carries two 597
charges irrespective of the number of phosphates present. The pyrimidine nucleobases 598
(upper row) and the purine nucleobases (lower row) are shown with the groups attached to 599
the heterocycles highlighted in red (oxo groups), blue (amino groups), and grey shading 600
(methyl group). 601
602
Figure 2. Schematic overview of plant nucleotide metabolism. 603
Nucleotides are synthesized ‘de novo’ from precursor molecules listed in the upper left box 604
(PRPP, 5-phosphoribosyl-1-pyrophosphate). The phosphorylation of nucleoside 605
monophosphates via nucleoside diphosphates (NDPs) generates nucleoside triphosphates 606
(NTPs), which serve as building blocks for RNA synthesis and as precursors for the 607
biosynthesis of the metabolites shown in the center (S-adenosyl methionine (SAM), UDP-608
glucose (UDP-Glc), and NADH are given as examples). However, the nucleoside 609
triphosphates, in particular ATP and GTP, are not only precursors for other metabolites, but 610
are also essential stores of chemical energy in the phosphoanhydride bonds used in a 611
multitude of energetic coupling reactions, as well as important donors of phosphate in 612
kinase reactions (not shown). NDPs can be reduced to dNDPs (deoxynucleoside 613
diphosphates), which after phosphorylation to dNTPs serve as precursors for DNA 614
biosynthesis. RNA degradation in the cytosol releases nucleoside monophosphates, whereas 615
nucleosides are produced during vacuolar RNA degradation. Adenosine and adenine are 616
products of biochemical reactions involving S-adenosyl methionine (SAM). Non-enzymatic 617
decay (depurination) and enzymatic repair reactions result in nucleoside and nucleobase 618
release from DNA. Nucleobases and nucleosides can be recycled to nucleotides in so called 619
‘salvage’ reactions. Plants are also capable of full nucleotide degradation via certain 620
nucleosides and nucleobases releasing the nitrogen of the nucleobases as ammonia. 621
Figure 3. Purine and pyrimidine de novo biosynthesis. 622
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21
(A) Purine de novo biosynthesis. (B) Pyrimidine de novo biosynthesis. Enzymes and 623
transporters: BT1 (1), brittle1; AMPD (2), AMP deaminase; IMPDH (3), IMP dehydrogenase; 624
GMPS (4), GMP synthetase; ATCase (5), asparate transcarbamoylase; DHOase (6), 625
dihydroorotatase; DHODH (7), dihydroorotate dehydrogenase; UMPS (8), UMP synthase; 626
CTPS (9), CTP synthetase. An anchor symbol denotes an association with the respective 627
membrane. 628
629
Figure 4. Synthesis of nucleoside and deoxynucleoside triphosphates. 630
Synthesis of (A) cytidylates, (B) uridylates and thymidylates, (C) guanylates, and (D) 631
adenylates. RNR (10), ribonucleotide reductase; dNK (11), deoxynucleoside kinase; UMK 632
(12), UMP kinase; NDPK (13), nucleoside diphosphate kinase; TK (14), thymidine kinase; 633
DHFR-TS (15), dihydrofolate reductase-thymidylate synthase; TMK (16), thymidylate kinase; 634
GMK (17), guanylate kinase; AMK (18), adenylate kinase. The subcellular locations where 635
enzymes with these activities are found are indicated. For TMK, a location in the plastids is 636
only assumed. The mononucleotides (AMP, GMP, UMP, and CMP) may also be derived from 637
salvage reactions (see Figures 5 and 6). 638
639
Figure 5. Salvage and degradation of purines. 640
(A) The reactions of purine nucleobase and nucleoside salvage as well as purine nucleotide 641
degradation, which overlaps partially with GMP synthesis. The salvage pathways are 642
highlighted by light grey shading, degradation reactions are encircled in dark gray. 643
Metabolites that can only undergo degradation and cannot be salvaged are shown with 644
brown shading. (B) Purine ring catabolism. The transport steps for urate and (S)-allantoin 645
are not shown explicitly. APRT (19), adenine phosphoribosyltransferase; ADK (20), 646
adenosine kinase; AMPD (2), AMP deaminase; IMPDH (3), IMP dehydrogenase; GMPS (4), 647
GMP synthetase; HGPRT (21), hypoxanthine guanine phosphoribosyltransferase; IGK (22), 648
inosine guanosine kinase; GMPP (23), GMP phosphatase; GSDA (24), guanosine deaminase; 649
XMPP (25), XMP phosphatase; NSH1 (26), nucleoside hydrolase 1; NSH2 (27), nucleoside 650
hydrolase 2; XDH (28), xanthine dehydrogenase; UOX (29), urate oxidase; ALNS (30), 651
allantoin synthase; ALN (31), allantoinase; AAH (32), allantoate amidohydrolase; UGAH (33), 652
ureidoglycine aminohydrolase; UAH (34), ureidoglycolate amidohydrolase. 653
654
Figure 6. Salvage and degradation of pyrimidines. 655
NC--alanine, N-carbamyl--alanine; malonate-SA, malonate semialdehyde. UCK (35), 656
uridine cytidine kinase; UCPP (36), UMP CMP phosphatase; CDA (37), cytidine deaminase; 657
NSH1 (26), nucleoside hydrolase 1; PLUTO (38), plastidic nucleobase transporter; UPRT (39), 658
uracil phosphoribosyltransferase; DPYD (40), dihydropyrimidine dehydrogenase; DPYH (41), 659
dihydropyrimidine hydrolase; β-UP (42), -ureidopropionase; BAAT (43) -alanine 660
aminotransferase. 661
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662
Figure 7. Excretion, perception, and degradation of extracellular ATP 663
pmANT1 (44), plasma membrane adenine nucleotide transporter; APY3 (45), apyrase 3; 5‘ 664
NT (46), 5’ nucleotidase; ENT3 (47), equilibrative nucleoside transporter 3; NSH3 (48), 665
nucleoside hydrolase 3, AZG1/2 (49), azaguanine resistant 1 / azaguanine resistant 2, 666
DORN1 (50), does not respond to nucleotides 1 . 667
668
Literature cited 669
Alamillo JM, Diaz-Leal JL, Sanchez-Moran MV, Pineda M (2010) Molecular analysis of 670
ureide accumulation under drought stress in Phaseolus vulgaris L. Plant Cell Environ 33: 671
1828–1837. 672
Ashihara H, Loukanina N, Stasolla C, Thorpe TA (2001) Pyrimidine metabolism during 673
somatic embryo development in white spruce (Picea glauca). J Plant Physiol 158: 613–674
621. 675
Ashihara H, Stasolla C, Fujimura T, Crozier A (2018) Purine salvage in plants. 676
Phytochemistry 147: 89–124. 677
Atkins CA, Shelp BJ, Storer PJ (1985) Purification and properties of inosine monophosphate 678
oxidoreductase from nitrogen-fixing nodules of cowpea (Vigna-Unguiculata-L WALP). 679
Arch Biochem Biophys 236: 807–814. 680
Atkins CA, Smith, P. M. C., Storer PJ (1997) Reexamination of the intracellular localization of 681
de novo purine synthesis in cowpea nodules. Plant Physiol 113: 127–135. 682
Baccolini C, Witte C-P (2019) AMP and GMP catabolism in Arabidopsis converge on 683
xanthosine, which is degraded by a nucleoside hydrolase heterocomplex. Plant Cell 31: 684
734–751. 685
Bahaji A, Muñoz FJ, Ovecka M, Baroja-Fernández E, Montero M, Li J, Hidalgo M, Almagro 686
G, Sesma MT, Ezquer I, Pozueta-Romero J (2011a) Specific delivery of AtBT1 to 687
mitochondria complements the aberrant growth and sterility phenotype of homozygous 688
Atbt1 Arabidopsis mutants. Plant J 68: 1115–1121. 689
Bahaji A, Ovecka M, Bárány I, Risueño MC, Muñoz FJ, Baroja-Fernández E, Montero M, Li J, 690
Hidalgo M, Sesma MT, Ezquer I, Testillano PS, Pozueta-Romero J (2011b) Dual targeting 691
to mitochondria and plastids of AtBT1 and ZmBT1, two members of the mitochondrial 692
carrier family. Plant Cell Physiol 52: 597–609. 693
Barbado C, Cordoba-Canero D, Arizaa RR, Roldan-Arjona T (2018) Nonenzymatic release of 694
N7-methylguanine channels repair of abasic sites into an AP endonuclease-independent 695
pathway in Arabidopsis. Proc Natl Acad Sci USA 115: E916-E924. 696
www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
23
Beaudoin GAW, Johnson TS, Hanson AD (2018) The PLUTO plastidial nucleobase 697
transporter also transports the thiamin precursor hydroxymethylpyrimidine. Biosci Rep 698
38. 699
Bernard C, Traub M, Kunz HH, Hach S, Trentmann O, Mohlmann T (2011) Equilibrative 700
nucleoside transporter 1 (ENT1) is critical for pollen germination and vegetative growth 701
in Arabidopsis. J Exp Bot 62: 4627–4637. 702
Bromley JR, Warnes BJ, Newell CA, Thomson JCP, James CM, Turnbull CGN, Hanke DE 703
(2014) A purine nucleoside phosphorylase in Solanum tuberosum L. (potato) with 704
specificity for cytokinins contributes to the duration of tuber endodormancy. Biochem J 705
458: 225–237. 706
Brychkova G, Alikulov Z, Fiuhr R, Sagi M (2008) A critical role for ureides in dark and 707
senescence-induced purine remobilization is unmasked in the Atxdh1 Arabidopsis 708
mutant. Plant J 54: 496–509. 709
Cao Y, Tanaka K, Nguyen CT, Stacey G (2014) Extracellular ATP is a central signaling 710
molecule in plant stress responses. Curr Opin Plant Biol 20: 82–87. 711
Carrari F, Coll-Garcia D, Schauer N, Lytovchenko A, Palacios-Rojas N, Balbo I, Rosso M, 712
Fernie AR (2005) Deficiency of a plastidial adenylate kinase in Arabidopsis results in 713
elevated photosynthetic amino acid biosynthesis and enhanced growth. Plant Physiol 714
137: 70–82. 715
Carter AM, Tegeder M (2016) Increasing nitrogen fixation and seed development in soybean 716
requires complex adjustments of nodule nitrogen metabolism and partitioning processes. 717
Current Biol 26: 2044–2051. 718
Casartelli A, Melino VJ, Baumann U, Riboni M, Suchecki R, Jayasinghe NS, Mendis H, 719
Watanabe M, Erban A, Zuther E, Hoefgen R, Roessner U, Okamoto M, Heuer S (2019) 720
Opposite fates of the purine metabolite allantoin under water and nitrogen limitations in 721
bread wheat. Plant Mol Biol 99: 477–497. 722
Chen F, Dong G, Ma X, Wang F, Zhang Y, Xiong E, Wu J, Wang H, Qian Q, Wu L, Yu Y (2018a) 723
UMP kinase activity is involved in proper chloroplast development in rice. Photosynth Res 724
137: 53–67. 725
Chen M, Herde M, Witte C-P (2016) Of the nine cytidine deaminase-like genes in 726
Arabidopsis, eight are pseudogenes and only one is required to maintain pyrimidine 727
homeostasis in vivo. Plant Physiol 171: 799–809. 728
Chen M, Urs MJ, Sánchez-González I, Olayioye MA, Herde M, Witte C-P (2018b) m6A RNA 729
degradation products are catabolized by an evolutionarily conserved N6-Methyl-AMP 730
deaminase in plant and mammalian cells. Plant Cell 30: 1511–1522. 731
Chen M, Witte C-P (2019) Functions and Dynamics of Methylation in Eukaryotic mRNA. In S 732
Jurga, J Barciszewski, eds, The DNA, RNA, and Histone Methylomes. Springer 733
International Publishing, Cham, pp. 333–351.Chen MJ, Thelen JJ (2011) Plastid uridine 734
www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
24
salvage activity is required for photoassimilate allocation and partitioning in Arabidopsis. 735
Plant Cell 23: 2991–3006. 736
Chen X, Zhu L, Xin L, Du K, Ran X, Cui X, Xiang Q, Zhang H, Xu P, Wu X (2015) Rice stripe1-2 737
and stripe1-3 mutants encoding the small subunit of ribonucleotide reductase are 738
temperature sensitive and are required for chlorophyll biosynthesis. PloS One 10: 739
e0130172. 740
Chiu T-Y, Lao J, Manalansan B, Loqué D, Roux SJ, Heazlewood JL (2015) Biochemical 741
characterization of Arabidopsis apyrase family reveals their roles in regulating 742
endomembrane NDP/NMP homoeostasis. Biochem J 472: 43–54. 743
Choi J, Tanaka K, Cao Y, Qi Y, Qiu J, Liang Y, Lee SY, Stacey G (2014) Identification of a plant 744
receptor for extracellular ATP. Science 343: 290–294. 745
Clausen AR, Girandon L, Ali A, Knecht W, Rozpedowska E, Sandrini MP, Andreasson E, 746
Munch-Petersen B, Piskur J (2012) Two thymidine kinases and one multisubstrate 747
deoxyribonucleoside kinase salvage DNA precursors in Arabidopsis thaliana. FEBS J 279: 748
3889–3897. 749
Clausen AR, Mutahir Z, Munch-Petersen B, Piškur J (2014) Plants salvage 750
deoxyribonucleosides in mitochondria. Nucleosides, Nucleotides Nucleic Acids 33: 291–751
295. 752
Collier R, Tegeder M (2012) Soybean ureide transporters play a critical role in nodule 753
development, function and nitrogen export. Plant J 72: 355–367. 754
Combes A, Lafleuriel J, Lefloch F (1989) The Inosine-Guanosine Kinase-Activity of 755
Mitochondria in Tubers of Jerusalem Artichoke. Plant Physiol Biochem 27: 729–736. 756
Cornelius S, Traub M, Bernard C, Salzig C, Lang P, Mohlmann T (2012) Nucleoside transport 757
across the plasma membrane mediated by equilibrative nucleoside transporter 3 758
influences metabolism of Arabidopsis seedlings. Plant Biol 14: 696–705. 759
Cornelius S, Witz S, Rolletschek H, Mohlmann T (2011) Pyrimidine degradation influences 760
germination seedling growth and production of Arabidopsis seeds. J Exp Bot 62: 5623–761
5632. 762
Dahncke K, Witte CP (2013) Plant purine nucleoside catabolism employs a guanosine 763
deaminase required for the generation of xanthosine in Arabidopsis. Plant Cell 25: 4101–764
4109. 765
Dancer JE, Hughes RG, Lindell SD (1997) Adenosine-5’-phosphate deaminase. A novel 766
herbicide target. Plant Physiol 114: 119–129. 767
Daumann M, Fischer M, Niopek-Witz S, Girke C, Möhlmann T (2015) Apoplastic nucleoside 768
accumulation in Arabidopsis leads to reduced photosynthetic performance and increased 769
susceptibility against Botrytis cinerea. Front Plant Sci 6: 1158. 770
www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
25
Daumann M, Hickl D, Zimmer D, DeTar RA, Kunz H-H, Möhlmann T (2018) Characterization 771
of filament-forming CTP synthases from Arabidopsis thaliana. Plant J: 96: 316–328. 772
Del Vecchio HA, Ying S, Park J, Knowles VL, Kanno S, Tanoi K, She Y-M, Plaxton WC (2014) 773
The cell wall-targeted purple acid phosphatase AtPAP25 is critical for acclimation of 774
Arabidopsis thaliana to nutritional phosphorus deprivation. Plant J 80: 569–581. 775
Deng WW, Ashihara H (2010) Profiles of purine metabolism in leaves and roots of Camellia 776
sinensis seedlings. Plant Cell Physiol 51: 2105–2118. 777
Desimone M, Catoni E, Ludewig U, Hilpert M, Schneider A, Kunze R, Tegeder M, Frommer 778
WB, Schumacher K (2002) A novel superfamily of transporters for allantoin and other oxo 779
derivatives of nitrogen heterocyclic compounds in Arabidopsis. Plant Cell 14: 847–856. 780
Diaz-Leal JL, Galvez-Valdivieso G, Fernandez J, Pineda M, Alamillo JM (2012) 781
Developmental effects on ureide levels are mediated by tissue-specific regulation of 782
allantoinase in Phaseolus vulgaris L. J Exp Bot 63: 4095–4106. 783
Díaz-Leal JL, Torralbo F, Antonio Quiles F, Pineda M, Alamillo JM (2014) Molecular and 784
functional characterization of allantoate amidohydrolase from Phaseolus vulgaris. Physiol 785
Plant 152: 43–58. 786
Dong Q, Zhang Y-X, Zhou Q, Liu Q-E, Chen D-B, Wang H, Cheng S-H, Cao L-Y, Shen X-H 787
(2019) UMP Kinase Regulates Chloroplast Development and Cold Response in Rice. Int J 788
Mol Sci 20: 2107. 789
Doremus HD, Jagendorf AT (1985) Subcellular localization of the pathway of de novo 790
pyrimidine nucleotide biosynthesis in pea leaves. Plant Physiol 79: 856–861. 791
Dorion S, Rivoal J (2015) Clues to the functions of plant NDPK isoforms. Naunyn-792
Schmiedeberg’s Arch Pharmacol 388: 119–132. 793
Dorion S, Rivoal J (2018) Plant nucleoside diphosphate kinase 1: A housekeeping enzyme 794
with moonlighting activity. Plant Signal Behav 13: e1475804. 795
Feng X, Yang R, Zheng X, Zhang F (2012) Identification of a novel nuclear-localized adenylate 796
kinase 6 from Arabidopsis thaliana as an essential stem growth factor. Plant Physiol 797
Biochem 61: 180–186. 798
Floyd BE, Morriss SC, MacIntosh GC, Bassham DC (2015) Evidence for autophagy-799
dependent pathways of rRNA turnover in Arabidopsis. Autophagy 11: 2199–2212. 800
Gaillard C, Moffatt BA, Blacker M, Laloue M (1998a) Male sterility associated with APRT 801
deficiency in Arabidopsis thaliana results from a mutation in the gene APT1. Mol Gen 802
Genet 257: 348–353. 803
Gaillard C, Moffatt BA, Blacker M, Laloue M (1998b) Male sterility associated with APRT 804
deficiency in Arabidopsis thaliana results from a mutation in the gene APT1. Mol Gen 805
Genet 257: 348–353. 806
www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
26
Garton S, Knight H, Warren GJ, Knight MR, Thorlby GJ (2007) Crinkled leaves 8 - a mutation 807
in the large subunit of ribonucleotide reductase - leads to defects in leaf development 808
and chloroplast division in Arabidopsis thaliana. Plant J 50: 118–127. 809
Girke C, Daumann M, Niopek-Witz S, Möhlmann T (2014) Nucleobase and nucleoside 810
transport and integration into plant metabolism. Front Plant Sci 5: 443. 811
Gorelova V, Lepeleire J de, van Daele J, Pluim D, Meï C, Cuypers A, Leroux O, Rébeillé F, 812
Schellens JHM, Blancquaert D, Stove CP, van der Straeten D (2017) Dihydrofolate 813
reductase/thymidylate synthase fine-tunes the folate status and controls redox 814
homeostasis in plants. Plant cell 29: 2831–2853. 815
Gupta A, Sharma CB (1996) Purification to homogeneity and characterization of plasma 816
membrane and Golgi apparatus-specific 5’-adenosine monophosphatases from peanut 817
cotyledons. Plant Sci 117: 65–74. 818
Han BW, Bingman CA, Mahnke DK, Bannen RM, Bednarek SY, Sabina RL, Phillips GN (2006) 819
Membrane association, mechanism of action, and structure of Arabidopsis embryonic 820
factor 1 (FAC1). J Biol Chem 81: 14939–14947. 821
Hauck OK, Scharnberg J, Escobar NM, Wanner G, Giavalisco P, Witte C-P 2014) Uric acid 822
accumulation in an Arabidopsis urate oxidase mutant impairs seedling establishment by 823
blocking peroxisome maintenance. Plant Cell 26: 3090–3100. 824
Hooper CM, Castleden IR, Tanz SK, Aryamanesh N, Millar AH (2017) SUBA4: the interactive 825
data analysis centre for Arabidopsis subcellular protein locations. Nucleic Acids Res 45: 826
D1064-D1074. 827
Hu D, Li Y, Jin W, Gong H, He Q, Li Y (2017) Identification and characterization of a plastidic 828
adenine nucleotide uniporter (OsBT1-3) required for chloroplast development in the 829
early leaf stage of rice. Sci Rep 7. 830
Irani S, Todd CD (2016) Ureide metabolism under abiotic stress in Arabidopsis thaliana. J 831
Plant Physiol 199: 87–95. 832
Irani S, Todd CD (2018) Exogenous allantoin increases Arabidopsis seedlings tolerance to 833
NaCl stress and regulates expression of oxidative stress response genes. J Plant Physiol 834
221: 43–50. 835
Ito J, Batth TS, Petzold CJ, Redding-Johanson AM, Mukhopadhyay A, Verboom R, Meyer 836
EH, Millar AH, Heazlewood JL (2011) Analysis of the Arabidopsis cytosolic proteome 837
highlights subcellular partitioning of central plant metabolism. J Proteome Res 10: 1571-838
1582. 839
Jewell JB, Sowders JM, He R, Willis MA, Gang DR, Tanaka K (2019) Extracellular ATP Shapes 840
a Defense-Related Transcriptome Both Independently and along with Other Defense 841
Signaling Pathways. Plant Physiol 179: 1144–1158. 842
www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
27
Jung B, Florchinger M, Kunz HH, Traub M, Wartenberg R, Jeblick W, Neuhaus HE, 843
Mohlmann T (2009) Uridine-ribohydrolase is a key regulator in the uridine degradation 844
pathway of Arabidopsis. Plant Cell 21: 876–891. 845
Jung B, Hoffmann C, Mohlmann T (2011) Arabidopsis nucleoside hydrolases involved in 846
intracellular and extracellular degradation of purines. Plant J 65: 703–711. 847
Kafer C, Zhou L, Santoso D, Guirgis A, Weers B, Park S, Thornburg R (2004) Regulation of 848
pyrimidine metabolism in plants. Front Biosci-Landmrk 9: 1611–1625. 849
Karran P, Lindahl T (1980) Hypoxanthine in deoxyribonucleic acid: generation by heat-850
induced hydrolysis of adenine residues and release in free form by a deoxyribonucleic 851
acid glycosylase from calf thymus. Biochem 19: 6005–6011. 852
Katahira R, Ashihara H (2002) Profiles of pyrimidine biosynthesis, salvage and degradation 853
in disks of potato (Solanum tuberosum L.) tubers. Planta 215: 821–828. 854
Katahira R, Ashihara H (2006) Profiles of purine biosynthesis, salvage and degradation in 855
disks of potato (Solanum tuberosum L.) tubers. Planta 225: 115–126. 856
Kihara A, Saburi W, Wakuta S, Kim M-H, Hamada S, Ito H, Imai R, Matsui H (2011) 857
Physiological and biochemical characterization of three nucleoside diphosphate kinase 858
isozymes from rice (Oryza sativa L.). Biosci Biotechnol Biochem 75: 1740–1745. 859
Kirchberger S, Tjaden J, Neuhaus HE (2008) Characterization of the Arabidopsis Brittle1 860
transport protein and impact of reduced activity on plant metabolism. Plant J 56: 51–63. 861
Kopecná M, Blaschke H, Kopecny D, Vigouroux A, Koncitíková R, Novák O, Kotland O, 862
Strnad M, Moréra S, Schwartzenberg K von (2013) Structure and function of nucleoside 863
hydrolases from Physcomitrella patens and maize catalyzing the hydrolysis of purine, 864
pyrimidine, and cytokinin ribosides. Plant Physiol 163: 1568–1583. 865
Kumar V, Spangenberg O, Konrad M (2000) Cloning of the guanylate kinase homologues 866
AGK-1 and AGK-2 from Arabidopsis thaliana and characterization of AGK-1. Eur J Biochem 867
267: 606–615. 868
Kurakawa T, Ueda N, Maekawa M, Kobayashi K, Kojima M, Nagato Y, Sakakibara H, 869
Kyozuka J (2007) Direct control of shoot meristem activity by a cytokinin-activating 870
enzyme. Nature 445: 652 EP -. 871
Kuroha T, Tokunaga H, Kojima M, Ueda N, Ishida T, Nagawa S, Fukuda H, Sugimoto K, 872
Sakakibara H (2009) Functional analyses of LONELY GUY cytokinin-activating enzymes 873
reveal the importance of the direct activation pathway in Arabidopsis. Plant Cell 21: 874
3152–3169. 875
Lamberto I, Percudani R, Gatti R, Folli C, Petrucco S (2010) Conserved alternative splicing of 876
Arabidopsis transthyretin-like determines protein localization and S-allantoin synthesis in 877
peroxisomes. Plant Cell 22: 1564–1574. 878
www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
28
Lange PR, Geserick C, Tischendorf G, Zrenner R (2008) Functions of chloroplastic adenylate 879
kinases in Arabidopsis. Plant Physiol 146: 492–504. 880
Lee S, Doxey AC, McConkey BJ, Moffatt BA (2012) Nuclear targeting of methyl-recycling 881
enzymes in Arabidopsis thaliana is mediated by specific protein interactions. Mol Plant 5: 882
231–248. 883
Leroch M, Kirchberger S, Haferkamp I, Wahl M, Neuhaus HE, Tjaden J (2005) Identification 884
and characterization of a novel plastidic adenine nucleotide uniporter from Solanum 885
tuberosum. J Biol Chem 280: 17992–18000. 886
Lescano CI, Martini C, González CA, Desimone M (2016) Allantoin accumulation mediated 887
by allantoinase downregulation and transport by ureide permease 5 confers salt stress 888
tolerance to Arabidopsis plants. Plant Mol Biol 91: 581-595 889
Lim MH, Wu J, Yao J, Gallardo IF, Dugger JW, Webb LJ, Huang J, Salmi ML, Song J, Clark G, 890
Roux SJ (2014) Apyrase suppression raises extracellular ATP levels and induces gene 891
expression and cell wall changes characteristic of stress responses. Plant Physiol 164: 892
2054–2067. 893
Lincker F, Philipps G, Chabouté M-E (2004) UV-C response of the ribonucleotide reductase 894
large subunit involves both E2F-mediated gene transcriptional regulation and protein 895
subcellular relocalization in tobacco cells. Nucleic Acids Res 32: 1430–1438. 896
Liu S, Kracher B, Ziegler J, Birkenbihl RP, Somssich IE (2015) Negative regulation of ABA 897
signaling by WRKY33 is critical for Arabidopsis immunity towards Botrytis cinerea. eLife 4: 898
e07295. 899
Liu XY, Qian WQ, Liu X, Qin HJ, Wang DW (2007) Molecular and functional analysis of 900
hypoxanthine-guanine phosphoribosyltransferase from Arabidopsis thaliana. New Phytol 901
175: 448–461. 902
Luzarowski M, Kosmacz M, Sokolowska E, Jasinska W, Willmitzer L, Veyel D, Skirycz A 903
(2017) Affinity purification with metabolomic and proteomic analysis unravels diverse 904
roles of nucleoside diphosphate kinases. J Exp Bot 68: 3487–3499. 905
Ma X, Wang W, Bittner F, Schmidt N, Berkey R, Zhang L, King H, Zhang Y, Feng J, Wen Y, 906
Tan L, Li Y, Zhang Q, Deng Z, Xiong X, Xiao S (2016) Dual and opposing roles of xanthine 907
dehydrogenase in defense-associated reactive oxygen species metabolism in Arabidopsis. 908
Plant Cell 28: 1108–1126. 909
Mainguet SE, Gakiere B, Majira A, Pelletier S, Bringel F, Guerard F, Caboche M, Berthome 910
R, Renou JP (2009) Uracil salvage is necessary for early Arabidopsis development. Plant J 911
60: 280–291. 912
Mansfield TA, Schultes NP, Mourad GS (2009) AtAzg1 and AtAzg2 comprise a novel family 913
of purine transporters in Arabidopsis. FEBS Lett 583: 481–486. 914
Moffatt B, Ashihara H (2002) Purine and pyrimdine nucleotide synthesis and metabolism, 915
The Arabidopsis book. American Society of Plant Biologists, Rockville, MD. 916
www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
29
Moffatt B, Pethe C, Laloue M (1991) Metabolism of benzyladenine is impaired in a mutant 917
of Arabidopsis thaliana lacking adenine phosphoribosyltransferase activity. Plant Physiol 918
95: 900–908. 919
Moffatt BA, Stevens YY, Allen MS, Snider JD, Pereira LA, Todorova MI, Summers PS, 920
Weretilnyk EA, Martin-McCaffrey L, Wagner C (2002) Adenosine kinase deficiency is 921
associated with developmental abnormalities and reduced transmethylation. Plant 922
Physiol 128: 812–821. 923
Niopek-Witz S, Deppe J, Lemieux MJ, Möhlmann T (2014) Biochemical characterization and 924
structure-function relationship of two plant NCS2 proteins, the nucleobase transporters 925
NAT3 and NAT12 from Arabidopsis thaliana. Biochim Biophys Acta 1838: 3025–3035. 926
Niu M, Wang Y, Wang C, Lyu J, Wang Y, Dong H, Long W, Di Wang, Kong W, Wang L, Guo X, 927
Sun L, Hu T, Zhai H, Wang H, Wan J (2017) ALR encoding dCMP deaminase is critical for 928
DNA damage repair, cell cycle progression and plant development in rice. J Exp Bot 68: 929
5773–5786. 930
Nizam S, Qiang X, Wawra S, Nostadt R, Getzke F, Schwanke F, Dreyer I, Langen G, Zuccaro 931
A (2019) Serendipita indica E5′NT modulates extracellular nucleotide levels in the plant 932
apoplast and affects fungal colonization. EMBO Rep 20: e47430. 933
Nomura Y, Izumi A, Fukunaga Y, Kusumi K, Iba K, Watanabe S, Nakahira Y, Weber APM, 934
Nozawa A, Tozawa Y (2014) Diversity in guanosine 3’,5’-bisdiphosphate (ppGpp) 935
sensitivity among guanylate kinases of bacteria and plants. J Biol Chem 289: 15631–936
15641. 937
Nourimand M, Todd CD (2019) There is a direct link between allantoin concentration and 938
cadmium tolerance in Arabidopsis. Plant Physiol Biochem 135: 441–449. 939
Ohler L, Niopek-Witz S, Mainguet SE, Möhlmann T (2019) Pyrimidine salvage: physiological 940
functions and interaction with chloroplast biogenesis. Plant Physiol 180: 1816–1828 941
Osugi A, Kojima M, Takebayashi Y, Ueda N, Kiba T, Sakakibara H (2017) Systemic transport 942
of trans-zeatin and its precursor have differing roles in Arabidopsis shoots. Nat Plants 3: 943
17112. 944
Pedroza-García J-A, Nájera-Martínez M, Mazubert C, Aguilera-Alvarado P, Drouin-Wahbi J, 945
Sánchez-Nieto S, Gualberto JM, Raynaud C, Plasencia J (2019) Role of pyrimidine salvage 946
pathway in the maintenance of organellar and nuclear genome integrity. Plant J 97: 430–947
446. 948
Pessoa J, Sarkany Z, Ferreira-da-Silva F, Martins S, Almeida MR, Li JM, Damas AM (2010) 949
Functional characterization of Arabidopsis thaliana transthyretin-like protein. BMC Plant 950
Biol 10: 30. 951
Phillips DA, Joseph CM, Hirsch PR (1997) Occurrence of flavonoids and nucleosides in 952
agricultural soils. Appl Environ Microbiol 63: 4573–4577. 953
www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
30
Quiles FA, Galvez-Valdivieso G, Guerrero-Casado J, Pineda M, Piedras P (2019) Relationship 954
between ureidic/amidic metabolism and antioxidant enzymatic activities in legume 955
seedlings. Plant Physiol Biochem 138: 1–8. 956
Rapp M, Schein J, Hunt KA, Nalam V, Mourad GS, Schultes NP (2016) The solute specificity 957
profiles of nucleobase cation symporter 1 (NCS1) from Zea mays and Setaria viridis 958
illustrate functional flexibility. Protoplasma 253: 611–623. 959
Redillas MCFR, Bang SW, Lee D‐K, Kim YS, Jung H, Chung PJ, Suh J‐W, Kim J‐K (2019) 960
Allantoin accumulation through overexpression of ureide permease1 improves rice 961
growth under limited nitrogen conditions. Plant Biotechnol J 17: 1289–1301. 962
Regierer B, Fernie AR, Springer F, Perez-Melis A, Leisse A, Koehl K, Willmitzer L, 963
Geigenberger P, Kossmann J (2002) Starch content and yield increase as a result of 964
altering adenylate pools in transgenic plants. Nat Biotechnol 20: 1256–1260. 965
Rieder B, Neuhaus HE (2011) Identification of an Arabidopsis plasma membrane-located 966
ATP transporter important for anther development. Plant Cell 23: 1932–1944. 967
Riegler H, Geserick C, Zrenner R (2011) Arabidopsis thaliana nucleosidase mutants provide 968
new insights into nucleoside degradation. New Phytol 191: 349–359. 969
Riewe D, Grosman L, Fernie AR, Wucke C, Geigenberger P (2008a) The potato-specific 970
apyrase is apoplastically localized and has influence on gene expression, growth, and 971
development. Plant Physiol 147: 1092–1109. 972
Riewe D, Grosman L, Fernie AR, Zauber H, Wucke C, Geigenberger P (2008b) A cell wall-973
bound adenosine nucleosidase is involved in the salvage of extracellular ATP in Solanum 974
tuberosum. Plant Cell Physiol 49: 1572–1579. 975
Riggs JW, Rockwell NC, Cavales PC, Callis J (2016) Identification of the plant ribokinase and 976
discovery of a role for Arabidopsis ribokinase in nucleoside metabolism. J Biol Chem 291: 977
22572–22582. 978
Romanov GA, Lomin SN, Schmülling T (2018) Cytokinin signaling: from the ER or from the 979
PM? That is the question! New Phytol 218: 41–53. 980
Ronceret A, Gadea-Vacas J, Guilleminot J, Lincker F, Delorme V, Lahmy S, Pelletier G, 981
Chabouté M-E, Devic M (2008) The first zygotic division in Arabidopsis requires de novo 982
transcription of thymidylate kinase. Plant J 53: 776–789. 983
Sabina RL, Paul AL, Ferl RJ, Laber B, Lindell SD (2007) Adenine nucleotide pool perturbation 984
is a metabolic trigger for AMP deaminase inhibitor-based herbicide toxicity. Plant Physiol 985
143: 1752–1760. 986
Sakakibara H (2005) Cytokinin biosynthesis and regulation. Vitam Horm 72: 271–287. 987
Sauge-Merle S, Falconet D, Fontecave M (1999) An active ribonucleotide reductase from 988
Arabidopsis thaliana - Cloning, expression and characterization of the large subunit. Eur J 989
Biochem 266: 62–69. 990
www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
31
Sauter M, Moffatt B, Saechao MC, Hell R, Wirtz M (2013) Methionine salvage and S-991
adenosylmethionine: essential links between sulfur, ethylene and polyamine 992
biosynthesis. Biochem J 451: 145–154. 993
Schmid L-M, Ohler L, Möhlmann T, Brachmann A, Muiño JM, Leister D, Meurer J, Manavski 994
N (2019) PUMPKIN, the sole plastid UMP kinase, associates with group II introns and 995
alters their metabolism. Plant Physiol 179: 248–264. 996
Schmidt A, Baumann N, Schwarzkopf A, Frommer WB, Desimone M (2006) Comparative 997
studies on ureide permeases in Arabidopsis thaliana and analysis of two alternative splice 998
variants of AtUPS5. Planta 224: 1329–1340. 999
Schmidt A, Su YH, Kunze R, Warner S, Hewitt M, Slocum RD, Ludewig U, Frommer WB, 1000
Desimone M (2004) UPS1 and UPS2 from Arabidopsis mediate high affinity transport of 1001
uracil and 5-fluorouracil. J Biol Chem 279: 44817–44824. 1002
Schmülling T, Werner T, Riefler M, Krupková E, Bartrina y Manns I (2003) Structure and 1003
function of cytokinin oxidase/dehydrogenase genes of maize, rice, Arabidopsis and other 1004
species. J Plant Res 116: 241–252. 1005
Schoor S, Farrow S, Blaschke H, Lee S, Perry G, Schwartzenberg K von, Emery N, Moffatt B 1006
(2011) Adenosine kinase contributes to cytokinin interconversion in Arabidopsis. Plant 1007
Physiol 157: 659–672. 1008
Schroeder RY, Zhu A, Eubel H, Dahncke K, Witte C-P (2018) The ribokinases of Arabidopsis 1009
thaliana and Saccharomyces cerevisiae are required for ribose recycling from nucleotide 1010
catabolism, which in plants is not essential to survive prolonged dark stress. New Phytol 1011
217: 233–244. 1012
Serventi F, Ramazzina I, Lamberto I, Puggioni V, Gatti R, Percudani R (2010) Chemical basis 1013
of nitrogen recovery through the ureide pathway. Formation and hydrolysis of S-1014
ureidoglycine in plants and bacteria. ACS Chem Biol 5: 203–214. 1015
Sharma CB, Mittal R, Tanner W (1986) Purification and properties of a glycoprotein 1016
adenosine 5′-monophosphatase from the plasma membrane fraction of Arachis 1017
hypogaea cotyledons. Biochim Biophys Acta 884: 567–577. 1018
Shelp BJ, Atkins CA (1983) Role of Inosine monophosphate oxidoreductase in the formation 1019
of ureides in nitrogen-fixing nodules of cowpea (Vigna-unguiculata-L Walp). Plant Physiol 1020
72: 1029–1034. 1021
Sigel H, Operschall BP, Griesser R (2009) Xanthosine 5 ‘-monophosphate (XMP). Acid-base 1022
and metal ion-binding properties of a chameleon-like nucleotide. Chem Soc Rev 38: 1023
2465–2494. 1024
Siu KKW, Lee JE, Sufrin JR, Moffatt BA, McMillan M, Cornell KA, Isom C, Howell PL (2008) 1025
Molecular determinants of substrate specificity in plant 5’-methylthioadenosine 1026
nucleosidases. J Mol Biol 378: 112–128. 1027
www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
32
Smith PM, Atkins CA (2002) Purine biosynthesis. Big in cell division, even bigger in nitrogen 1028
assimilation. Plant Physiol 128: 793–802. 1029
Soltabayeva A, Srivastava S, Kurmanbayeva A, Bekturova A, Fluhr R, Sagi M (2018) Early 1030
senescence in older leaves of low nitrate-grown Atxdh1 uncovers a role for purine 1031
catabolism in N supply. Plant Physiol 178: 1027–1044. 1032
Spetea C, Lundin B (2012) Evidence for nucleotide-dependent processes in the thylakoid 1033
lumen of plant chloroplasts—an update. FEBS Lett 586: 2946–2954. 1034
Stasolla C, Katahira R, Thorpe TA, Ashihara H (2003) Purine and pyrimidine nucleotide 1035
metabolism in higher plants. J Plant Physiol 160: 1271–1295. 1036
Stitt M, Lilley RM, Heldt HW (1982) Adenine-nucleotide levels in the cytosol, chloroplasts, 1037
and mitochondria of wheat leaf protoplasts. Plant Physiol 70: 971–977. 1038
Sugimoto H, Kusumi K, Noguchi K, Yano M, Yoshimura A, Iba K (2007) The rice nuclear 1039
gene, VIRESCENT 2, is essential for chloroplast development and encodes a novel type of 1040
guanylate kinase targeted to plastids and mitochondria. Plant J 52: 512–527. 1041
Sukrong S, Yun K-Y, Stadler P, Kumar C, Facciuolo T, Moffatt BA, Falcone DL (2012) 1042
Improved growth and stress tolerance in the Arabidopsis oxt1 mutant triggered by 1043
altered adenine metabolism. Mol Plant 5: 1310–1332. 1044
Tegeder M (2014) Transporters involved in source to sink partitioning of amino acids and 1045
ureides. Opportunities for crop improvement. J Exp Bot 65: 1865–1878. 1046
Tintemann H, Wasternack C, Benndorf R, Reinbothe H (1985) The rate-limiting step of 1047
uracil degradation in tomato cell-suspension cultures and Euglena-gracilis invivo studies. 1048
Comp Biochem Physiol, Part B: Biochem Mol Biol 82: 787–792. 1049
Todd CD, Polacco JC (2006) AtAAH encodes a protein with allantoate amidohydrolase 1050
activity from Arabidopsis thaliana. Planta 223: 1108–1113. 1051
Torres RJ, Puig JG (2007) Hypoxanthine-guanine phosophoribosyltransferase (HPRT) 1052
deficiency: Lesch-Nyhan syndrome. Orphanet J Rare Dis. 2: 48. 1053
Traub M, Florchinger M, Piecuch J, Kunz HH, Weise-Steinmetz A, Deitmer JW, Neuhaus HE, 1054
Mohlmann T (2007) The fluorouridine insensitive 1 (fur1) mutant is defective in 1055
equilibrative nucleoside transporter 3 (ENT3), and thus represents an important 1056
pyrimidine nucleoside uptake system in Arabidopsis thaliana. Plant J 49: 855–864. 1057
Tripathi D, Zhang T, Koo AJ, Stacey G, Tanaka K (2017) Extracellular ATP acts on jasmonate 1058
signaling to reinforce plant defense. Plant Physiol 176: 511–523. 1059
Ullrich A, Knecht W, Piskur J, Loffler M (2002) Plant dihydroorotate dehydrogenase differs 1060
significantly in substrate specificity and inhibition from the animal enzymes. FEBS Lett 1061
529: 346–350. 1062
Urarte E, Esteban R, Moran JF, Bittner F (2015) Established and proposed roles of xanthine 1063
oxidoreductase in oxidative and reductive pathways in plants. In KJ Gupta, AU 1064
www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
33
Igamberdiev, eds, Reactive oxygen and nitrogen species signaling and communication in 1065
plants. Springer, Cham, Switzerland, pp. 15–42. 1066
Wagner KG, Backer AI (1992) Dynamics of nucleotides in plants studied on a cellular basis. 1067
In JK W, F M, eds, International Review of Cytology Vol. 134, pp. 1–84. 1068
Walsh TA, Green SB, Larrinua IM, Schmitzer PR (2001) Characterization of plant beta-1069
ureidopropionase and functional overexpression in Escherichia coli. Plant Physiol 125: 1070
1001–1011. 1071
Wang L, Li Z, Qian W, Guo W, Gao X, Huang L, Wang H, Zhu H, Wu JW,Wang D, Liu D (2011) 1072
The Arabidopsis purple acid phosphatase At-PAP10 is predominantly associated with the 1073
root surface and plays an important role in plant tolerance to phosphate limitation. Plant 1074
Physiol 157: 1283–1299. 1075
Wang C, Liu Z (2006) Arabidopsis ribonucleotide reductases are critical for cell cycle 1076
progression, DNA damage repair, and plant development. Plant Cell 18: 350–365. 1077
Wang C, Zhou M, Zhang X, Yao J, Zhang Y, Mou Z (2017) A lectin receptor kinase as a 1078
potential sensor for extracellular nicotinamide adenine dinucleotide in Arabidopsis 1079
thaliana. eLife 6: e25474 1080
Watanabe S, Matsumoto M, Hakomori Y, Takagi H, Shimada H, Sakamoto A (2014) The 1081
purine metabolite allantoin enhances abiotic stress tolerance through synergistic 1082
activation of abscisic acid metabolism. Plant Cell Environ 37: 1022–1036. 1083
Wei X, Song X, Wei L, Tang S, Sun J, Hu P, Cao X (2017) An epiallele of rice AK1 affects 1084
photosynthetic capacity. J Integr Plant Biol 59: 158–163. 1085
Werner AK, Medina-Escobar N, Zulawski M, Sparkes IA, Cao F-Q, Witte CP (2013) The 1086
ureide-degrading reactions of purine ring catabolism employ three amidohydrolases and 1087
one aminohydrolase in Arabidopsis, soybean, and rice. Plant Physiol 163: 672–681. 1088
Werner AK, Romeis T, Witte CP (2010) Ureide catabolism in Arabidopsis thaliana and 1089
Escherichia coli. Nat Chem Biol 6: 19–21. 1090
Werner AK, Sparkes IA, Romeis T, Witte CP (2008) Identification, biochemical 1091
characterization, and subcellular localization of allantoate amidohydrolases from 1092
Arabidopsis and soybean. Plant Physiol 146: 418–430. 1093
Werner AK, Witte CP (2011) The biochemistry of nitrogen mobilization: purine ring 1094
catabolism. Trends Plant Sci 16: 381–387. 1095
Witz S, Jung B, Furst S, Mohlmann T (2012) De novo pyrimidine nucleotide synthesis mainly 1096
occurs outside of plastids, but a previously undiscovered nucleobase importer provides 1097
substrates for the essential salvage pathway in Arabidopsis. Plant Cell 24: 1549–1559. 1098
Wu S, Alseekh S, Cuadros-Inostroza A, Fusari CM, Mutwil M, Kooke R, Keurentjes JB, 1099
Fernie AR, Willmitzer L, Brotman Y (2016) Combined use of genome-wide association 1100
www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
34
data and correlation networks unravels key regulators of primary metabolism in 1101
Arabidopsis thaliana. PLoS GENET 12. 1102
Xu J, Deng Y, Li Q, Zhu X, He Z (2014) STRIPE2 encodes a putative dCMP deaminase that 1103
plays an important role in chloroplast development in rice. J Genet Genomics 41: 539–1104
548. 1105
Xu J, Zhang HY, Xie CH, Xue HW, Dijkhuis P, Liu CM (2005) EMBRYONIC FACTOR 1 encodes 1106
an AMP deaminase and is essential for the zygote to embryo transition in Arabidopsis. 1107
Plant J 42: 743–756. 1108
Xu J, Zhang L, Yang D-L, Li Q, He Z (2015) Thymidine kinases share a conserved function for 1109
nucleotide salvage and play an essential role in Arabidopsis thaliana growth and 1110
development. New Phytol 208: 1089–1103. 1111
Yamada H, Suzuki T, Terada K, Takei K, Ishikawa K, Miwa K, Yamashino T, Mizuno T (2001) 1112
The Arabidopsis AHK4 histidine kinase is a cytokinin-binding receptor that transduces 1113
cytokinin signals across the membrane. Plant Cell Physiol 42: 1017–1023. 1114
Ye W, Hu S, Wu L, Ge C, Cui Y, Chen P, Wang X, Xu J, Ren D, Dong G, Qian Q, Guo L (2016) 1115
White stripe leaf 12 (WSL12), encoding a nucleoside diphosphate kinase 2 (OsNDPK2), 1116
regulates chloroplast development and abiotic stress response in rice (Oryza sativa L.). 1117
Mol Breeding 36: 57. 1118
Yin Y, Katahira R, Ashihara H (2014) Metabolism of purine nucleosides and bases in 1119
suspension-cultured Arabidopsis thaliana cells. Eur Chem Bull 3: 925–934. 1120
Young LS, Harrison BR, Narayana, M. U. M., Moffatt BA, Gilroy S, Masson PH (2006) 1121
Adenosine kinase modulates root gravitropism and cap morphogenesis in arabidopsis. 1122
Plant Physiol 142: 564–573. 1123
Zarepour M, Kaspari K, Stagge S, Rethmeier R, Mendel RR, Bittner F (2010) Xanthine 1124
dehydrogenase AtXDH1 from Arabidopsis thaliana is a potent producer of superoxide 1125
anions via its NADH oxidase activity. Plant Mol Biol 72: 301–310. 1126
Zhang T, Feng P, Li Y, Yu P, Yu G, Sang X, Ling Y, Zeng X, Li Y, Huang J, Zhang T, Zhao F, 1127
Wang N, Zhang C, Yang Z, Wu R, He G (2018) VIRESCENT-ALBINO LEAF 1 regulates leaf 1128
colour development and cell division in rice. J Exp Bot 69: 4791–4804. 1129
Zhang X, Chen Y, Lin X, Hong X, Zhu Y, Li W, He W, An F, Guo H (2013) Adenine 1130
phosphoribosyl transferase 1 is a key enzyme catalyzing cytokinin conversion from 1131
nucleobases to nucleotides in Arabidopsis. Mol Plant 6: 1661–1672. 1132
Zhou K, Xia J, Wang Y, Ma T, Li Z (2017) A Young Seedling Stripe2 phenotype in rice is 1133
caused by mutation of a chloroplast-localized nucleoside diphosphate kinase 2 required 1134
for chloroplast biogenesis. Genet Mol Biol 40: 630–642. 1135
Zhou L, Lacroute F, Thornburg R (1998) Cloning, expression in Escherichia coli, and 1136
characterization of Arabidopsis thaliana UMP/CMP kinase. Plant Physiol 117: 245–254. 1137
www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
35
Zhu X, Guo S, Wang Z, Du Q, Xing Y, Zhang T, Shen W, Sang X, Ling Y, He G (2016) Map-1138
based cloning and functional analysis of YGL8, which controls leaf colour in rice (Oryza 1139
sativa). BMC Plant Biol 16: 134. 1140
Zrenner R, Ashihara H (2011) Nucleotide Metabolism. In H Ashihara, A Crozier, A 1141
Komamine, eds, Plant metabolism and biotechnology. Wiley, Cambridge, New York, 1142
pp. 135–162. 1143
Zrenner R, Riegler H, Marquard CR, Lange PR, Geserick C, Bartosz CE, Chen CT, Slocum RD 1144
(2009) A functional analysis of the pyrimidine catabolic pathway in Arabidopsis. New 1145
Phytol 183: 117–132. 1146
Zrenner R, Stitt M, Sonnewald U, Boldt R (2006) Pyrimidine and purine biosynthesis and 1147
degradation in plants. Annu Rev Plant Biol 57: 805–836. 1148
1149
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ADVANCES
• The pathways of plant nucleotide metabolism have been better defined through the detailed analyses of mutants and the discovery of many new genes / proteins involved, for example the plastid uracil transporter, the nucleoside hydrolases, the CTP synthases, and guanosine deaminase.
• It has become clear that purine nucleotide catabolism may not only be involved in recycling nitrogen, but also in producing catabolic intermediates which dampen stress responses.
• Extracellular ATP has emerged as a new signaling molecule.
• Cells contain many modified nucleotides. A first enzyme for the degradation of a modified nucleotide, N6-methyl-AMP, has been discovered.
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OUTSTANDING QUESTIONS
• How is nucleotide metabolism regulated (i) on the enzymatic level (ii) by transcriptional and post-transcriptional mechanisms (iii) by compartmentalization or organization in protein complexes (iv) by transport (v) by tissue-specific gene expression?
• Which transporters mediate purine and pyrimidine metabolite movement, specifically (i) catabolic intermediates between different cellular compartments (ii) nucleotides into the organelles (iii) metabolites over long distances?
• How are the nucleotide and deoxynucleotide species in the distinct cellular compartments balanced? Is this adjusted upon developmental and environmental stimuli, and how is this achieved?
• Which nucleotide phosphatases mediate dephosphorylation in vivo, for example dephosphorylation of mononucleotides to nucleosides?
• How are modified and damaged nucleotides degraded, and how do they re-enter nucleotide metabolism?
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N
NN
N 6
6
5
79
1
NH2
HN
NN
N
O
H2N
HN
NN
N
O
HN
NR
R R R R
O
O
HN
N
O
O
H C3N
N
NH2
O
O
HNN
NN O
adenineadenosine / deoxyadenosineAMP / dAMP
uracil
R = HR = ribose /
dexoyriboseR = ribose monophosphate /
deoxyribose monophosphate
uridine / dexoyuridineUMP / dUMP
cytosinecytidine / deoxycytidineCMP / dCMP
hypoxanthineinosine / deoxyinosineIMP /dIMP
guanineguanosine / deoxyguanosineGMP /dGMP
xanthinexanthosine / deoxyxanthosineXMP /dXMP
thyminethymidine= deoxythymidineTMP= dTMP
2’3’
= ribose
nucleoside / deoxynucleoside
nucleoside monophosphate (nucleoside mononucleotide)
nucleoside diphosphate
nucleoside triphosphate
nucleotides
= dexoyribose
nucleobase
O
OH OHH
OPO
O
O
OP
O
O
OP
O
O
R R
Figure 1. Structural composi�on of nucleobases, nucleosides, and nucleo�des.
For the nucleobases ‘R’ is simply a proton. For the nucleosides ‘R’ is a sugar moiety which can be ribose or deoxyribose (carrying a proton instead of a hydroxyl group at the 2’ carbon of the ribose). Nucleo�des have up to three phosphate groups esterified to the hydroxyl group of the 5’ carbon of the nucleoside sugar determining the prefix mono- di- and triphosphate in the name of the molecule. The terminal phosphate always carries two charges irrespec�ve of the number of phosphates present. The pyrimidine nucleobases (upper row) and the purine nucleobases (lower row) are shown with the groups a�ached to the heterocycles highlighted in red (oxo groups), blue (amino groups), and grey shading (methyl group).
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AMPPRPPglutamineaspartatebicarbonateglycineformyl-tetrahydrofolate
NDPsNTPs
dNDPsdNTPs
DNA
RNA
nucleobasesnucleosides
UDP-GlcNADHetc.
S-adenosylmethionine
GMPUMP CTP
de novobiosynthesis
degradation
SAM metabolismribose
carbon dioxideammoniaglyoxylatemalonate- semialdehyde
biosynthesisdegradation
degradation
biosynthesis
phosphorylation
degradation
salvage
reduction
(via dNDPs)
(to nucleosides) decay, repair
AAAAA
Figure 2. Schema�c overview of plant nucleo�de metabolism.
Nucleo�des are synthesized ‘de novo’ from precursor molecules listed in the upper le� box. The phosphoryla�on of nucleoside monophosphates via nucleoside diphosphates (NDPs) generates nucleoside triphosphates (NTPs), which serve as building blocks for RNA synthesis and as precursors for the biosynthesis of the metabolites shown in the center (S-adenosyl methionine, UDP-glucose, and NADH are given as examples). However, the nucleoside triphosphates, in par�cular ATP and GTP, are not only precursors for other metabolites, but are also essen�al stores of chemical energy in the phosphoanhydride bonds used in a mul�tude of energe�c coupling reac�ons, as well as important donors of phosphate in kinase reac�ons (not shown). NDPs can be reduced to dNDPs (deoxynucleoside diphosphates), which a�er phosphoryla�on to dNTPs serve as precursors for DNA biosynthesis. RNA degrada�on in the cytosol releases nucleoside monophosphates, whereas nucleosides are produced during vacuolar RNA degrada�on. Adenosine and adenine are products of biochemical reac�ons involving S-adenosyl methionine (SAM). Non-enzyma�c decay (depurina�on) and enzyma�c repair reac�ons result in nucleoside and nucleobase release from DNA. Nucleobases and nucleosides can be recycled to nucleo�des in so called ‘salvage’ reac�ons. Plants are also capable of full nucleo�de degrada�on via certain nucleosides and nucleobases releasing the nitrogen of the nucleobases as ammonia.
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AMP AMP
PLASTIDSA B MITOCHONDRIA
outer membrane
IMP IMP
XMP
GMP
purine de novo biosynthesis
2 reactions
At4g32400At3g20330
At4g22930
At5g23300
At3g54470
At1g30820CTPS1 to 5
At3g12670At4g02120At4g20320At4g34890
2 reactions
carbamoylasparate
carbamoylasparate
dihydroorotate
dihydroorotate
?
?
( )
10 reactions
orotate
orotate
UMP
pyrimidine de novo biosynthesis
UTP CTP
AMPDAt2g38280
IMPDH
At1g79470At1g16350
GMPS
ATCase
DHODH
DHOase
At1g63660
BT1
?
?
CYTOSOL PLASTIDS CYTOSOL
UMPS
CTPS
1
2
4 8
9
7
6
5
3
Figure 3. Purine and pyrimidine de novo biosynthesis.
(A) Purine de novo biosynthesis. (B) Pyrimidine de novo biosynthesis. Enzymes and transporters: BT1 (1), bri�le1; AMPD (2), AMP deaminase; IMPDH (3), IMP dehydrogenase; GMPS (4), GMP synthetase; ATCase (5), asparate transcarbamoylase; DHOase (6), dihydroorotatase; DHODH (7), dihydroorotate dehydrogenase; UMPS (8), UMP synthase; CTPS (9), CTP synthetase. An anchor symbol denotes an associa�on with the respec�ve membrane.
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GMP
GDP
GTP
GMK
de novovia IMP
de novo
from synthesis
NDPK
deoxy adenosine AMP
ADP ADPdADP
dAMP
dATPATP
dGDP
dGMP
dGTP
AMK
dNK
synthesis
salvage
RNR
substrate level and oxidativephosphorylation
GDPsynthesis
RNR
NDPK
At2g37250
At1g72040
At3g07800At5g23070
At5g59440
At2g16370At4g34570At2g21550
deoxy guanosine dNK
salvage
salvage
At1g72040
At5g47840At5g50370At5g63400At5g35170
At4g09320At5g63310
At3g27060At2g21790
At3g23580At5g40942
At4g11010At4g23900At4g23895
At2g39270At3g01820
At3g60180At4g25280At5g26667At3g60961At3g18680At3g10030
CYTOSOL CYTOSOL
CYTOSOLCYTOSOL
CYTOSOLPLASTIDSMITOCHONDRIA
CYTOSOLPLASTIDSMITOCHONDRIA
de novovia UTP
de novo
AMK1 to 7
UMK1 to 6
NDPK1 to 5
RNR1RNR2 (tso2)RNR2ARNR2B
DC
BA
CMP
CDP
CTP CTP
UMK
NDPK
dCDP
dCMP
dCTP
CDPsynthesisRNR
deoxy cytidine dNK
salvage
At1g72040
CYTOSOLPLASTIDSMITOCHONDRIA
RNR
CYTOSOLPLASTIDSMITOCHONDRIA
CYTOSOLMITOCHONDRIA
UMP
UDP
dUDP dUMP TMP
TMP
TDP
TTPUTP
UMK
DHFR-TS
TMKTK
NDPK
?
?
thymidine
de novovia UTP
10
10
10
10
11 11
11
1212
1313
1313
14
15
16
1817
At2g41880
At3g06200At3g57550
GMK 1 to 3
Figure 4. Synthesis of nucleoside and deoxynucleoside triphosphates. 1
Synthesis of (A) cy�dylates, (B) uridylates and thymidylates, (C) guanylates, and (D) 2 adenylates. RNR (10), ribonucleo�de reductase; dNK (11), deoxynucleoside kinase; UMK (12), 3 UMP kinase; NDPK (13), nucleoside diphosphate kinase; TK (14), thymidine kinase; DHFR-TS 4 (15), dihydrofolate reductase-thymidylate synthase; TMK (16), thymidylate kinase; GMK (17), 5 guanylate kinase; AMK (18), adenylate kinase. The subcellular loca�ons where enzymes with 6 these ac�vi�es are found are indicated. For TMK, a loca�on in the plas�ds is only assumed. 7 The mononucleo�des (AMP, GMP, UMP, and CMP) may also be derived from salvage 8 reac�ons (see Figures 5 and 6). 9
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IMPadenosine AMP guanosine
xanthosineinosine
hypoxantine xanthine
urate
ringcatabolism
XMP GMP
adenine guanine
At4g34890
At2g36310At1g05620
XDHXDH
NSH1NSH2
NSH1NSH2
GSDA
ADK IGK
IGK
IMPDH
HGPRT
HGPRT
GMPS
XMPP
AMPD
GMPP
At5g28050
At1g71750APRT
At1g71750
At2g38280 At1g63660At1g79470At1g16350
At3g09820
At1g27450At1g80050At4g22570At4g12440At5g11160
At5g03300
At?
At?
At?
At?
CYTOSOL
urate
HIU
OHCU
(S)-allantoin
At2g26230
allantoate
(S)-ureidoglycine
glyoxylate
(S)-ureidoglycolate
UOX
At5g43600UAH
At4g17050
At4g20070
At4g04955 ALN
AAHNH3
NH3
NH32
At5g58220 ALNS
At5g58220 ALNS
UGAH
PERO
XISOM
EEN
DO
PLASM
IC R
ETICU
LUM
2. SAM, ethylene biosynthesis1. SAM, polyamine + nicotianamine biosynthesis
4. cytokinin degradation5. uptake
4. uptake
2. SAM, methylation reactions 3. AMP phosphotransferase
1. (vacuolar) RNA turnover
3. spontaneous depurination
1. (vacuolar) RNA turnover2. uptake
1. spontaneous depurination2. uptake
t-RNA turnover
‚A‘ deamination in DNAand base excision repair
sources
NH
O
NH
NH2
O H O
NH2O-NH
HN
OO
NH
NH2
O H
NH
HN
ON
HN-O
O
NH
O
HOH O
NH2O-
A
B
19
20
21
21
22
22 23
2425
26
27
29
30
30
31
32
33
34
2828
2 3 4
Figure 5. Salvage and degrada�on of purines.
(A) The reac�ons of purine nucleobase and nucleoside salvage as well as purine nucleo�de degrada�on, which overlaps par�ally with GMP synthesis. The salvage pathways are highlighted by light grey shading, degrada�on reac�ons are encircled in dark gray. Metabolites that can only undergo degrada�on and cannot be salvaged are shown with brown shading. (B) Purine ring catabolism. The transport steps for urate and (S)-allantoin are not shown explicitly. APRT (19), adenine phosphoribosyltransferase; ADK (20), adenosine kinase; AMPD (2), AMP deaminase; IMPDH (3), IMP dehydrogenase; GMPS (4), GMP synthetase; HGPRT (21), hypoxanthine guanine phosphoribosyltransferase; IGK (22), inosine guanosine kinase; GMPP (23), GMP phosphatase; GSDA (24), guanosine deaminase; XMPP (25), XMP phosphatase; NSH1 (26), nucleoside hydrolase 1; NSH2 (27), nucleoside hydrolase 2; XDH (28), xanthine dehydrogenase; UOX (29), urate oxidase; ALNS (30), allantoin synthase; ALN (31), allantoinase; AAH (32), allantoate amidohydrolase; UGAH (33), ureidoglycine aminohydrolase; UAH (34), ureidoglycolate amidohydrolase.
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PLASTIDS CYTOSOL
ER
UMPUMP
UCK1 to 5
At3g17810
At2g36310At3g53900 At2g19570
At5g03555
At5g12200
At5g64370
DPYH
DPYD
NSH1
UCPP
UPRT
β-UP
uracil uracil
uridine
CMP
cytidine
dihydrouracil
NC-β-alanine
malonate-SA
β-alanine
PLUTO
At?
CDA
UCK UCKUCPPAt?
At5g40870At3g27190At1g55810At4g26510At3g27440
H/
H
N
N O
OHCH
53
*H
/CH3
*
H2
H
HN
N
O
O
OH
H
/CH3*
H
O
H2N
OH
H
/CH3 H
O
O
O
H
H
1. (vacuolar) RNA turnover2. uptake
sources
2. uptake
1. ‚C‘ deamination in DNA and base excision repair
BAATAt?
3535 3636
37
38
26
41
42
43
39
40
Figure 6. Salvage and degrada�on of pyrimidines.
NC-β-alanine, N-carbamyl-β-alanine; malonate-SA, malonate semialdehyde. UCK (35), uridine cy�dine kinase; UCPP (36), UMP CMP phosphatase; CDA (37), cy�dine deaminase; NSH1 (26), nucleoside hydrolase 1; PLUTO (38), plas�dic nucleobase transporter; UPRT (39), uracil phosphoribosyltransferase; DPYD (40), dihydropyrimidine dehydrogenase; DPYH (41), dihydropyrimidine hydrolase; β-UP (42), β-ureidopropionase; BAAT (43) β-alanine aminotransferase.
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ATPATP
AMP
APOPLAST
signals
CELL
At1g14240
At5g18860
At4g05120
At5g56450
exocytosis
rupture
At3g10960At5g50300
NSH3
?
?
?
DORN1
adenosine
adenine
5‘ NT
APY3
AZG1/2NSH3
ENT3
pmANT1
4544
46
48
47
49
50
Figure 7. Excre�on, percep�on, and degrada�on of extracellular ATP
pmANT1 (44), plasma membrane adenine nucleo�de transporter; APY3 (45), apyrase 3; 5‘ NT (46), 5’ nucleo�dase; ENT3 (47), equilibra�ve nucleoside transporter 3; NSH3 (48), nucleoside hydrolase 3, AZG1/2 (49), azaguanine resistant 1 / azaguanine resistant 2, DORN1 (50), does not respond to nucleo�des 1 .
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Parsed CitationsAlamillo JM, Diaz-Leal JL, Sanchez-Moran MV, Pineda M (2010) Molecular analysis of ureide accumulation under drought stress inPhaseolus vulgaris L. Plant Cell Environ 33: 1828–1837.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Ashihara H, Loukanina N, Stasolla C, Thorpe TA (2001) Pyrimidine metabolism during somatic embryo development in white spruce(Picea glauca). J Plant Physiol 158: 613–621.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Ashihara H, Stasolla C, Fujimura T, Crozier A (2018) Purine salvage in plants. Phytochemistry 147: 89–124.Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Atkins CA, Shelp BJ, Storer PJ (1985) Purification and properties of inosine monophosphate oxidoreductase from nitrogen-fixingnodules of cowpea (Vigna-Unguiculata-L WALP). Arch Biochem Biophys 236: 807–814.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Atkins CA, Smith, P. M. C., Storer PJ (1997) Reexamination of the intracellular localization of de novo purine synthesis in cowpeanodules. Plant Physiol 113: 127–135.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Baccolini C, Witte C-P (2019) AMP and GMP catabolism in Arabidopsis converge on xanthosine, which is degraded by a nucleosidehydrolase heterocomplex. Plant Cell 31: 734–751.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Bahaji A, Muñoz FJ, Ovecka M, Baroja-Fernández E, Montero M, Li J, Hidalgo M, Almagro G, Sesma MT, Ezquer I, Pozueta-Romero J(2011a) Specific delivery of AtBT1 to mitochondria complements the aberrant growth and sterility phenotype of homozygous Atbt1Arabidopsis mutants. Plant J 68: 1115–1121.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Bahaji A, Ovecka M, Bárány I, Risueño MC, Muñoz FJ, Baroja-Fernández E, Montero M, Li J, Hidalgo M, Sesma MT, Ezquer I, TestillanoPS, Pozueta-Romero J (2011b) Dual targeting to mitochondria and plastids of AtBT1 and ZmBT1, two members of the mitochondrialcarrier family. Plant Cell Physiol 52: 597–609.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Barbado C, Cordoba-Canero D, Arizaa RR, Roldan-Arjona T (2018) Nonenzymatic release of N7-methylguanine channels repair ofabasic sites into an AP endonuclease-independent pathway in Arabidopsis. Proc Natl Acad Sci USA 115: E916-E924.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Beaudoin GAW, Johnson TS, Hanson AD (2018) The PLUTO plastidial nucleobase transporter also transports the thiamin precursorhydroxymethylpyrimidine. Biosci Rep 38.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Bernard C, Traub M, Kunz HH, Hach S, Trentmann O, Mohlmann T (2011) Equilibrative nucleoside transporter 1 (ENT1) is critical forpollen germination and vegetative growth in Arabidopsis. J Exp Bot 62: 4627–4637.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Bromley JR, Warnes BJ, Newell CA, Thomson JCP, James CM, Turnbull CGN, Hanke DE (2014) A purine nucleoside phosphorylase inSolanum tuberosum L. (potato) with specificity for cytokinins contributes to the duration of tuber endodormancy. Biochem J 458: 225–237.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Brychkova G, Alikulov Z, Fiuhr R, Sagi M (2008) A critical role for ureides in dark and senescence-induced purine remobilization isunmasked in the Atxdh1 Arabidopsis mutant. Plant J 54: 496–509.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Cao Y, Tanaka K, Nguyen CT, Stacey G (2014) Extracellular ATP is a central signaling molecule in plant stress responses. Curr OpinPlant Biol 20: 82–87.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
Carrari F, Coll-Garcia D, Schauer N, Lytovchenko A, Palacios-Rojas N, Balbo I, Rosso M, Fernie AR (2005) Deficiency of a plastidialadenylate kinase in Arabidopsis results in elevated photosynthetic amino acid biosynthesis and enhanced growth. Plant Physiol 137:70–82.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Carter AM, Tegeder M (2016) Increasing nitrogen fixation and seed development in soybean requires complex adjustments of nodulenitrogen metabolism and partitioning processes. Current Biol 26: 2044–2051.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Casartelli A, Melino VJ, Baumann U, Riboni M, Suchecki R, Jayasinghe NS, Mendis H, Watanabe M, Erban A, Zuther E, Hoefgen R,Roessner U, Okamoto M, Heuer S (2019) Opposite fates of the purine metabolite allantoin under water and nitrogen limitations inbread wheat. Plant Mol Biol 99: 477–497.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Chen F, Dong G, Ma X, Wang F, Zhang Y, Xiong E, Wu J, Wang H, Qian Q, Wu L, Yu Y (2018a) UMP kinase activity is involved in properchloroplast development in rice. Photosynth Res 137: 53–67.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Chen M, Herde M, Witte C-P (2016) Of the nine cytidine deaminase-like genes in Arabidopsis, eight are pseudogenes and only one isrequired to maintain pyrimidine homeostasis in vivo. Plant Physiol 171: 799–809.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Chen M, Urs MJ, Sánchez-González I, Olayioye MA, Herde M, Witte C-P (2018b) m6A RNA degradation products are catabolized by anevolutionarily conserved N6-Methyl-AMP deaminase in plant and mammalian cells. Plant Cell 30: 1511–1522.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Chen M, Witte C-P (2019) Functions and Dynamics of Methylation in Eukaryotic mRNA. In S Jurga, J Barciszewski, eds, The DNA, RNA,and Histone Methylomes. Springer International Publishing, Cham, pp. 333–351.Chen MJ, Thelen JJ (2011) Plastid uridine salvageactivity is required for photoassimilate allocation and partitioning in Arabidopsis. Plant Cell 23: 2991–3006.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Chen X, Zhu L, Xin L, Du K, Ran X, Cui X, Xiang Q, Zhang H, Xu P, Wu X (2015) Rice stripe1-2 and stripe1-3 mutants encoding the smallsubunit of ribonucleotide reductase are temperature sensitive and are required for chlorophyll biosynthesis. PloS One 10: e0130172.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Chiu T-Y, Lao J, Manalansan B, Loqué D, Roux SJ, Heazlewood JL (2015) Biochemical characterization of Arabidopsis apyrase familyreveals their roles in regulating endomembrane NDP/NMP homoeostasis. Biochem J 472: 43–54.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Choi J, Tanaka K, Cao Y, Qi Y, Qiu J, Liang Y, Lee SY, Stacey G (2014) Identification of a plant receptor for extracellular ATP. Science343: 290–294.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Clausen AR, Girandon L, Ali A, Knecht W, Rozpedowska E, Sandrini MP, Andreasson E, Munch-Petersen B, Piskur J (2012) Twothymidine kinases and one multisubstrate deoxyribonucleoside kinase salvage DNA precursors in Arabidopsis thaliana. FEBS J 279:3889–3897.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Clausen AR, Mutahir Z, Munch-Petersen B, Piškur J (2014) Plants salvage deoxyribonucleosides in mitochondria. Nucleosides,Nucleotides Nucleic Acids 33: 291–295.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Collier R, Tegeder M (2012) Soybean ureide transporters play a critical role in nodule development, function and nitrogen export.Plant J 72: 355–367.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Combes A, Lafleuriel J, Lefloch F (1989) The Inosine-Guanosine Kinase-Activity of Mitochondria in Tubers of Jerusalem Artichoke.Plant Physiol Biochem 27: 729–736.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
Cornelius S, Traub M, Bernard C, Salzig C, Lang P, Mohlmann T (2012) Nucleoside transport across the plasma membrane mediated byequilibrative nucleoside transporter 3 influences metabolism of Arabidopsis seedlings. Plant Biol 14: 696–705.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Cornelius S, Witz S, Rolletschek H, Mohlmann T (2011) Pyrimidine degradation influences germination seedling growth and productionof Arabidopsis seeds. J Exp Bot 62: 5623–5632.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Dahncke K, Witte CP (2013) Plant purine nucleoside catabolism employs a guanosine deaminase required for the generation ofxanthosine in Arabidopsis. Plant Cell 25: 4101–4109.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Dancer JE, Hughes RG, Lindell SD (1997) Adenosine-5'-phosphate deaminase. A novel herbicide target. Plant Physiol 114: 119–129.Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Daumann M, Fischer M, Niopek-Witz S, Girke C, Möhlmann T (2015) Apoplastic nucleoside accumulation in Arabidopsis leads toreduced photosynthetic performance and increased susceptibility against Botrytis cinerea. Front Plant Sci 6: 1158.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Daumann M, Hickl D, Zimmer D, DeTar RA, Kunz H-H, Möhlmann T (2018) Characterization of filament-forming CTP synthases fromArabidopsis thaliana. Plant J: 96: 316–328.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Del Vecchio HA, Ying S, Park J, Knowles VL, Kanno S, Tanoi K, She Y-M, Plaxton WC (2014) The cell wall-targeted purple acidphosphatase AtPAP25 is critical for acclimation of Arabidopsis thaliana to nutritional phosphorus deprivation. Plant J 80: 569–581.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Deng WW, Ashihara H (2010) Profiles of purine metabolism in leaves and roots of Camellia sinensis seedlings. Plant Cell Physiol 51:2105–2118.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Desimone M, Catoni E, Ludewig U, Hilpert M, Schneider A, Kunze R, Tegeder M, Frommer WB, Schumacher K (2002) A novelsuperfamily of transporters for allantoin and other oxo derivatives of nitrogen heterocyclic compounds in Arabidopsis. Plant Cell 14:847–856.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Diaz-Leal JL, Galvez-Valdivieso G, Fernandez J, Pineda M, Alamillo JM (2012) Developmental effects on ureide levels are mediated bytissue-specific regulation of allantoinase in Phaseolus vulgaris L. J Exp Bot 63: 4095–4106.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Díaz-Leal JL, Torralbo F, Antonio Quiles F, Pineda M, Alamillo JM (2014) Molecular and functional characterization of allantoateamidohydrolase from Phaseolus vulgaris. Physiol Plant 152: 43–58.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Dong Q, Zhang Y-X, Zhou Q, Liu Q-E, Chen D-B, Wang H, Cheng S-H, Cao L-Y, Shen X-H (2019) UMP Kinase Regulates ChloroplastDevelopment and Cold Response in Rice. Int J Mol Sci 20: 2107.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Doremus HD, Jagendorf AT (1985) Subcellular localization of the pathway of de novo pyrimidine nucleotide biosynthesis in pea leaves.Plant Physiol 79: 856–861.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Dorion S, Rivoal J (2015) Clues to the functions of plant NDPK isoforms. Naunyn-Schmiedeberg's Arch Pharmacol 388: 119–132.Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Dorion S, Rivoal J (2018) Plant nucleoside diphosphate kinase 1: A housekeeping enzyme with moonlighting activity. Plant SignalBehav 13: e1475804.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Feng X, Yang R, Zheng X, Zhang F (2012) Identification of a novel nuclear-localized adenylate kinase 6 from Arabidopsis thaliana as an www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
essential stem growth factor. Plant Physiol Biochem 61: 180–186.Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Floyd BE, Morriss SC, MacIntosh GC, Bassham DC (2015) Evidence for autophagy-dependent pathways of rRNA turnover inArabidopsis. Autophagy 11: 2199–2212.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Gaillard C, Moffatt BA, Blacker M, Laloue M (1998a) Male sterility associated with APRT deficiency in Arabidopsis thaliana results froma mutation in the gene APT1. Mol Gen Genet 257: 348–353.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Gaillard C, Moffatt BA, Blacker M, Laloue M (1998b) Male sterility associated with APRT deficiency in Arabidopsis thaliana results froma mutation in the gene APT1. Mol Gen Genet 257: 348–353.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Garton S, Knight H, Warren GJ, Knight MR, Thorlby GJ (2007) Crinkled leaves 8 - a mutation in the large subunit of ribonucleotidereductase - leads to defects in leaf development and chloroplast division in Arabidopsis thaliana. Plant J 50: 118–127.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Girke C, Daumann M, Niopek-Witz S, Möhlmann T (2014) Nucleobase and nucleoside transport and integration into plant metabolism.Front Plant Sci 5: 443.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Gorelova V, Lepeleire J de, van Daele J, Pluim D, Meï C, Cuypers A, Leroux O, Rébeillé F, Schellens JHM, Blancquaert D, Stove CP,van der Straeten D (2017) Dihydrofolate reductase/thymidylate synthase fine-tunes the folate status and controls redox homeostasis inplants. Plant cell 29: 2831–2853.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Gupta A, Sharma CB (1996) Purification to homogeneity and characterization of plasma membrane and Golgi apparatus-specific 5'-adenosine monophosphatases from peanut cotyledons. Plant Sci 117: 65–74.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Han BW, Bingman CA, Mahnke DK, Bannen RM, Bednarek SY, Sabina RL, Phillips GN (2006) Membrane association, mechanism ofaction, and structure of Arabidopsis embryonic factor 1 (FAC1). J Biol Chem 81: 14939–14947.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Hauck OK, Scharnberg J, Escobar NM, Wanner G, Giavalisco P, Witte C-P 2014) Uric acid accumulation in an Arabidopsis urate oxidasemutant impairs seedling establishment by blocking peroxisome maintenance. Plant Cell 26: 3090–3100.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Hooper CM, Castleden IR, Tanz SK, Aryamanesh N, Millar AH (2017) SUBA4: the interactive data analysis centre for Arabidopsissubcellular protein locations. Nucleic Acids Res 45: D1064-D1074.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Hu D, Li Y, Jin W, Gong H, He Q, Li Y (2017) Identification and characterization of a plastidic adenine nucleotide uniporter (OsBT1-3)required for chloroplast development in the early leaf stage of rice. Sci Rep 7.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Irani S, Todd CD (2016) Ureide metabolism under abiotic stress in Arabidopsis thaliana. J Plant Physiol 199: 87–95.Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Irani S, Todd CD (2018) Exogenous allantoin increases Arabidopsis seedlings tolerance to NaCl stress and regulates expression ofoxidative stress response genes. J Plant Physiol 221: 43–50.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Ito J, Batth TS, Petzold CJ, Redding-Johanson AM, Mukhopadhyay A, Verboom R, Meyer EH, Millar AH, Heazlewood JL (2011) Analysisof the Arabidopsis cytosolic proteome highlights subcellular partitioning of central plant metabolism. J Proteome Res 10: 1571-1582.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Jewell JB, Sowders JM, He R, Willis MA, Gang DR, Tanaka K (2019) Extracellular ATP Shapes a Defense-Related Transcriptome Both www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
Independently and along with Other Defense Signaling Pathways. Plant Physiol 179: 1144–1158.Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Jung B, Florchinger M, Kunz HH, Traub M, Wartenberg R, Jeblick W, Neuhaus HE, Mohlmann T (2009) Uridine-ribohydrolase is a keyregulator in the uridine degradation pathway of Arabidopsis. Plant Cell 21: 876–891.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Jung B, Hoffmann C, Mohlmann T (2011) Arabidopsis nucleoside hydrolases involved in intracellular and extracellular degradation ofpurines. Plant J 65: 703–711.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Kafer C, Zhou L, Santoso D, Guirgis A, Weers B, Park S, Thornburg R (2004) Regulation of pyrimidine metabolism in plants. FrontBiosci-Landmrk 9: 1611–1625.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Karran P, Lindahl T (1980) Hypoxanthine in deoxyribonucleic acid: generation by heat-induced hydrolysis of adenine residues andrelease in free form by a deoxyribonucleic acid glycosylase from calf thymus. Biochem 19: 6005–6011.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Katahira R, Ashihara H (2002) Profiles of pyrimidine biosynthesis, salvage and degradation in disks of potato (Solanum tuberosum L.)tubers. Planta 215: 821–828.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Katahira R, Ashihara H (2006) Profiles of purine biosynthesis, salvage and degradation in disks of potato (Solanum tuberosum L.)tubers. Planta 225: 115–126.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Kihara A, Saburi W, Wakuta S, Kim M-H, Hamada S, Ito H, Imai R, Matsui H (2011) Physiological and biochemical characterization ofthree nucleoside diphosphate kinase isozymes from rice (Oryza sativa L.). Biosci Biotechnol Biochem 75: 1740–1745.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Kirchberger S, Tjaden J, Neuhaus HE (2008) Characterization of the Arabidopsis Brittle1 transport protein and impact of reducedactivity on plant metabolism. Plant J 56: 51–63.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Kopecná M, Blaschke H, Kopecny D, Vigouroux A, Koncitíková R, Novák O, Kotland O, Strnad M, Moréra S, Schwartzenberg K von(2013) Structure and function of nucleoside hydrolases from Physcomitrella patens and maize catalyzing the hydrolysis of purine,pyrimidine, and cytokinin ribosides. Plant Physiol 163: 1568–1583.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Kumar V, Spangenberg O, Konrad M (2000) Cloning of the guanylate kinase homologues AGK-1 and AGK-2 from Arabidopsis thalianaand characterization of AGK-1. Eur J Biochem 267: 606–615.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Kurakawa T, Ueda N, Maekawa M, Kobayashi K, Kojima M, Nagato Y, Sakakibara H, Kyozuka J (2007) Direct control of shoot meristemactivity by a cytokinin-activating enzyme. Nature 445: 652 EP -.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Kuroha T, Tokunaga H, Kojima M, Ueda N, Ishida T, Nagawa S, Fukuda H, Sugimoto K, Sakakibara H (2009) Functional analyses ofLONELY GUY cytokinin-activating enzymes reveal the importance of the direct activation pathway in Arabidopsis. Plant Cell 21: 3152–3169.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Lamberto I, Percudani R, Gatti R, Folli C, Petrucco S (2010) Conserved alternative splicing of Arabidopsis transthyretin-like determinesprotein localization and S-allantoin synthesis in peroxisomes. Plant Cell 22: 1564–1574.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Lange PR, Geserick C, Tischendorf G, Zrenner R (2008) Functions of chloroplastic adenylate kinases in Arabidopsis. Plant Physiol 146:492–504.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from
Copyright © 2019 American Society of Plant Biologists. All rights reserved.
Google Scholar: Author Only Title Only Author and Title
Lee S, Doxey AC, McConkey BJ, Moffatt BA (2012) Nuclear targeting of methyl-recycling enzymes in Arabidopsis thaliana is mediated byspecific protein interactions. Mol Plant 5: 231–248.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Leroch M, Kirchberger S, Haferkamp I, Wahl M, Neuhaus HE, Tjaden J (2005) Identification and characterization of a novel plastidicadenine nucleotide uniporter from Solanum tuberosum. J Biol Chem 280: 17992–18000.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Lescano CI, Martini C, González CA, Desimone M (2016) Allantoin accumulation mediated by allantoinase downregulation and transportby ureide permease 5 confers salt stress tolerance to Arabidopsis plants. Plant Mol Biol 91: 581-595
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Lim MH, Wu J, Yao J, Gallardo IF, Dugger JW, Webb LJ, Huang J, Salmi ML, Song J, Clark G, Roux SJ (2014) Apyrase suppressionraises extracellular ATP levels and induces gene expression and cell wall changes characteristic of stress responses. Plant Physiol164: 2054–2067.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Lincker F, Philipps G, Chabouté M-E (2004) UV-C response of the ribonucleotide reductase large subunit involves both E2F-mediatedgene transcriptional regulation and protein subcellular relocalization in tobacco cells. Nucleic Acids Res 32: 1430–1438.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Liu S, Kracher B, Ziegler J, Birkenbihl RP, Somssich IE (2015) Negative regulation of ABA signaling by WRKY33 is critical forArabidopsis immunity towards Botrytis cinerea. eLife 4: e07295.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Liu XY, Qian WQ, Liu X, Qin HJ, Wang DW (2007) Molecular and functional analysis of hypoxanthine-guanine phosphoribosyltransferasefrom Arabidopsis thaliana. New Phytol 175: 448–461.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Luzarowski M, Kosmacz M, Sokolowska E, Jasinska W, Willmitzer L, Veyel D, Skirycz A (2017) Affinity purification with metabolomic andproteomic analysis unravels diverse roles of nucleoside diphosphate kinases. J Exp Bot 68: 3487–3499.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Ma X, Wang W, Bittner F, Schmidt N, Berkey R, Zhang L, King H, Zhang Y, Feng J, Wen Y, Tan L, Li Y, Zhang Q, Deng Z, Xiong X, Xiao S(2016) Dual and opposing roles of xanthine dehydrogenase in defense-associated reactive oxygen species metabolism in Arabidopsis.Plant Cell 28: 1108–1126.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Mainguet SE, Gakiere B, Majira A, Pelletier S, Bringel F, Guerard F, Caboche M, Berthome R, Renou JP (2009) Uracil salvage isnecessary for early Arabidopsis development. Plant J 60: 280–291.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Mansfield TA, Schultes NP, Mourad GS (2009) AtAzg1 and AtAzg2 comprise a novel family of purine transporters in Arabidopsis. FEBSLett 583: 481–486.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Moffatt B, Ashihara H (2002) Purine and pyrimdine nucleotide synthesis and metabolism, The Arabidopsis book. American Society ofPlant Biologists, Rockville, MD.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Moffatt B, Pethe C, Laloue M (1991) Metabolism of benzyladenine is impaired in a mutant of Arabidopsis thaliana lacking adeninephosphoribosyltransferase activity. Plant Physiol 95: 900–908.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Moffatt BA, Stevens YY, Allen MS, Snider JD, Pereira LA, Todorova MI, Summers PS, Weretilnyk EA, Martin-McCaffrey L, Wagner C(2002) Adenosine kinase deficiency is associated with developmental abnormalities and reduced transmethylation. Plant Physiol 128:812–821.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
Niopek-Witz S, Deppe J, Lemieux MJ, Möhlmann T (2014) Biochemical characterization and structure-function relationship of two plantNCS2 proteins, the nucleobase transporters NAT3 and NAT12 from Arabidopsis thaliana. Biochim Biophys Acta 1838: 3025–3035.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Niu M, Wang Y, Wang C, Lyu J, Wang Y, Dong H, Long W, Di Wang, Kong W, Wang L, Guo X, Sun L, Hu T, Zhai H, Wang H, Wan J (2017)ALR encoding dCMP deaminase is critical for DNA damage repair, cell cycle progression and plant development in rice. J Exp Bot 68:5773–5786.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Nizam S, Qiang X, Wawra S, Nostadt R, Getzke F, Schwanke F, Dreyer I, Langen G, Zuccaro A (2019) Serendipita indica E5′NTmodulates extracellular nucleotide levels in the plant apoplast and affects fungal colonization. EMBO Rep 20: e47430.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Nomura Y, Izumi A, Fukunaga Y, Kusumi K, Iba K, Watanabe S, Nakahira Y, Weber APM, Nozawa A, Tozawa Y (2014) Diversity inguanosine 3',5'-bisdiphosphate (ppGpp) sensitivity among guanylate kinases of bacteria and plants. J Biol Chem 289: 15631–15641.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Nourimand M, Todd CD (2019) There is a direct link between allantoin concentration and cadmium tolerance in Arabidopsis. PlantPhysiol Biochem 135: 441–449.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Ohler L, Niopek-Witz S, Mainguet SE, Möhlmann T (2019) Pyrimidine salvage: physiological functions and interaction with chloroplastbiogenesis. Plant Physiol 180: 1816–1828
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Osugi A, Kojima M, Takebayashi Y, Ueda N, Kiba T, Sakakibara H (2017) Systemic transport of trans-zeatin and its precursor havediffering roles in Arabidopsis shoots. Nat Plants 3: 17112.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Pedroza-García J-A, Nájera-Martínez M, Mazubert C, Aguilera-Alvarado P, Drouin-Wahbi J, Sánchez-Nieto S, Gualberto JM, Raynaud C,Plasencia J (2019) Role of pyrimidine salvage pathway in the maintenance of organellar and nuclear genome integrity. Plant J 97: 430–446.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Pessoa J, Sarkany Z, Ferreira-da-Silva F, Martins S, Almeida MR, Li JM, Damas AM (2010) Functional characterization of Arabidopsisthaliana transthyretin-like protein. BMC Plant Biol 10: 30.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Phillips DA, Joseph CM, Hirsch PR (1997) Occurrence of flavonoids and nucleosides in agricultural soils. Appl Environ Microbiol 63:4573–4577.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Quiles FA, Galvez-Valdivieso G, Guerrero-Casado J, Pineda M, Piedras P (2019) Relationship between ureidic/amidic metabolism andantioxidant enzymatic activities in legume seedlings. Plant Physiol Biochem 138: 1–8.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Rapp M, Schein J, Hunt KA, Nalam V, Mourad GS, Schultes NP (2016) The solute specificity profiles of nucleobase cation symporter 1(NCS1) from Zea mays and Setaria viridis illustrate functional flexibility. Protoplasma 253: 611–623.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Redillas MCFR, Bang SW, Lee D‐K, Kim YS, Jung H, Chung PJ, Suh J‐W, Kim J‐K (2019) Allantoin accumulation throughoverexpression of ureide permease1 improves rice growth under limited nitrogen conditions. Plant Biotechnol J 17: 1289–1301.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Regierer B, Fernie AR, Springer F, Perez-Melis A, Leisse A, Koehl K, Willmitzer L, Geigenberger P, Kossmann J (2002) Starch contentand yield increase as a result of altering adenylate pools in transgenic plants. Nat Biotechnol 20: 1256–1260.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Rieder B, Neuhaus HE (2011) Identification of an Arabidopsis plasma membrane-located ATP transporter important for antherdevelopment. Plant Cell 23: 1932–1944.
www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Riegler H, Geserick C, Zrenner R (2011) Arabidopsis thaliana nucleosidase mutants provide new insights into nucleoside degradation.New Phytol 191: 349–359.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Riewe D, Grosman L, Fernie AR, Wucke C, Geigenberger P (2008a) The potato-specific apyrase is apoplastically localized and hasinfluence on gene expression, growth, and development. Plant Physiol 147: 1092–1109.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Riewe D, Grosman L, Fernie AR, Zauber H, Wucke C, Geigenberger P (2008b) A cell wall-bound adenosine nucleosidase is involved inthe salvage of extracellular ATP in Solanum tuberosum. Plant Cell Physiol 49: 1572–1579.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Riggs JW, Rockwell NC, Cavales PC, Callis J (2016) Identification of the plant ribokinase and discovery of a role for Arabidopsisribokinase in nucleoside metabolism. J Biol Chem 291: 22572–22582.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Romanov GA, Lomin SN, Schmülling T (2018) Cytokinin signaling: from the ER or from the PM? That is the question! New Phytol 218:41–53.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Ronceret A, Gadea-Vacas J, Guilleminot J, Lincker F, Delorme V, Lahmy S, Pelletier G, Chabouté M-E, Devic M (2008) The first zygoticdivision in Arabidopsis requires de novo transcription of thymidylate kinase. Plant J 53: 776–789.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Sabina RL, Paul AL, Ferl RJ, Laber B, Lindell SD (2007) Adenine nucleotide pool perturbation is a metabolic trigger for AMP deaminaseinhibitor-based herbicide toxicity. Plant Physiol 143: 1752–1760.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Sakakibara H (2005) Cytokinin biosynthesis and regulation. Vitam Horm 72: 271–287.Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Sauge-Merle S, Falconet D, Fontecave M (1999) An active ribonucleotide reductase from Arabidopsis thaliana - Cloning, expressionand characterization of the large subunit. Eur J Biochem 266: 62–69.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Sauter M, Moffatt B, Saechao MC, Hell R, Wirtz M (2013) Methionine salvage and S-adenosylmethionine: essential links betweensulfur, ethylene and polyamine biosynthesis. Biochem J 451: 145–154.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Schmid L-M, Ohler L, Möhlmann T, Brachmann A, Muiño JM, Leister D, Meurer J, Manavski N (2019) PUMPKIN, the sole plastid UMPkinase, associates with group II introns and alters their metabolism. Plant Physiol 179: 248–264.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Schmidt A, Baumann N, Schwarzkopf A, Frommer WB, Desimone M (2006) Comparative studies on ureide permeases in Arabidopsisthaliana and analysis of two alternative splice variants of AtUPS5. Planta 224: 1329–1340.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Schmidt A, Su YH, Kunze R, Warner S, Hewitt M, Slocum RD, Ludewig U, Frommer WB, Desimone M (2004) UPS1 and UPS2 fromArabidopsis mediate high affinity transport of uracil and 5-fluorouracil. J Biol Chem 279: 44817–44824.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Schmülling T, Werner T, Riefler M, Krupková E, Bartrina y Manns I (2003) Structure and function of cytokinin oxidase/dehydrogenasegenes of maize, rice, Arabidopsis and other species. J Plant Res 116: 241–252.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Schoor S, Farrow S, Blaschke H, Lee S, Perry G, Schwartzenberg K von, Emery N, Moffatt B (2011) Adenosine kinase contributes tocytokinin interconversion in Arabidopsis. Plant Physiol 157: 659–672.
Pubmed: Author and Title www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
Google Scholar: Author Only Title Only Author and Title
Schroeder RY, Zhu A, Eubel H, Dahncke K, Witte C-P (2018) The ribokinases of Arabidopsis thaliana and Saccharomyces cerevisiae arerequired for ribose recycling from nucleotide catabolism, which in plants is not essential to survive prolonged dark stress. New Phytol217: 233–244.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Serventi F, Ramazzina I, Lamberto I, Puggioni V, Gatti R, Percudani R (2010) Chemical basis of nitrogen recovery through the ureidepathway. Formation and hydrolysis of S-ureidoglycine in plants and bacteria. ACS Chem Biol 5: 203–214.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Sharma CB, Mittal R, Tanner W (1986) Purification and properties of a glycoprotein adenosine 5′-monophosphatase from the plasmamembrane fraction of Arachis hypogaea cotyledons. Biochim Biophys Acta 884: 567–577.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Shelp BJ, Atkins CA (1983) Role of Inosine monophosphate oxidoreductase in the formation of ureides in nitrogen-fixing nodules ofcowpea (Vigna-unguiculata-L Walp). Plant Physiol 72: 1029–1034.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Sigel H, Operschall BP, Griesser R (2009) Xanthosine 5 '-monophosphate (XMP). Acid-base and metal ion-binding properties of achameleon-like nucleotide. Chem Soc Rev 38: 2465–2494.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Siu KKW, Lee JE, Sufrin JR, Moffatt BA, McMillan M, Cornell KA, Isom C, Howell PL (2008) Molecular determinants of substratespecificity in plant 5'-methylthioadenosine nucleosidases. J Mol Biol 378: 112–128.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Smith PM, Atkins CA (2002) Purine biosynthesis. Big in cell division, even bigger in nitrogen assimilation. Plant Physiol 128: 793–802.Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Soltabayeva A, Srivastava S, Kurmanbayeva A, Bekturova A, Fluhr R, Sagi M (2018) Early senescence in older leaves of low nitrate-grown Atxdh1 uncovers a role for purine catabolism in N supply. Plant Physiol 178: 1027–1044.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Spetea C, Lundin B (2012) Evidence for nucleotide-dependent processes in the thylakoid lumen of plant chloroplasts-an update. FEBSLett 586: 2946–2954.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Stasolla C, Katahira R, Thorpe TA, Ashihara H (2003) Purine and pyrimidine nucleotide metabolism in higher plants. J Plant Physiol 160:1271–1295.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Stitt M, Lilley RM, Heldt HW (1982) Adenine-nucleotide levels in the cytosol, chloroplasts, and mitochondria of wheat leaf protoplasts.Plant Physiol 70: 971–977.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Sugimoto H, Kusumi K, Noguchi K, Yano M, Yoshimura A, Iba K (2007) The rice nuclear gene, VIRESCENT 2, is essential for chloroplastdevelopment and encodes a novel type of guanylate kinase targeted to plastids and mitochondria. Plant J 52: 512–527.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Sukrong S, Yun K-Y, Stadler P, Kumar C, Facciuolo T, Moffatt BA, Falcone DL (2012) Improved growth and stress tolerance in theArabidopsis oxt1 mutant triggered by altered adenine metabolism. Mol Plant 5: 1310–1332.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Tegeder M (2014) Transporters involved in source to sink partitioning of amino acids and ureides. Opportunities for cropimprovement. J Exp Bot 65: 1865–1878.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Tintemann H, Wasternack C, Benndorf R, Reinbothe H (1985) The rate-limiting step of uracil degradation in tomato cell-suspensioncultures and Euglena-gracilis invivo studies. Comp Biochem Physiol, Part B: Biochem Mol Biol 82: 787–792.
Pubmed: Author and Title www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
Google Scholar: Author Only Title Only Author and Title
Todd CD, Polacco JC (2006) AtAAH encodes a protein with allantoate amidohydrolase activity from Arabidopsis thaliana. Planta 223:1108–1113.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Torres RJ, Puig JG (2007) Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome. Orphanet JRare Dis. 2: 48.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Traub M, Florchinger M, Piecuch J, Kunz HH, Weise-Steinmetz A, Deitmer JW, Neuhaus HE, Mohlmann T (2007) The fluorouridineinsensitive 1 (fur1) mutant is defective in equilibrative nucleoside transporter 3 (ENT3), and thus represents an important pyrimidinenucleoside uptake system in Arabidopsis thaliana. Plant J 49: 855–864.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Tripathi D, Zhang T, Koo AJ, Stacey G, Tanaka K (2017) Extracellular ATP acts on jasmonate signaling to reinforce plant defense. PlantPhysiol 176: 511–523.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Ullrich A, Knecht W, Piskur J, Loffler M (2002) Plant dihydroorotate dehydrogenase differs significantly in substrate specificity andinhibition from the animal enzymes. FEBS Lett 529: 346–350.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Urarte E, Esteban R, Moran JF, Bittner F (2015) Established and proposed roles of xanthine oxidoreductase in oxidative and reductivepathways in plants. In KJ Gupta, AU Igamberdiev, eds, Reactive oxygen and nitrogen species signaling and communication in plants.Springer, Cham, Switzerland, pp. 15–42.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Wagner KG, Backer AI (1992) Dynamics of nucleotides in plants studied on a cellular basis. In JK W, F M, eds, International Review ofCytology Vol. 134, pp. 1–84.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Walsh TA, Green SB, Larrinua IM, Schmitzer PR (2001) Characterization of plant beta-ureidopropionase and functional overexpressionin Escherichia coli. Plant Physiol 125: 1001–1011.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Wang L, Li Z, Qian W, Guo W, Gao X, Huang L, Wang H, Zhu H, Wu JW,Wang D, Liu D (2011) The Arabidopsis purple acid phosphataseAt-PAP10 is predominantly associated with the root surface and plays an important role in plant tolerance to phosphate limitation. PlantPhysiol 157: 1283–1299.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Wang C, Liu Z (2006) Arabidopsis ribonucleotide reductases are critical for cell cycle progression, DNA damage repair, and plantdevelopment. Plant Cell 18: 350–365.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Wang C, Zhou M, Zhang X, Yao J, Zhang Y, Mou Z (2017) A lectin receptor kinase as a potential sensor for extracellular nicotinamideadenine dinucleotide in Arabidopsis thaliana. eLife 6: e25474
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Watanabe S, Matsumoto M, Hakomori Y, Takagi H, Shimada H, Sakamoto A (2014) The purine metabolite allantoin enhances abioticstress tolerance through synergistic activation of abscisic acid metabolism. Plant Cell Environ 37: 1022–1036.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Wei X, Song X, Wei L, Tang S, Sun J, Hu P, Cao X (2017) An epiallele of rice AK1 affects photosynthetic capacity. J Integr Plant Biol 59:158–163.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Werner AK, Medina-Escobar N, Zulawski M, Sparkes IA, Cao F-Q, Witte CP (2013) The ureide-degrading reactions of purine ringcatabolism employ three amidohydrolases and one aminohydrolase in Arabidopsis, soybean, and rice. Plant Physiol 163: 672–681.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
Werner AK, Romeis T, Witte CP (2010) Ureide catabolism in Arabidopsis thaliana and Escherichia coli. Nat Chem Biol 6: 19–21.Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Werner AK, Sparkes IA, Romeis T, Witte CP (2008) Identification, biochemical characterization, and subcellular localization of allantoateamidohydrolases from Arabidopsis and soybean. Plant Physiol 146: 418–430.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Werner AK, Witte CP (2011) The biochemistry of nitrogen mobilization: purine ring catabolism. Trends Plant Sci 16: 381–387.Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Witz S, Jung B, Furst S, Mohlmann T (2012) De novo pyrimidine nucleotide synthesis mainly occurs outside of plastids, but a previouslyundiscovered nucleobase importer provides substrates for the essential salvage pathway in Arabidopsis. Plant Cell 24: 1549–1559.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Wu S, Alseekh S, Cuadros-Inostroza A, Fusari CM, Mutwil M, Kooke R, Keurentjes JB, Fernie AR, Willmitzer L, Brotman Y (2016)Combined use of genome-wide association data and correlation networks unravels key regulators of primary metabolism inArabidopsis thaliana. PLoS GENET 12.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Xu J, Deng Y, Li Q, Zhu X, He Z (2014) STRIPE2 encodes a putative dCMP deaminase that plays an important role in chloroplastdevelopment in rice. J Genet Genomics 41: 539–548.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Xu J, Zhang HY, Xie CH, Xue HW, Dijkhuis P, Liu CM (2005) EMBRYONIC FACTOR 1 encodes an AMP deaminase and is essential forthe zygote to embryo transition in Arabidopsis. Plant J 42: 743–756.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Xu J, Zhang L, Yang D-L, Li Q, He Z (2015) Thymidine kinases share a conserved function for nucleotide salvage and play an essentialrole in Arabidopsis thaliana growth and development. New Phytol 208: 1089–1103.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Yamada H, Suzuki T, Terada K, Takei K, Ishikawa K, Miwa K, Yamashino T, Mizuno T (2001) The Arabidopsis AHK4 histidine kinase is acytokinin-binding receptor that transduces cytokinin signals across the membrane. Plant Cell Physiol 42: 1017–1023.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Ye W, Hu S, Wu L, Ge C, Cui Y, Chen P, Wang X, Xu J, Ren D, Dong G, Qian Q, Guo L (2016) White stripe leaf 12 (WSL12), encoding anucleoside diphosphate kinase 2 (OsNDPK2), regulates chloroplast development and abiotic stress response in rice (Oryza sativa L.).Mol Breeding 36: 57.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Yin Y, Katahira R, Ashihara H (2014) Metabolism of purine nucleosides and bases in suspension-cultured Arabidopsis thaliana cells.Eur Chem Bull 3: 925–934.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Young LS, Harrison BR, Narayana, M. U. M., Moffatt BA, Gilroy S, Masson PH (2006) Adenosine kinase modulates root gravitropism andcap morphogenesis in arabidopsis. Plant Physiol 142: 564–573.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Zarepour M, Kaspari K, Stagge S, Rethmeier R, Mendel RR, Bittner F (2010) Xanthine dehydrogenase AtXDH1 from Arabidopsisthaliana is a potent producer of superoxide anions via its NADH oxidase activity. Plant Mol Biol 72: 301–310.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Zhang T, Feng P, Li Y, Yu P, Yu G, Sang X, Ling Y, Zeng X, Li Y, Huang J, Zhang T, Zhao F, Wang N, Zhang C, Yang Z, Wu R, He G (2018)VIRESCENT-ALBINO LEAF 1 regulates leaf colour development and cell division in rice. J Exp Bot 69: 4791–4804.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Zhang X, Chen Y, Lin X, Hong X, Zhu Y, Li W, He W, An F, Guo H (2013) Adenine phosphoribosyl transferase 1 is a key enzymecatalyzing cytokinin conversion from nucleobases to nucleotides in Arabidopsis. Mol Plant 6: 1661–1672.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.
Zhou K, Xia J, Wang Y, Ma T, Li Z (2017) A Young Seedling Stripe2 phenotype in rice is caused by mutation of a chloroplast-localizednucleoside diphosphate kinase 2 required for chloroplast biogenesis. Genet Mol Biol 40: 630–642.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Zhou L, Lacroute F, Thornburg R (1998) Cloning, expression in Escherichia coli, and characterization of Arabidopsis thaliana UMP/CMPkinase. Plant Physiol 117: 245–254.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Zhu X, Guo S, Wang Z, Du Q, Xing Y, Zhang T, Shen W, Sang X, Ling Y, He G (2016) Map-based cloning and functional analysis of YGL8,which controls leaf colour in rice (Oryza sativa). BMC Plant Biol 16: 134.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Zrenner R, Ashihara H (2011) Nucleotide Metabolism. In H Ashihara, A Crozier, A Komamine, eds, Plant metabolism and biotechnology.Wiley, Cambridge, New York, pp. 135–162.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Zrenner R, Riegler H, Marquard CR, Lange PR, Geserick C, Bartosz CE, Chen CT, Slocum RD (2009) A functional analysis of thepyrimidine catabolic pathway in Arabidopsis. New Phytol 183: 117–132.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
Zrenner R, Stitt M, Sonnewald U, Boldt R (2006) Pyrimidine and purine biosynthesis and degradation in plants. Annu Rev Plant Biol 57:805–836.
Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title
www.plantphysiol.orgon April 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.