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5. Polyketides5. Polyketides
RA Macahig
FM Dayrit
5. Polyketides (Dayrit) 2
• Polyketides rank among the largest group of secondary metabolites in terms of diversity of structure and biological diversity.
• Polyketide biosynthesis shares some similarities with the initial steps of fatty acid acetyl polymerization. Like the fats, the polyketide pathway probably arose early in biological evolution before the rise of plants.
Introduction• Polyketides (which literally means “many ketone groups”)
make up a diverse biogenetic group which starts from acetyl-CoA to form a linear chain without extensive reduction. The polyketide chain can cyclize to form aromatic rings or undergo extensive derivatization.
5. Polyketides (Dayrit) 3
Examples of polyketide natural products which illustrate the wide variety of structures which comprise this group.
CH3
CO2H
OHHO
orsellinic acid
O
HO
O
OH
OH
alternariolfrom the mould Alternaria tenius
OH3C
O
OOCH3
CH3O
Cl
OCH3
griseofulvinfrom Penicillium griseofulvum
O O
O
O
O
OCH3
aflatoxin B1from Apergillus species
O
O
OH
CH3
ORCH3
OR
CH3
O
H3C
HO
H3C CH3
macrolide antibioticerythromycin-typefrom Streptomyces species
5. Polyketides (Dayrit) 4
• The polyketides have great diversity of structures and chemical functionalities. These structures range from saturated macrocyclic lactones (macrolides), which are unique polyketide metabolites, to various types of aromatic compounds.
Introduction
• Polyketides occur widely in bacteria, fungi and lichens, but are of relatively minor occurrence in higher plants. Bacteria, in particular Actinomycetes and Cyanobacteria, are prolific sources of polyketides, many of which possess antibiotic activity. Other significant polyketide producers are Aspergillus (aflatoxins) and Penicillium and Streptomyces species (tetracycline antibiotics).
5. Polyketides (Dayrit) 5
Polyketides are produced from poly-acetyl intermediates (poly-1,3-diketo compounds) which do not undergo complete reduction, as in the case of the fats. The polyketides then branch into two major pathways:
Overview of polyketide biosynthesis
1. Aromatic compounds. The reactive 1,3-diketo groups undergo intramolecular Claisen or lactonization reactions forming cyclic compounds. Dehydration produces aromatic compounds.
2. Macrolides. The keto- groups are reduced to alcohols, which are subsequently dehydrated to form linear compounds. The final products are macrocyclic esters. Macrolides generally >12 carbon atoms in the ring.
5. Polyketides (Dayrit) 6
S-CoAC
CH2
CCH2
CCH2
CH3C
OOOO
a ab b
c cdd
a
87
6 5 4 3 2 1
Claisen6 1
b
Aldol2 7
cd
C
CH3
O
OHHO
OH
xanthoxylin(a phloroglucinol)
CH3
CO2H
OHHO
(8)
(1)
(8)
(1)
orsellinic acid(a resorcinol)
O
HO O
CH2
C
CH3
O
(an -pyrone)
O
O
H3C CH2CO2H
(1)
(1)
(8)
(8)
(a -pyrone)
O
O
O
S-CoA
OS-CoA
O
OO
O O
O
S-CoAO
O O S-CoA
O
O
O
Aromatic polyketides. Major cyclization pathways for a tetraketide followed by aromatization.
5. Polyketides (Dayrit) 7
Biosynthetic studies on polyketides (Arthur Birch)
4 x H3C
CO
O
_
*
*#
ratio: 14C # 1
--------- = ----18O * 2
S-CoA
O O O O* * * *
# # # #
# 1
------ = ---- * 1
O O
OH
S-CoA
O
* *
**
#
#
#
#-H O*2#
#
#
#
*
**HO OH
CH3O
OH
# 4
------ = ---- * 3
orsellinic acid
The elucidation of the polyketide pathway was pioneered by Arthur Birch in 1953. Birch used 14C and 18O-labeled acetate which he fed to microorganisms to establish the incorporation pattern and from this to postulate the steps in the biosynthesis of polyketides.
5. Polyketides (Dayrit) 8
Birch proposal for polyketide biosynthesis:
Overview of polyketide biosynthesis
1. Starting with a starter unit, C2 units are added to form the polyketide chain (chain assembly).
2. Reduction and/or alkylation of the polyketide chain before cyclization.
3. Intra- or intermolecular cyclization. (The more common pathway is intramolecular cyclization.)
4. Secondary processes which modify the intermediate product after cyclization, such as: halogenation, O-methylation, C-methylation, reduction, oxidation, decarboxylation and skeletal rearrangement.
5. Polyketides (Dayrit) 9
Variations in number of C2 units and mode of cyclization Starting polyketide Secondary metabolite
O
HO
O
triketide:
o
o
o
tetraketides:
o
oo
o
oo
o o
CH3
CO2H
OHHO
orsellinic acid
(1)
xanthoxylin(1)
OH
CH3
O
OHHO
Short-hand representation of polyketides:
CH3
S-CoAO
O
O O
a tetraketide
o
o o
=
o
5. Polyketides (Dayrit) 10
Starting polyketide Secondary metabolite
OH
CH3
O
HOCO2H(1)
curvulinic acid(Curvularia siddiqui)
(1) O
O
CH3HO
OH
oo
o o
o
o o
o
pentaketides:
o
o
OH O
OHO CH3(1)
o
o
o
o
o
Variations in number of C2 units and mode of cyclization
hexaketide:
oo
oo
o o
O OH
CH3CH3O
OH O
diaporthin(Endothia parasitica)
5. Polyketides (Dayrit) 11
Starting polyketide Secondary metabolite
monocerin(Helminthosporium
monoceras)
oo
o o
o o
heptaketide:
o
O
CH3O
OH O
O
CH3O
oo
o o o
oogriseofulvin(Penicillium
griseofulvum)OH3C
O
OOCH3
CH3O
Cl
OCH3
o
o
o
o
o
o
o
O
CH3
OH
O
HO
HO
alternariol(Alternaria tenius)
Variations in number of C2 units and mode of cyclization
5. Polyketides (Dayrit) 12
Starting polyketide Secondary metaboliteoctaketide:
oo
oo
o oCH3HO
OH O
O
CO2H
endocrocin(Centralia endocrocea)
o o
oo
oo
o o
o
o
O
HO
HO
O
O
curvularin(Curvularia spp.))
Variations in number of C2 units and mode of cyclization
nonaketide:
o
o
oo
o o
O
O
HO
Cl
OCH3
O
HO
radiciciol(Nectaria radiciola)
o o
o
ooooo
o o o o OH
CH3
O
O
CH3O
HO OH
nalgiovensin(Penicillium
nalgiovensis)
5. Polyketides (Dayrit) 13
Inter- vs. intramolecular
cyclization:
A. Colletodiol;
B. Use of labeling
experiments to distinguish intra- from
intermolecular
cyclization.
o o o
o o o o
O O
O
O
OHOH
colletodiol
A. Example of intermolecular cyclization.
B. Use of labeling experiment to distinguish inter- vs. intramolecular cyclization.
o
ooo
oo
o
o o o o
oooo
[Me*]
OH OH O
*-CO2
2-2CO
5. Polyketides (Dayrit) 14
(from: The World of Polyketides, http://linux1.nii.res.in/)
Biosynthesis of macrolides:
Step-wise chemical
transformations and enzymes.
5. Polyketides (Dayrit) 15
Hypothetical scheme of the biosynthesis of
phenol polyketides
on the
Polyketide Synthase
(PKS) multienzyme
complex.
multi-enzyme complex
HS HS HS HS HS H3C S-CoA
O
S
O
HSHSHSHSS-CoA
O
O2C_
4 x
S
O2C
O
S
O
__
S
O2C
O
_
S
O2C
O
__
S
O2C
O
S
O2C
O
__
S
O2C
O
_
S
O2C
O
_
S
O
o
HS
*
*
*
HSHSHSHSS
O
O
O
*
O
o
S
OO
O
O
O
_
base_
SO
O
O
OH
O
HO
OH
CO2H
O
*
*
*
5. Polyketides (Dayrit) 16
Polyketide synthase (PKS)
The PKS family share a number of characteristics with the family of fatty acid synthases (FAS): the PKS is a multienzyme complex which is arranged so that the stepwise transformations are carried out sequentially.
Hypothetical model for one type of PKS multienzyme system which produces 6-methylsalicylic acid and lovastatin. The growing chain is assembled on two multienzyme complexes.
• ACP: acyl carrying protein• KS: -keto acyl synthase• MAT: malonyl (acyl) transferase• DH: dehydratase• ER: enoyl reductase• KR: keto reductase• TE: thiol esterase(from: The World of Polyketides, http://linux1.nii.res.in/)
H3C
O
O
CH3 CH3
O
O OH
Lovastatin
CO2H
H3C OH
6-Methylsalicylic acid
The biosynthetic pathway for the fungal polyketide 6-methylsalicylic acid (6-MSA). 6-MSA is assembled from four ketide units (one acetate and three malonates). 6-MSAS contains the following domains (in order): KS, MAT, DH, KR and ACP. These act repeatedly to catalyse three rounds of chain extension, carrying out different levels of reductive processing at each stage. The first condensation is followed by reaction with a second equivalent of malonate extender unit, while the second condensation is followed by reduction and dehydration of the newly-formed keto group. After the third cycle, the chain undergoes cyclisation, dehydration and enolisation. The absence of a thioesterase domain suggests that release of the chain from the PKS does not occur by hydrolysis but by an alternative mechanism which is still not verified. (Staunton and Weismann, Nat. Prod. Rep., 2001, 18, 380–416)
KS: ketosynthase MAT: malonyl-acetyl transferase DH: dehydratase KR: ketoreductaseACP: acyl carrier protein
5. Polyketides (Dayrit) 18
Biosynthesis of macrolides on a modular Polyketide Synthase (PKS) multienzyme complex.
(from: The World of Polyketides, http://linux1.nii.res.in/)
5. Polyketides (Dayrit) 19
Domain organization of the erythromycin polyketide synthase. Putative domains are represented as circles. Each module incorporates the essential KS, AT and ACP domains, while all but one include optional reductive activities (KR, DH, ER).
The one-to-one correspondence between domains and biosynthetic transformations explains how programming is achieved in this modular PKS. (Staunton and Weismann, Nat. Prod. Rep., 2001, 18, 380–416)
5. Polyketides (Dayrit) 20
Predicted domain organization of the 6-deoxyerythronolide B synthase (DEBS) proteins. KR indicates the inactive ketoreductase domain. The ruler shows the residue number within the primary structure of the constituent proteins. The linker regions are also given in proportion. (Staunton and Weismann, Nat. Prod. Rep., 2001, 18, 380–416)
KS: ketosynthase AT: acyltransferase DH: dehydratase ER: enoyl reductase KR: ketoreductaseACP: acyl carrier proteinTE: thioesterase
5. Polyketides (Dayrit) 21
Inactivation of KR5 of DEBS results in the production of erythromycin analogues with keto groups at the C-5 position. (Staunton and Weismann, Nat. Prod. Rep., 2001, 18, 380–416)
KS: ketosynthase AT: acyltransferase DH: dehydratase ER: enoyl reductase KR: ketoreductaseACP: acyl carrier proteinTE: thioesterase
5. Polyketides (Dayrit) 22
Inactivation of ER4 results in an analogue of erythromycin with a double bond at the expected site. (Staunton and Weismann, Nat. Prod. Rep., 2001, 18, 380–416)
KS: ketosynthase AT: acyltransferase DH: dehydratase ER: enoyl reductase KR: ketoreductase ACP: acyl carrier proteinTE: thioesterase
5. Polyketides (Dayrit) 23
Domain organization of the rapamycin polyketide synthase (RAPS). As with the erythromycin PKS there is a co-linearity between the sequence of modules and the order of biosynthetic steps. (Staunton and Weismann, Nat. Prod. Rep., 2001, 18, 380–416)
5. Polyketides (Dayrit) 24
What is the link between FAS and PKS?
The PKS system is likely derived from bacterial FAS. Different PKS pathways in bacteria illustrate the selective evolutionary advantage that multiple secondary metabolite biosyntheses confer to individual bacteria and taxonomic kingdoms.
KS: ketoacyl synthaseAT: acyl transferaseDH: dehydrataseER: enoyl reductaseACP: acyl carrying protein
Organization of fatty acid synthases (FAS) and polyketide synthases (PKS). (Jenke-Kodama et al. J Mol Bio Evol 2005)
5. Polyketides (Dayrit) 25
What is the link between FAS and PKS?
Enzymes in a PKS module. (Jenke-Kodama et al. J Mol Bio Evol 2005)
Common sequence of reactions performed by FAS and PKS.
KS: ketoacyl synthaseACP: acyl carrying proteinKR: ketoreductaseDH: dehydrataseER: enoyl reductase
5. Polyketides (Dayrit) 26
Four proteins comprise the minimal PKS: ketosynthase (KS), chain length factor (CLF), acyl carrier protein (ACP), and a malonyl-CoA:ACP transacylase (MAT) which is usually recruited from fatty acid synthases. Other common enzymes include: aromatase (ARO) and cyclase (CYC). (Ridley et al., PNAS, 2008, 105:4595-4600)
-O2C
S-CoA
O
starter unit
min PKS
R
O
OO
O
O O O
SACP
OKS-CLF
R
O
OO
O
O O
SACP
O
OH
15
9
C-9 KR
9
R
O
OO
HO
O O
SACP
O
OH
ARO
R
O
OOH
O O
SACP
OCYC
R
O
OOH
O
S-ACP
O5
common aromatic intermediate principal common intermediatewith varying R group
Common enzymes in aromatic polyketides
5. Polyketides (Dayrit) 27
“Deciphering the mechanism for the assembly of aromaticpolyketides by a bacterial polyketide synthase,” Shen and Hutchinson, Proc. Natl.
Acad. Sci. USA, 93, 6600-6604, June 1996.
Acyl-CoA +9 Mal-CoA
TcmJKLM
CH3
O
OOO
O
O O O
O
SCoA
OTcmN
unidentified productsaberrantcyclization
CH3
CO2HO
OH
OHOHOH
HO
Tcm F2
Tcm F1
CH3
CO2H
OH
OHOOH
HO
TcmI
TcmH
CH3
CO2H
OH
OHOOH
HO
O
Tcm D3Tcm B3
CH3
CO2H
OH
OHOOH
CH3O
O
TcmN
Tetracenomycin PKS J K L M N
7 kb0
The optimal Tcm PKS is a complex consisting of the TcmJKLMN proteins. It is the integrity of this complex that maximizes the efficiency for the synthesis of aromatic polyketides from acetyl- and malonyl-CoA.
5. Polyketides (Dayrit) 28
Polyketide modifications: before cyclization and after cyclization (secondary processes). Note: F: fungi; P: plant refers to the biological system where the process has been studied. The number of marks denote frequency of occurrence; denotes not observed.
Modification Before cyclization After cyclization (Secondary process)
1. reduction (F) ? 2. oxidation (F,P) 3. C-methyation (F) 4. O-methylation (F,P) 5. C-prenylation (F,P) (F,P) 6. O-prenylation (P) 7. C-glycosylation (P) 8. O-glycosylation (P) 9. decarboxylation 10. aromatic radical coupling • The various Kingdoms exhibit different characteristics of their PKS enzymes. In the microbial kingdom, at least three types of PKS enzymes have been recognized.
5. Polyketides (Dayrit) 29
Reduction and alkylation of the polyketide chain before cyclization. The polyketide can be reduced to the alcohol and be subsequently dehydrated to produce the double bond. The resulting aromatic ring will not have a OH substituent in the particular position.
S-CoA
O
+ 2 x S-CoA
O
O2C_
S-CoA
O O O
1. NADPH2. -H O2
S-CoA
O
O_
S-CoA
O
O2C
O
O
S-CoA
O
o
o
o
CH3
CO2H
OH
6-methylsalicylic acidfrom Penicillium urticae
5. Polyketides (Dayrit) 30
Reduction and alkylation of the polyketide chain before cyclization. The polyketide can be C-alkylated (e.g., with methyl or isopentyl groups) prior to cyclization although it may be difficult to determine whether C-alkylation is carried out before or after cyclization.
oo
o o
[CH ]3
3[CH ]
CH3
OH
H3C
HO
CH3
O
clavatol
CH3
OH
HO
O
CH3
OH
H3C
HO
O
5. Polyketides (Dayrit) 31
Secondary processes: examples of oxidation, decarboxylation and methylation.
6-methylsalicylic acid
CH3
CO2H
OH
[O]
CHO
CO2H
OH
-CO2
CHO
OH
CO2H
OH
HO
[O]
gentisic acid
A. Gentisic acid
B. Fumigatin
fumigatin
[CH ]
CH3
OH
OCH3
HO
HO2-CO
CH3
OHHO
1. [O]2.
CH3
CO2H
OHHO
orsellinic acid
3 [O]
CH3
O
OCH3
HO
O
5. Polyketides (Dayrit) 32
Erythromycin, first isolated from Streptomyces
erythreus from soil samples from Iloilo
sent by Abelardo Aguilar in 1949. It was first marketed
by Eli Lilly as Ilosone®.
R.B.Woodward accomplished its
stereospecific synthesis in 1981.
It is used for the treatment of gram-
positive bacterial infections.
S-CoA
O
S-CoA
CO2H
O
*
*
starter unit
+ 6
oo
o
oo
o
o
13
5
79
11
13
O
O
O
OHHO
OR3
OR2
OR1
*
1 3
5
7
9
11
13
Erythromycin R1 R2 R3
A OH 1 2
B H 1 2
C OH 1 3
1 : D-desosamine:
2 : L-cladinosine:
3 : L-mycarose:
O
CH3
N(CH3)2
OH
OHO
CH3
CH3
CH3
OHO
CH3
CH3
OH
5. Polyketides (Dayrit) 33
5. Polyketides (Dayrit) 34
Intramolecular aromatic radical coupling: biosynthesis of griseofulvin (from a fungus, Penicilliumgriseofulvum) involves extensive secondary modification of a heptaketide.
griseofulvin
OOH
C H3 O O
OCH3
O
C H3C l
+2 [H]
dehydrogriseofulvin
OOH
C H3 O O
OCH3
O
C H3C l
OOH
C H3 O O
OCH3
O
C H3C l
...
.
OOH
C H3 O O
OCH3
O
C H3C l
[O]
3+[CH ]
griseophenone A
OOCH3
C H3 O OH
OCH3
OH
C H3C l
+[Cl], -[H]
OOH
C H3 O OH
OCH3
OH
C H3C l
griseophenone B griseophenone C
OOH
C H3 O OH
OCH3
OH
C H3
3+2 [CH ]
OOH
H O OH
OH
OH
C H3
o o
ooo
o o
5. Polyketides (Dayrit) 35
Nature of starting unit
Fatty acid synthase (FAS)
H3CC
SCoA
O
Acetyl CoA
Malonyl CoA
CH2
CSCoA
O
CHO
O
CHC
SCoA
O
CHO
O
CH3
Methylmalonyl CoA
Polyketide synthase (PKS)
Isobutyryl CoA
SCoA
O
H3C
O
Acetoacetyl CoA
Acetyl CoA
H3CC
SCoA
O
Hexanoyl CoA, R=C5H11
Octanoyl CoA, R=C7H15
OH
O
OH
O
Propionyl CoA
Butyryl CoAOH
O
SCoA
O
Benzoyl CoA
R1 R2Cinnamoyl CoA H Hp-Coumaroyl CoA H OHCaffeoyl CoA OH OHFeruloyl CoA OH OMe
SCoA
O
R1
R2
N-Methylanthranyloyl CoA
SCoA
O
MeHN
R OH
O
Acetamidoacetyl CoA
SCoA
O
H2N
O
5. Polyketides (Dayrit) 36
Nature of starting unit
Examples of metabolites where the starting unit is not acetyl-CoA. In the case of tetracycline, extensivesecondary processes take place.
o
o o o o
oooo
o
HO
CO2H
HO OH O
O OH
OH
7S, 9R, 10R--pyrramycinine
CONH2
oooo
o o o o
o
Cl
OH O OH O
CONH2
OH
OHH3C
OH
HN(CH3)2
tetracycline
5. Polyketides (Dayrit) 37
The polyketide metabolites can be classified into five groups:
1. Phenols 2. Quinones3. Aflatoxins4. Tetracyclines5. Macrolide antibiotics
Metabolites from polyketides
1. Phenols
Cyclization and aromatization of polyketides form phenols as the initial product. In plants however, phenols are also formed from the shikimate pathway. Therefore, phenols and their methylated derivatives are common natural products. Some common phenols are formed via different pathways.
Aromatic compounds
5. Polyketides (Dayrit) 38
2. Quinones
Quinones often occur as the final product from a series of oxidation reactions on mono- or polycyclic aromatic ring systems.
The biosynthetic pathway differs in microorganisms and plants. In microorganisms, quinones arise predominatly via the polyketide pathway. In plants, however, quinones can arise via the polyketide or shikimate pathways and sometimes via the mixed biosynthetic route involving the ring-formation of an added terpenoid unit. The presence of multiple pathways to the quinone ring system may reflect the importance of this type of functionality.
Metabolites from polyketides
39
Overview of biosynthesis of quinones. Depending
on the organism, quinones can arise via
the polyketide or shikimate pathways.
In microorganisms: [O] polyketide aromatic compound quinone
In plants: [O] polyketide aromatic compound quinone
shikimate aromatic compound + terpene [O]
quinone(mixed metabolite)
quinone
OH
CO2H
OH
OH
OH
O
O
OHH
quinones from shikimate + terpene: quinone from shikimate:
homogentisic acid alkarinin
R
O
O
H
n
ubiquinones: R = H, CH ; n = 4-133
• Aromatic metabolites in microorganisms are likely
to be formed via the polyketide pathway while
aromatic compounds in plants are likely to come
from the shikimate pathway.
5. Polyketides (Dayrit) 40
1,4-Benzoquinone
1,4-Benzoquinone itself is the simplest member of this group. However, because it is toxic, it is not found in this form but rather as a protected precursor, such as arbutin, a glycosylated 1,4-hydroquinone, the reduced form of 1,4-benzoquinone.
Metabolites from polyketides
O-Glu
OH
Arbutin
Arbutin occurs in the leaves of various plant species and may be a plant defense compound. The ability to detoxify phenols or to store them as glycosides appears to be a common characteristic of plants.
5. Polyketides (Dayrit) 41
5. Polyketides (Dayrit) 42
Para-quinone is a toxic compound which
various organisms use.
A. Various trees secrete a precursor (arbutin) to “clear” its surroundings
of competing plants;
B. The bombardier beetle produces para-
quinone in its collecting bladder from para-
hydroquinone + H2O2.
A. Plants store precursors of para-quinone in various glycosylated forms.
O-Glucose
OH
arbutin
O-Glu-O-Glu
OH
O-Glu-O-Glu-O-Glu
OH
O
O
para-quinone
(toxic)
B. Para-quinone as a defensive secretion of the bombardier beetle.
lobe
O
O
+ H O2 2
collecting bladder
explosion chamber withenzyme gland
OH
OH
+ H O + heat2
5. Polyketides (Dayrit) 43
5. Polyketides (Dayrit) 44
Aflatoxins
• The aflatoxins are a group of fungal metabolites which have closely similar chemical structures, the most evident feature being two fused furan rings.
• Aflatoxins were first discovered following investigations into the deaths of turkeys after being being fed mouldy peanuts.
Metabolites from polyketides
O O
O
O
O
OCH3
aflatoxin B1from Apergillus species
5. Polyketides (Dayrit) 45
Aflatoxins
• Aflatoxins are among the most toxic naturally-occuring compounds known. They are potent hepatocarcinogens and cause lesions in the mammalian liver. They are toxic to rats down to a dose level of 1 g/day.
• Various strains of Aspergillus produce aflatoxins, in particular, A. parasiticus, A. versicolor and A. flavus. Aspergillus fungi are usually encountered growing on various types of organic matter, especially in damp places. They cause the decay of many stored fruits and vegetables, bread, leather goods and various fabrics.
• Aflatoxins are one of the major causes of concern in our copra industry. The European Commission limit is currently set at 5 ppb.
Metabolites from polyketides
5. Polyketides (Dayrit) 46
ooo
o o o o
o o o
decaketide
[O]
HO
OH
O
O OH
OH
O O O
+2[H] +2[H], -H O, +2[H]2
HO
OH
O
O OH
OH
OH
OH
+HO
OH
O
O OH
O
OH
HO
HO
OH
O
O OH
O
O
-H O2
averufin [O]
[O] HO
OH
O
O OH
OH
OH
O - H
OH
O
-H O2
O - H
OOH
OHO
O
OH
HO
CHO
-C2OH
OHO
O
OH
HOCHO CHO
OHO
O
OH
HO O O
versicolorin A
[O], Bayer-Villiger
versicolorin B
OHO
O
OH
HO O O
Aflatoxins make up a family of
polyketide metabolites.
The very complex
biosynthesis of aflatoxins
was elucidated by George
Büchi.
5. Polyketides (Dayrit) 47
versicolorin A
OHO
O
OH
HO O O [O]
Bayer-Villiger
OHOOH
HO O OCO2H HO
+2[H]
+2[H],
-CO2
OHOOH
HO O
O
OHOOH
O O
O
H
H
sterigmatocystin
OHOOH
O O
O
H
H
O
[O]
OHOOH
O O
O
H
H
O
[O]
[O]
OHOO
HO2CO O
O
H
H
O
OHO
O O
O
H
H
O
CO2H
O
_OH
OH
O O
O
H
H
O
CO2H
O
[CH ]3
-CO ,
+[CH ],
-H O
2
2
3
OCH3
O O
O
H
H
O
O
aflatoxin B1
5. Polyketides (Dayrit) 48
ooo
o o o o
o o o
decaketide
[O]
HO
OH
O
O OH
OH
O O O
+2[H] +2[H], -H O, +2[H]2
HO
OH
O
O OH
OH
OH
OH
+HO
OH
O
O OH
O
OH
HO
HO
OH
O
O OH
O
O
-H O2
averufin [O]
[O] HO
OH
O
O OH
OH
OH
O - H
OH
O
-H O2
O - H
OOH
OHO
O
OH
HO
CHO
-C2OH
OHO
O
OH
HOCHO CHO
OHO
O
OH
HO O O
versicolorin A
[O], Bayer-Villiger
versicolorin B
OHO
O
OH
HO O O
5. Polyketides (Dayrit) 49
ooo
o o o o
o o o
decaketide
[O]
HO
OH
O
O OH
OH
O O O
+2[H] +2[H], -H O, +2[H]2
HO
OH
O
O OH
OH
OH
OH
+HO
OH
O
O OH
O
OH
HO
HO
OH
O
O OH
O
O
-H O2
averufin [O]
[O] HO
OH
O
O OH
OH
OH
O - H
OH
O
-H O2
O - H
OOH
OHO
O
OH
HO
CHO
-C2OH
OHO
O
OH
HOCHO CHO
OHO
O
OH
HO O O
versicolorin A
[O], Bayer-Villiger
versicolorin B
OHO
O
OH
HO O O
5. Polyketides (Dayrit) 50
versicolorin A
OHO
O
OH
HO O O [O]
Bayer-Villiger
OHOOH
HO O OCO2H HO
+2[H]
+2[H],
-CO2
OHOOH
HO O
O
OHOOH
O O
O
H
H
sterigmatocystin
OHOOH
O O
O
H
H
O
[O]
OHOOH
O O
O
H
H
O
[O]
[O]
OHOO
HO2CO O
O
H
H
O
OHO
O O
O
H
H
O
CO2H
O
_OH
OH
O O
O
H
H
O
CO2H
O
[CH ]3
-CO ,
+[CH ],
-H O
2
2
3
OCH3
O O
O
H
H
O
O
aflatoxin B1
5. Polyketides (Dayrit) 51
versicolorin A
OHO
O
OH
HO O O [O]
Bayer-Villiger
OHOOH
HO O OCO2H HO
+2[H]
+2[H],
-CO2
OHOOH
HO O
O
OHOOH
O O
O
H
H
sterigmatocystin
OHOOH
O O
O
H
H
O
[O]
OHOOH
O O
O
H
H
O
[O]
[O]
OHOO
HO2CO O
O
H
H
O
OHO
O O
O
H
H
O
CO2H
O
_OH
OH
O O
O
H
H
O
CO2H
O
[CH ]3
-CO ,
+[CH ],
-H O
2
2
3
OCH3
O O
O
H
H
O
O
aflatoxin B1
5. Polyketides (Dayrit) 52
Biosynthesis of tetracyclines from
Streptomyces species.
R=H : tetracyclineR=OH : terramycin
OH O OH O
CONH2
OH
OHH3C
OH
HN(CH3)2R
o
oooo
o o o o
+2[H] [CH ] [O]
CONH2
3
NH2
OH
HO
CH3
HO OH OH O
OH
[O]
NH2
OH
HO
CH3
HO OH O O
O
NH2
OH
HO
CH3
HO O O O
OH H
NH2
OH
HO
CH3
HO O O O
OH
OH
+H O2
NH2
OH
HO
CH3
HO O O O
OH
OH
+2[H]
NH2
OH
HO
CH3
HO O O O
H
OH
OH
+[NH ],+2[CH ]
2
3
NH2
OH
HO
CH3
HO O O O
H
OH
N(CH3)2
A B C D
NH2
OH
HO
CH3
HO O O O
H
OH
N(CH3)2Cl
DCBA
Cl
OH O OH O
CONH2
OH
OHH3C
OH
HN(CH3)2
aureomycin
[Cl]
5. Polyketides (Dayrit) 53
R=H : tetracyclineR=OH : terramycin
OH O OH O
CONH2
OH
OHH3C
OH
HN(CH3)2R
o
oooo
o o o o
+2[H] [CH ] [O]
CONH2
3
NH2
OH
HO
CH3
HO OH OH O
OH
[O]
NH2
OH
HO
CH3
HO OH O O
O
NH2
OH
HO
CH3
HO O O O
OH H
NH2
OH
HO
CH3
HO O O O
OH
OH
+H O2
NH2
OH
HO
CH3
HO O O O
OH
OH
+2[H]
NH2
OH
HO
CH3
HO O O O
H
OH
OH
+[NH ],+2[CH ]
2
3
NH2
OH
HO
CH3
HO O O O
H
OH
N(CH3)2
A B C D
NH2
OH
HO
CH3
HO O O O
H
OH
N(CH3)2Cl
DCBA
Cl
OH O OH O
CONH2
OH
OHH3C
OH
HN(CH3)2
aureomycin
[Cl]
Biosynthesis of tetracyclines
from Streptomyces
species.
5. Polyketides (Dayrit) 54
R=H : tetracyclineR=OH : terramycin
OH O OH O
CONH2
OH
OHH3C
OH
HN(CH3)2R
o
oooo
o o o o
+2[H] [CH ] [O]
CONH2
3
NH2
OH
HO
CH3
HO OH OH O
OH
[O]
NH2
OH
HO
CH3
HO OH O O
O
NH2
OH
HO
CH3
HO O O O
OH H
NH2
OH
HO
CH3
HO O O O
OH
OH
+H O2
NH2
OH
HO
CH3
HO O O O
OH
OH
+2[H]
NH2
OH
HO
CH3
HO O O O
H
OH
OH
+[NH ],+2[CH ]
2
3
NH2
OH
HO
CH3
HO O O O
H
OH
N(CH3)2
A B C D
NH2
OH
HO
CH3
HO O O O
H
OH
N(CH3)2Cl
DCBA
Cl
OH O OH O
CONH2
OH
OHH3C
OH
HN(CH3)2
aureomycin
[Cl]
5. Polyketides (Dayrit) 55
FAS and PKS probably share an evolutionary history. Like the fats, polyketides also arise from polymerization of acetyl CoA. The key features and steps are:
1. Alternative starter units are used, in particular in the formation of tetracyclic antibiotics and macrocylic lactones.
2.No reduction of the carbonyls, or reduction to alcohol level only.
3. Cyclization via Claisen displacement or aldol reaction. There are many modes of cyclization depending on the chain length.
Summary
5. Polyketides (Dayrit) 56
4. Aromatization often follows with loss of H2O.
5. wider range of compounds are produced: macrocyclic lactones, phenols, quinones, and polycylic aromatic compounds.
6. Polyketides are attractive research targets because of their strong and varied biological activity, the modular nature of the genetic system and polyketide synthases, and relatively accessible biosynthetic expression systems.
Summary