Reactome | Glutathione conjugation (R-HSA-156590)The microsomal glutathione S-transferases (MGSTs)...

Glutathione conjugation

D'Eustachio, P., Jassal, B.

European Bioinformatics Institute, New York University Langone Medical Center, Ontario Institute for Cancer Research, Oregon Health and Science University.

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05/04/2021

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Introduction

Reactome is open-source, open access, manually curated and peer-reviewed pathway database. Pathway annotations are authored by expert biologists, in collaboration with Reactome editorial staff and cross-referenced to many bioinformatics databases. A system of evidence tracking ensures that all assertions are backed up by the primary literature. Reactome is used by clinicians, geneticists, genomics research-ers, and molecular biologists to interpret the results of high-throughput experimental studies, by bioin-formaticians seeking to develop novel algorithms for mining knowledge from genomic studies, and by systems biologists building predictive models of normal and disease variant pathways.

The development of Reactome is supported by grants from the US National Institutes of Health (P41 HG003751), University of Toronto (CFREF Medicine by Design), European Union (EU STRP, EMI-CD), and the European Molecular Biology Laboratory (EBI Industry program).

Literature references

Fabregat, A., Sidiropoulos, K., Viteri, G., Forner, O., Marin-Garcia, P., Arnau, V. et al. (2017). Reactome pathway ana-lysis: a high-performance in-memory approach. BMC bioinformatics, 18, 142. ↗

Sidiropoulos, K., Viteri, G., Sevilla, C., Jupe, S., Webber, M., Orlic-Milacic, M. et al. (2017). Reactome enhanced path-way visualization. Bioinformatics, 33, 3461-3467. ↗

Fabregat, A., Jupe, S., Matthews, L., Sidiropoulos, K., Gillespie, M., Garapati, P. et al. (2018). The Reactome Pathway Knowledgebase. Nucleic Acids Res, 46, D649-D655. ↗

Fabregat, A., Korninger, F., Viteri, G., Sidiropoulos, K., Marin-Garcia, P., Ping, P. et al. (2018). Reactome graph data-base: Efficient access to complex pathway data. PLoS computational biology, 14, e1005968. ↗

Reactome database release: 76

This document contains 2 pathways and 5 reactions (see Table of Contents)

https://reactome.orghttp://www.ncbi.nlm.nih.gov/pubmed/28249561http://www.ncbi.nlm.nih.gov/pubmed/29077811http://www.ncbi.nlm.nih.gov/pubmed/29145629http://www.ncbi.nlm.nih.gov/pubmed/29377902


Glutathione conjugation ↗

Stable identifier: R-HSA-156590

Glutathione S-Transferases (GSTs; EC 2.5.1.18) are another major set of phase II conjugation enzymes. They can be found in the cytosol as well as being microsomal membrane-bound. Cytosolic GSTs are en-coded by at least 5 gene families (alpha, mu, pi, theta and zeta GST) whereas membrane-bound enzymes are encoded by single genes. Soluble GSTs are homo- or hetero-dimeric enzymes (approximately 25KDa subunits) which can act on a wide range of endogenous and exogenous electrophiles. GSTs mediate con-jugation using glutathione (GSH), a tripeptide synthesized from its precursor amino acids gamma-glutamate, cysteine and glycine. A generalized reaction is

RX + GSH -> HX + GSR

Glutathione conjugates are excreted in bile and converted to cysteine and mercapturic acid conjugates in the intestine and kidneys. GSH is the major, low molecular weight, non-protein thiol synthesized de novo in mammalian cells. As well as taking part in conjugation reactions, GSH also has antioxidant ability and can metabolize endogenous and exogenous compounds. The nucleophilic GSH attacks the electrophilic substrate forming a thioether bond between the cysteine residue of GSH and the electrophile. The result is generally a less reactive and more water-soluble conjugate that can be easily excreted. In some cases, GSTs can activate compounds to reactive species such as certain haloalkanes and haloalkenes. Substrates for GSTs include epoxides, alkenes and compounds with electrophilic carbon, sulfur or nitrogen centres. There are two types of conjugation reaction with glutathione: displacement reactions where glutathione displaces an electron-withdrawing group and addition reactions where glutathione is added to activated double bond structures or strained ring systems.


Parkinson, A. (1995). Casarett and Doull's Toxicology 5th Edn. McGraw Hill, 113-186.

Editions2004-11-30 Authored Jassal, B.

2008-05-19 Edited Jassal, B.

2011-05-23 Reviewed D'Eustachio, P.

2014-06-23 Revised Jassal, B.

https://reactome.orghttps://reactome.org/content/detail/R-HSA-156590


Glutathione synthesis and recycling ↗

Location: Glutathione conjugation


The combination of glutamate, cysteine and ATP is required to form glutathione. The steps involved in the synthesis and recycling of glutathione are outlined (Meister, 1988).


Meister, A. (1988). Glutathione metabolism and its selective modification. J Biol Chem, 263, 17205-8. ↗

Editions2004-11-30 Authored Jassal, B.

2008-05-19 Edited Jassal, B.




https://reactome.orghttps://reactome.org/content/detail/R-HSA-174403http://www.ncbi.nlm.nih.gov/pubmed/3053703


ESD dimer hydrolyses S-FGSH to GSH ↗



Type: transition

Compartments: endoplasmic reticulum lumen

S-formylglutathione hydrolase (ESD, esterase D) is a homodimeric enzyme in the ER lumen of red blood cells that can hydrolyse S-formylglutathione (S-FGSH) to glutathione (GSH) and formate (Hopkinson et al. 1973, Eiberg & Mohr 1986). It is also able to hydrolyse 4-methylumbelliferyl acetate (not shown here).


Hopkinson, DA., Mestriner, MA., Cortner, J., Harris, H. (1973). Esterase D: a new human polymorphism. Ann. Hum. Genet., 37, 119-37. ↗

Eiberg, H., Mohr, J. (1986). Identity of the polymorphisms for esterase D and S-formylglutathione hydrolase in red blood cells. Hum. Genet., 74, 174-5. ↗

Editions2015-05-18 Authored, Edited Jassal, B.


https://reactome.orghttps://reactome.org/content/detail/R-HSA-5693724http://www.ncbi.nlm.nih.gov/pubmed/4768551http://www.ncbi.nlm.nih.gov/pubmed/3770744


GST trimers transfer GS from GSH to luminal substrates ↗



Type: transition

Compartments: endoplasmic reticulum lumen, endoplasmic reticulum membrane

The microsomal glutathione S-transferases (MGSTs) catalyse the nucleophilic attack by reduced gluta-thione (GSH) on nonpolar compounds that contain an electrophilic C, N, or S atom. Three major families of proteins are widely distributed in nature. The cytosolic and mitochondrial GST families comprise sol-uble enzymes that are only distantly related whilst the third family comprises microsomal GST, referred to as membrane-associated proteins in eicosanoid and glutathione (MAPEG) metabolism. Three mem-bers of this family function as detoxification enzymes, MGST1-3 (DeJong et al. 1988, Kelner et al. 1996, Jakobsson et al. 1996, Jakobsson et al. 1997). Electron crystallography studies in rat Mgst1 indicate these enzymes function as homotrimers (Holm et al. 2002). Both aflatoxin B1 exo- and endo-epoxides (AFXBO and AFNBO) conjugate with glutathione. These conjugates are eventually excreted in urine as mercaptur-ic acids.


DeJong, JL., Morgenstern, R., Jörnvall, H., DePierre, JW., Tu, CP. (1988). Gene expression of rat and human micro-somal glutathione S-transferases. J. Biol. Chem., 263, 8430-6. ↗

Kelner, MJ., Stokely, MN., Stovall, NE., Montoya, MA. (1996). Structural organization of the human microsomal glutathione S-transferase gene (GST12). Genomics, 36, 100-3. ↗

Jakobsson, PJ., Mancini, JA., Ford-Hutchinson, AW. (1996). Identification and characterization of a novel human mi-crosomal glutathione S-transferase with leukotriene C4 synthase activity and significant sequence identity to 5-lipoxygenase-activating protein and leukotriene C4 synthase. J. Biol. Chem., 271, 22203-10. ↗

Jakobsson, PJ., Mancini, JA., Riendeau, D., Ford-Hutchinson, AW. (1997). Identification and characterization of a novel microsomal enzyme with glutathione-dependent transferase and peroxidase activities. J. Biol. Chem., 272, 22934-9. ↗

Holm, PJ., Morgenstern, R., Hebert, H. (2002). The 3-D structure of microsomal glutathione transferase 1 at 6 A resol-ution as determined by electron crystallography of p22(1)2(1) crystals. Biochim. Biophys. Acta, 1594, 276-85. ↗

Editions2008-05-28 Reviewed D'Eustachio, P.

https://reactome.orghttps://reactome.org/content/detail/R-HSA-176059http://www.ncbi.nlm.nih.gov/pubmed/3372534http://www.ncbi.nlm.nih.gov/pubmed/8812420http://www.ncbi.nlm.nih.gov/pubmed/8703034http://www.ncbi.nlm.nih.gov/pubmed/9278457http://www.ncbi.nlm.nih.gov/pubmed/11904223


GST dimers conjugate GSH with cytosolic substrates ↗



Type: transition

Compartments: cytosol

The glutathione S-transferases (GSTs) catalyze the nucleophilic attack by reduced glutathione (GSH) on nonpolar compounds that contain an electrophilic carbon, nitrogen, or sulphur atom. Their substrates include halogenonitrobenzenes, arene oxides, quinones, and alpha, beta-unsaturated carbonyls. Three major families of proteins are widely distributed in nature. Two of these, the cytosolic and mitochondrial GST, comprise soluble enzymes that are only distantly related whilst the third family comprises micro-somal GST, referred to as membrane-associated proteins in eicosanoid and glutathione (MAPEG) meta-bolism.

At least 16 cytosolic GST subunits exist in human which are all in a dimeric form. Based on amino acid sequence similarities, seven classes of cytosolic GST are recognized in mammalian species; Alpha, Mu, Pi, Sigma, Theta, Omega, and Zeta (2–5). As well as being homodimers, the Alpha and Mu classes are also able to form heterodimers so a large number of isozymes are possible from all cytosolic GST subunits (Sinning et al. 1993, LeTrong et al. 2002, Ahmad et al. 1993, Pastore et al. 1998, Tars et al. 2010, Bruns et al. 1999, Balogh et al. 2010, Morel et al. 2002, Li et al. 2005, Patskovsky et al. 2006, Raghunathan et al. 1994, Patskovsky et al. 1999, Comstock et al. 1994, Board et al. 2000, Zhou et al. 2011, Zhou et al. 2012, Sun et al. 2011, Tars et al. 2006, Rossjohn et al. 1998, Polekhina et al. 2001, Inoue et al. 2003). Typical electro-philic substrates are chosen as examples for which the majority of the cytosolic GST isozymes act on.


Sinning, I., Kleywegt, GJ., Cowan, SW., Reinemer, P., Dirr, HW., Huber, R. et al. (1993). Structure determination and refinement of human alpha class glutathione transferase A1-1, and a comparison with the Mu and Pi class en-zymes. J. Mol. Biol., 232, 192-212. ↗

Le Trong, I., Stenkamp, RE., Ibarra, C., Atkins, WM., Adman, ET. (2002). 1.3-A resolution structure of human gluta-thione S-transferase with S-hexyl glutathione bound reveals possible extended ligandin binding site. Proteins, 48, 618-27. ↗

Ahmad, H., Singhal, SS., Saxena, M., Awasthi, YC. (1993). Characterization of two novel subunits of the alpha-class glutathione S-transferases of human liver. Biochim. Biophys. Acta, 1161, 333-6. ↗

Pastore, A., Lo Bello, M., Aureli, G., Federici, G., Ricci, G., Di Ilio, C. et al. (1998). Purification and characterization of a novel alpha-class glutathione transferase from human liver. Int. J. Biochem. Cell Biol., 30, 1235-43. ↗

https://reactome.orghttps://reactome.org/content/detail/R-HSA-176054http://www.ncbi.nlm.nih.gov/pubmed/8331657http://www.ncbi.nlm.nih.gov/pubmed/12211029http://www.ncbi.nlm.nih.gov/pubmed/8431482http://www.ncbi.nlm.nih.gov/pubmed/9839448


Tars, K., Olin, B., Mannervik, B. (2010). Structural basis for featuring of steroid isomerase activity in alpha class glutathione transferases. J. Mol. Biol., 397, 332-40. ↗

Editions2008-05-28 Reviewed D'Eustachio, P.

https://reactome.orghttp://www.ncbi.nlm.nih.gov/pubmed/20083122


GSTK1 dimer transfers GS from GSH to CDNB ↗



Type: transition

Compartments: mitochondrial matrix

Glutathione S-transferase Kappa isozyme (GSTK1) is widely expressed in human tissues and exists as a di-mer in mitochondria and peroxisomes. It has high activity towards aryl halides such as the model sub-strate 1-chloro-2,4-dinitrobenzene (CDNB) to which it can conjugate with glutathionate (GS-) from gluta-thione (GSH) (Morel et al. 2004). Mouse, rat and human possess only one GST Kappa isozyme.


Morel, F., Rauch, C., Petit, E., Piton, A., Theret, N., Coles, B. et al. (2004). Gene and protein characterization of the human glutathione S-transferase kappa and evidence for a peroxisomal localization. J. Biol. Chem., 279, 16246-53. ↗





AKR1A1 oxidises BaPtDHD to BaP-7,8-dione ↗



Type: transition

Compartments: cytosol

Polycyclic aromatic hydrocarbons (PAHs) are pro-carcinogens which require further metabolic activa-tion to ellicit their harmful effects. Aldo-keto reductases (AKRs) such as alcohol dehydrogenase [NADP+] (AKR1A1) can catalyse the oxidation of proximate carcinogenic PAH trans-dihydrodiols to reactive and redox active PAH o-quinones. Redox-cycling of PAH o-quinones generate reactive oxygen species and subsequent oxidative DNA damage. The proximate PAH carcinogen benzo[a]pyrene-7,8-trans-dihydrodi-ol (BaPtDHD) is oxidised by AKR1A1 to yield BaP-7,8-catechol which is unstable and auto-oxidises to yield BaP-7,8-dione (Zhang et al. 2012).


Zhang, L., Jin, Y., Huang, M., Penning, TM. (2012). The Role of Human Aldo-Keto Reductases in the Metabolic Activ-ation and Detoxication of Polycyclic Aromatic Hydrocarbons: Interconversion of PAH Catechols and PAH o-Quinones. Front Pharmacol, 3, 193. ↗





Table of ContentsIntroduction 1

Glutathione conjugation 2

Glutathione synthesis and recycling 3

ESD dimer hydrolyses S-FGSH to GSH 4

GST trimers transfer GS from GSH to luminal substrates 5

GST dimers conjugate GSH with cytosolic substrates 6

GSTK1 dimer transfers GS from GSH to CDNB 8

AKR1A1 oxidises BaPtDHD to BaP-7,8-dione 9

Table of Contents 10
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