Metabolism of Glutathione S-Conjugates: Multiple Pathways

Cooper, Arthur J. L.; Hanigan, Marie H.

doi:10.1016/b978-0-12-801238-3.01973-5

Cited by 52 publications

(55 citation statements)

References 419 publications

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“…Cys S-conjugates, formed as intermediates in the mercapturic acid pathway or by the aminoacylase-catalyzed hydrolysis of mercapturic acids, may undergo bioactivation by Cys S-conjugate b-lyase to give nephrotoxic metabolites. An extended discussion about the bioactivation of mercapturic acids ispathway is beyond the scope of this review, but several reviews are available (Lock and Berndt 1988;Bakke 1990;Anders 1991;Monks and Lau 1992;Anders and Dekant 1994;Guengerich 2003;Anders 2008;Cooper and Hanigan 2018).…”

Section: Bioactivation By the Mercapturic Acid Pathwaymentioning

confidence: 99%

The mercapturic acid pathway

Hanna

Anders

2019

Critical Reviews in Toxicology

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The mercapturic acid pathway is a major route for the biotransformation of xenobiotic and endobiotic electrophilic compounds and their metabolites. Mercapturic acids (N-acetyl-L-cysteine S-conjugates) are formed by the sequential action of the glutathione transferases, c-glutamyltransferases, dipeptidases, and cysteine S-conjugate N-acetyltransferase to yield glutathione S-conjugates, L-cysteinylglycine S-conjugates, L-cysteine S-conjugates, and mercapturic acids; these metabolites constitute a "mercapturomic" profile. Aminoacylases catalyze the hydrolysis of mercapturic acids to form cysteine S-conjugates. Several renal transport systems facilitate the urinary elimination of mercapturic acids; urinary mercapturic acids may serve as biomarkers for exposure to chemicals. Although mercapturic acid formation and elimination is a detoxication reaction, L-cysteine S-conjugates may undergo bioactivation by cysteine Sconjugate b-lyase. Moreover, some L-cysteine S-conjugates, particularly L-cysteinyl-leukotrienes, exert significant pathophysiological effects. Finally, some enzymes of the mercapturic acid pathway are described as the so-called "moonlighting proteins," catalytic proteins that exert multiple biochemical or biophysical functions apart from catalysis.

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Section: Bioactivation By the Mercapturic Acid Pathwaymentioning

confidence: 99%

The mercapturic acid pathway

Hanna

Anders

2019

Critical Reviews in Toxicology

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“…A major biotransformation route for electrophilic compounds, be they drugs, environmental pollutants, reactive intermediates, or endogenous molecules, is conjugation with glutathione and further processing to mercapturic acids (Figure 1) (Armstrong et al 2018;Cooper and Hanigan 2018). In this route, electrophilic compounds are conjugated with the sulfhydryl group of the nucleophile glutathione (GSH) by the enzyme family glutathione S-transferases (GSTs) to produce glutathione-conjugates (Armstrong 1997;Habig et al 1974).…”

Section: Introductionmentioning

confidence: 99%

Biotransformation Capacity of Zebrafish (Danio rerio) Early Life Stages: Functionality of the Mercapturic Acid Pathway

Tierbach

Groh

Schönenberger

et al. 2020

Toxicological Sciences

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Zebrafish (Danio rerio) early life stages offer a versatile model system to study the efficacy and safety of drugs or other chemicals with regard to human and environmental health. This is because, aside from the well-characterized genome of zebrafish and the availability of a broad range of experimental and computational research tools, they are exceptionally well suited for high-throughput approaches. Yet, one important pharmacokinetic aspect is thus far only poorly understood in zebrafish embryo and early larvae: their biotransformation capacity. Especially, biotransformation of electrophilic compounds is a critical pathway because they easily react with nucleophile molecules, such as DNA or proteins, potentially inducing adverse health effects. To combat such adverse effects, conjugation reactions with glutathione and further processing within the mercapturic acid pathway have evolved. We here explore the functionality of this pathway in zebrafish early life stages using a reference substrate (1-chloro-2,4-dinitrobenzene, CDNB). With this work, we show that zebrafish embryos can biotransform CDNB to the respective glutathione conjugate as early as 4 h postfertilization. At all examined life stages, the glutathione conjugate is further biotransformed to the last metabolite of the mercapturic acid pathway, the mercapturate, which is slowly excreted. Being able to biotransform electrophiles within the mercapturic acid pathway shows that zebrafish early life stages possess the potential to process xenobiotic compounds through glutathione conjugation and the formation of mercapturates. The presence of this chemical biotransformation and clearance route in zebrafish early life stages supports the application of this model in toxicology and chemical hazard assessment.

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“…γ-glutamyl transpeptidase (GGT1, aka γ-glutamyl transferase) is a cell surface enzyme that cleaves extracellular glutathione (GSH), GSH S -conjugates, and other γ-glutamyl compounds ( 1 , 2 ). Overexpression of GGT1 contributes to the severity of a variety of pathological conditions including asthma, reperfusion injury, and cardiovascular disease ( 3 , 4 , 5 , 6 ).…”

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confidence: 99%

Crystal structures of glutathione- and inhibitor-bound human GGT1: critical interactions within the cysteinylglycine binding site

Terzyan

Nguyen

Burgett

et al. 2021

Journal of Biological Chemistry

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Overexpression of γ-glutamyl transpeptidase(GGT1) has been implicated in an array of humandiseases including asthma, reperfusion injury,and cancer. Inhibitors are needed for therapy, butdevelopment of potent, specific inhibitors ofGGT1 has been hampered by a lack of structuralinformation regarding substrate binding andcleavage. To enhance our understanding of themolecular mechanism of substrate cleavage, wehave solved the crystal structures of humanGGT1 (hGGT1) with glutathione (a substrate)and a phosphate-glutathione analog (anirreversible inhibitor) bound in the active site.These are the first structures of any eukaryoticGGT with the cysteinylglycine region of thesubstrate-binding site occupied. These structuresand the structure of apo-hGGT reveal movementof amino acid residues within the active site as thesubstrate binds. Asn-401 and Thr-381 each formhydrogen bonds with two atoms of GSH spanningthe γ-glutamyl bond. Three different atoms ofhGGT1 interact with the carboxyl-oxygen of thecysteine of GSH. Interactions between theenzyme and substrate change as the substratemoves deeper into the active site cleft. Thesubstrate reorients and a new hydrogen bond isformed between the substrate and the oxyanionhole. Thr-381 is locked into a singleconformation as an acyl bond forms between thesubstrate and the enzyme. These data provideinsight on a molecular level into the substratespecificity of hGGT1 and provide an explanationfor seemingly disparate observations regardingthe enzymatic activity of hGGT1 mutants. Thisknowledge will aid in the design of clinicallyuseful hGGT1 inhibitors.

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Metabolism of Glutathione S-Conjugates: Multiple Pathways

Cited by 52 publications

References 419 publications

The mercapturic acid pathway

The mercapturic acid pathway

Biotransformation Capacity of Zebrafish (Danio rerio) Early Life Stages: Functionality of the Mercapturic Acid Pathway

Crystal structures of glutathione- and inhibitor-bound human GGT1: critical interactions within the cysteinylglycine binding site

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