The mercapturic acid pathway

Hanna, Patrick E.; Anders, M. W.

doi:10.1080/10408444.2019.1692191

Cited by 70 publications

(70 citation statements)

References 1,398 publications

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“…GSTs primarily carry out the catalytic detoxification of the above-mentioned exogenous compounds via synthesis of mercapturic acids [ 32 ]. The γ-glutamyl and the glycine fragment of the resulting glutathione conjugate are trimmed, followed by N-acetylation of the cysteine S-conjugates [ 33 ]. It is important to note that GSTs are a part of a unified cellular defense system.…”

Section: Metabolism Of Xenobiotic Compoundsmentioning

confidence: 99%

Glutathione S-Transferases in Cancer

2021

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In humans, the glutathione S-transferases (GST) protein family is composed of seven members that present remarkable structural similarity and some degree of overlapping functionalities. GST proteins are crucial antioxidant enzymes that regulate stress-induced signaling pathways. Interestingly, overactive GST proteins are a frequent feature of many human cancers. Recent evidence has revealed that the biology of most GST proteins is complex and multifaceted and that these proteins actively participate in tumorigenic processes such as cell survival, cell proliferation, and drug resistance. Structural and pharmacological studies have identified various GST inhibitors, and these molecules have progressed to clinical trials for the treatment of cancer and other diseases. In this review, we discuss recent findings in GST protein biology and their roles in cancer development, their contribution in chemoresistance, and the development of GST inhibitors for cancer treatment.

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Section: Metabolism Of Xenobiotic Compoundsmentioning

confidence: 99%

Glutathione S-Transferases in Cancer

2021

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“…APAP is activated in the liver to form the toxic NAPQI under the mediation of CYP450 enzymes which is then almost immediately detoxified in the liver through the action of the glutathione transferases (Bessems and Vermeulen, 2001). Glutathione conjugates are then biotransformed in the liver as APAP-Cys and then NAC-APAP through the mercapturic acid pathway by the sequential action of the γglutamyltransferases, dipeptidases, and cysteine S-conjugate N-acetyltransferase (Hanna and Anders, 2019). Finally, we also detected in this +1-6h group catechol APAP metabolites originating from another phase I oxidation pathway (i.e., 3-OH-APAP and 3-OCH3-APAP present as non-conjugated and conjugated forms).…”

Section: Detection Of New Apap Metabolites In Humans Using Hrms-basedmentioning

confidence: 99%

Acetaminophen Metabolism Revisited Using Non-Targeted Analyses: Implications for Human Biomonitoring

David

Chaker²,

Léger³

et al. 2020

Preprint

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The analgesic paracetamol (N-acetyl-4-aminophenol, APAP) is commonly used to relieve pain, fever and malaise. While sales have increased worldwide, a growing body of experimental and epidemiological evidence has suggested APAP as a possible risk factor for various health disorders. To perform internal exposure-based risk assessment, the use of accurate and optimized biomonitoring methods is criticical. However, retrospectively assessing pharmaceutical use of APAP in humans is challenging because of its short half-life. The objective of this study was to address the key biomonitoring issues with APAP using current standard analytical methods based on urinary analyses of free APAP and its phase II conjugates. Using non-targeted analyses based on high-resolution mass spectrometry, we identified in a controlled longitudinal exposure study with male volunteers, unrecognized APAP metabolites with delayed formation and excretion rates. We postulate that these metabolites are formed via the thiomethyl shunt after the enterohepatic circulation as already observed in rodents. Importantly, the conjugated thiomethyl metabolites were (i) of comparable diagnostic sensitivity as the free APAP and its phase II conjugates detected by current methods; (ii) had delayed peak levels in blood and urine compared to other APAP metabolites and therefore potentially extend the window of exposure assessment; and (iii) provide relevant information regarding metabolic pathways of interest from a toxicological point of view. Including these metabolites in future APAP biomonitoring methods provide an option to decrease potential underestimation of APAP use and challenges the notion that the standard methods in biomonitoring based exclusively on the parent compound and its phase II metabolites are adequate for human biomonitoring of non-persistant chemical such as APAP. <br>

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“…Overexpression of GGT1 contributes to the severity of a variety of pathological conditions including asthma, reperfusion injury, and cardiovascular disease (3)(4)(5)(6). It stimulates tumor growth and activates compounds including the chemotherapy drug cisplatin to nephrotoxins (7)(8)(9)(10)(11). Inhibiting the enzyme would be therapeutic in the treatment of multiple diseases, and development of novel GGT1 inhibitors has been the focus of intense research (12)(13)(14).…”

Section: Introductionmentioning

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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The mercapturic acid pathway

Cited by 70 publications

References 1,398 publications

Glutathione S-Transferases in Cancer

Glutathione S-Transferases in Cancer

Acetaminophen Metabolism Revisited Using Non-Targeted Analyses: Implications for Human Biomonitoring

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

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