The extended catalysis of glutathione transferase

Fabrini, Raffaele; Bocedi, Alessio; Dawood, Kutayba F.; Turella, Paola; Stella, Lorenzo; Parker, Michael W.; Pedersen, Jens Z.; Federici, Giorgio; Antonini, Giovanni; Ricci, Giorgio

doi:10.1016/j.febslet.2010.12.009

Cited by 11 publications

(14 citation statements)

References 20 publications

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“…One of the most controversial aspects of the previous studies is the idea that only the monomeric form of GSTP1-1 might be able to efficiently inhibit JNK. 15 However, recent evidence suggests that the GST dimer is extremely stable with a dissociation constant of ≪1 nM, 32 and therefore, GSTP1-1 exists mainly in the dimeric state under our experimental conditions. Thus, when fitting our experimental data, we assumed that each subunit of a GSTP1-1 dimer may interact with JNK1α2, even though we cannot strictly rule out the possibility of a 1:1 complex between one JNK1α2 molecule and the GSTP1-1 dimer.…”

Section: ■ Discussionmentioning

confidence: 91%

The Lipid Dependence of Antimicrobial Peptide Activity Is an Unreliable Experimental Test for Different Pore Models

et al. 2012

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The role played by glutathione transferase P1-1 (GSTP1-1) in modulating the c-Jun N-terminal kinase (JNK) pathway has been extensively investigated using JNK isoforms known to exert opposite effects in the cells. We have expressed isoform JNK1α2, which has been reported to transmit a pro-apoptotic signal, and we have analyzed both the phosphorylation level and the activity of this kinase in the presence of GSTP1-1. Contrary to what previous studies suggest, we found that GSTP1-1 is able to form a complex with the unphosphorylated and inactive JNK1α2 isoform, even in the absence of the substrate. We also analyzed the consequences of this interaction on the activity of both enzymes. The complex strongly reduced the extent of activation of JNK1α2 and preserved GSTP1-1 from inactivation. Unexpectedly, glutathione (GSH) exerted a negative effect on the affinity of GSTP1-1 for JNK1α2, suggesting that the intracellular levels of this thiol may allow a fine-tuning of the MAPK signaling pathway. Moreover, we found that the adduct formed by GSH and the strong GSTP1-1 inhibitor NBDHEX abolishes the interaction between GSTP1-1 and JNK1α2. These data confirm and extend at the molecular level previous evidence obtained in tumor cell lines.

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Section: ■ Discussionmentioning

confidence: 91%

The Lipid Dependence of Antimicrobial Peptide Activity Is an Unreliable Experimental Test for Different Pore Models

et al. 2012

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“…By considering that GSTs present in the cytosol of the mammalian cells account for about 5%–8% of all soluble proteins, they represent the most prominent defense line (Phase II) able to biotransform xenobiotics via enzymatic activity or to sweep dangerous toxins by binding them and promoting their extrusion from the cell (Figure 5) [13].…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, GSTs reach a 0.5–0.8 mM concentration in the cell so it works in vivo under the unusual conditions of [xenobiotic] << [GST]. As GST lowers the p K a of GSH bound to the active site, it increases the concentration of deprotonated GSH in the cytosol by about five times thus accelerating its conjugation with toxins even if they are not typical substrates of this enzyme [13]. This catalysis becomes more evident in the case of cell acidification and GSH depletion [13].…”

Section: Introductionmentioning

confidence: 99%

“…As GST lowers the p K a of GSH bound to the active site, it increases the concentration of deprotonated GSH in the cytosol by about five times thus accelerating its conjugation with toxins even if they are not typical substrates of this enzyme [13]. This catalysis becomes more evident in the case of cell acidification and GSH depletion [13]. The peculiar enzymatic conjugation of GSH to these toxic compounds is possible assuming a simple bimolecular collision between enzyme and substrate [13].…”

Section: Introductionmentioning

confidence: 99%

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Glutathione Transferase P1-1 an Enzyme Useful in Biomedicine and as Biomarker in Clinical Practice and in Environmental Pollution

et al. 2019

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Glutathione transferase P1-1 (GSTP1-1) is expressed in some human tissues and is abundant in mammalian erythrocytes (here termed e-GST). This enzyme is able to detoxify the cell from endogenous and exogenous toxic compounds by using glutathione (GSH) or by acting as a ligandin. This review collects studies that propose GSTP1-1 as a useful biomarker in different fields of application. The most relevant studies are focused on GSTP1-1 as a biosensor to detect blood toxicity in patients affected by kidney diseases. In fact, this detoxifying enzyme is over-expressed in erythrocytes when unusual amounts of toxins are present in the body. Here we review articles concerning the level of GST in chronic kidney disease patients, in maintenance hemodialysis patients and to assess dialysis adequacy. GST is also over-expressed in autoimmune disease like scleroderma, and in kidney transplant patients and it may be used to check the efficiency of transplanted kidneys. The involvement of GSTP in the oxidative stress and in other human pathologies like cancer, liver and neurodegenerative diseases, and psychiatric disorders is also reported. Promising applications of e-GST discussed in the present review are its use for monitoring human subjects living in polluted areas and mammals for veterinary purpose.

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“…In addition to nonenzymatic conjugation with GSH, glutathione S-transferase (GST) isoforms, which are expressed ubiquitously throughout the body (Pacifici et al, 1988;de Waziers et al, 1990;Awasthi et al, 1994;Rowe et al, 1997), accelerate GSH conjugation by lowering the pKa of the sulfhydryl group of GSH from 9.0 to 6.2-6.7 and increasing the cytosolic concentration of deprotonated GSH (Armstrong, 1997;Fabrini et al, 2011). Therefore, both nonenzymatic and GST-dependent GSH conjugation of the acrylamide moiety in extrahepatic organs as well as in the liver is likely to play a significant role in the pharmacokinetics (PK) of TCI compounds.…”

Section: Introductionmentioning

confidence: 99%

The Role of Extrahepatic Metabolism in the Pharmacokinetics of the Targeted Covalent Inhibitors Afatinib, Ibrutinib, and Neratinib

Shibata

Chiba

2014

Drug Metab Dispos

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Despite the fact that much progress has been made recently in the development of targeted covalent inhibitors (TCIs), their pharmacokinetics (PK) have not been well characterized in the light of extrahepatic clearance (CL extH ) by glutathione (GSH)/glutathione S-transferase (GST)-dependent conjugation attributable to the unique electrophilic structure (e.g., acrylamide moiety) of TCI compounds. In the present study, CL extH values were examined in rat, dog, and monkey to predict the contribution of CL extH to the PK of the TCIs afatinib, ibrutinib, and neratinib in humans. Afatinib and neratinib both underwent extensive conjugation with GSH in buffer and cytosol fractions of liver and kidney, whereas ibrutinib showed much lower reactivity/susceptibility to GSH/GST-dependent conjugation. The CL extH in each species was calculated from the difference between observed total body clearance and predicted hepatic clearance (CL H ) in cryopreserved hepatocytes suspended in 100% serum of the corresponding species. The power-based simple allometry relating the CL extH for the unbound compound to animal body weight was applicable across species for afatinib and neratinib (R 2 ‡ 0.9) but not for ibrutinib (R 2 = 0.04). The predicted AUC after oral administration of afatinib and neratinib agreed reasonably closely with reported values in phase I dose-escalation studies. Comparisons of CL extH and CL H predicted that CL extH largely determined the PK of afatinib (>90% as a proportion of total body clearance) and neratinib (∼34%) in humans. The present method can serve as one of the tools for the optimization of PK in humans at the discovery stage for the development of TCI candidates.

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The extended catalysis of glutathione transferase

Cited by 11 publications

References 20 publications

The Lipid Dependence of Antimicrobial Peptide Activity Is an Unreliable Experimental Test for Different Pore Models

The Lipid Dependence of Antimicrobial Peptide Activity Is an Unreliable Experimental Test for Different Pore Models

Glutathione Transferase P1-1 an Enzyme Useful in Biomedicine and as Biomarker in Clinical Practice and in Environmental Pollution

The Role of Extrahepatic Metabolism in the Pharmacokinetics of the Targeted Covalent Inhibitors Afatinib, Ibrutinib, and Neratinib

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