Interaction of glutathione analogues with Hydra attenuata gamma-glutamyltransferase.
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ABSTRACT:
SUBMITTER: Danner J
PROVIDER: S-EPMC1186102 | biostudies-other | 1978 Nov
REPOSITORIES: biostudies-other
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Project description:L-γ-Glutamyl-L-cysteinyl-glycine is commonly referred to as glutathione (GSH); this ubiquitous thiol plays essential roles in animal life. Conjugation and electron donation to enzymes such as glutathione peroxidase (GPX) are prominent functions of GSH. Cellular glutathione balance is robustly maintained via regulated synthesis, which is catalyzed via the coordination of γ-glutamyl-cysteine synthetase (γ-GCS) and glutathione synthetase, as well as by reductive recycling by glutathione reductase. A prevailing short supply of L-cysteine (Cys) tends to limit glutathione synthesis, which leads to the production of various other γ-glutamyl peptides due to the unique enzymatic properties of γ-GCS. Extracellular degradation of glutathione by γ-glutamyltransferase (GGT) is a dominant source of Cys for some cells. GGT catalyzes the hydrolytic removal of the γ-glutamyl group of glutathione or transfers it to amino acids or to dipeptides outside cells. Such processes depend on an abundance of acceptor substrates. However, the physiological roles of extracellularly preserved γ-glutamyl peptides have long been unclear. The identification of γ-glutamyl peptides, such as glutathione, as allosteric modulators of calcium-sensing receptors (CaSRs) could provide insights into the significance of the preservation of γ-glutamyl peptides. It is conceivable that GGT could generate a new class of intercellular messaging molecules in response to extracellular microenvironments.
| S-EPMC10741565 | biostudies-literature
Project description: Not available
| S-EPMC7155009 | biostudies-literature
Project description:Glutathione (GSH, γ-L-glutamyl-L-cysteinyl-glycine) has been implicated in a multitude of cellular functions, such as protection of cells against oxidative stress, detoxification of xenobiotics via degradation of GSH S-conjugates, and disease resistance. Glutathione also serves as a precursor of phytochelatins, and thereby plays an essential role in heavy metal detoxification. The Arabidopsis genome encodes three functional γ-glutamyltransferase genes (AtGGT1, AtGGT2, AtGGT4) and two phytochelatin synthase genes (AtPCS1, AtPCS2). The function of plant GGT has not yet been clearly defined, although it is thought to be involved in GSH and GSH S-conjugate catabolism. On the other hand, besides its role in heavy metal detoxification, PCS has also been involved in GSH S-conjugate catabolism. Herein we describe the HPLC characterization of GSH and GSH S-conjugate catabolism in Arabidopsis mutants deficient in GSH biosynthesis (pad2-1/gsh1), atggt and atpcs1 T-DNA insertion mutants, atggt pad2-1, atggt atpcs1 double mutants, and the atggt1 atggt4 atpcs1 triple mutant. The results of our HPLC analysis confirm that AtGGT and AtPCS play important roles in two different pathways related with GSH and GSH S-conjugate (GS-bimane) catabolism in Arabidopsis.
| S-EPMC10240914 | biostudies-literature
Project description:Observational epidemiological evidence supports a linear and independent association between serum gamma-glutamyltransferase (GGT) concentrations and the risk of Alzheimer's disease (AD). However, the causality of this association has not been previously investigated. We sought to assess the causal nature of this association using a Mendelian randomization (MR) approach. Using inverse-variance weighted MR analysis, we assessed the association between GGT and AD using summary statistics for single nucleotide polymorphism (SNP)-AD associations obtained from the International Genomics of Alzheimer's Project of 17,008 individuals with AD and 37,154 controls. We used 26 SNPs significantly associated with GGT in a previous genome-wide association study on liver enzymes as instruments. Sensitivity analyses to account for potential genetic pleiotropy included MR-Egger and weighted median MR. The odds ratio of AD was 1.09 (95% confidence interval, 0.98 to 1.22; p = 0.10) per one standard deviation genetically elevated GGT based on all 26 SNPs. The results were similar in both MR-Egger and weighted median MR methods. Overall, our findings cannot confirm a strong causal effect of GGT on AD risk. Further MR investigations using individual-level data are warranted to confirm or rule out causality.
| S-EPMC5915296 | biostudies-literature
Project description:Analogues of GSH in which either the gamma-glutamyl or the glycyl moiety is modified were synthesized and tested as both substrates for and inhibitors of glutathione S-transferases (GSTs) 7-7 and 8-8. Acceptor substrates for GST 7-7 were 1-chloro-2,4-dinitrobenzene (CDNB) and ethacrynic acid (ETA) and for GST 8-8 CDNB, ETA and 4-hydroxynon-trans-2-enal (HNE). The relative ability of each combination of enzyme and GSH analogue to catalyse the conjugation of all acceptor substrates was similar with the exception of the combination of GST 7-7 and gamma-L-Glu-L-Cys-L-Asp, which used CDNB but not ETA as acceptor substrate. In general, GST 7-7 was better than GST 8-8 in utilizing these analogues as substrates, and glycyl analogues were better than gamma-glutamyl analogues as both substrates and inhibitors. These results are compared with those obtained earlier with GSH analogues and GST isoenzymes 1-1, 2-2, 3-3 and 4-4 [Adang, Brussee, Meyer, Coles, Ketterer, van der Gen & Mulder (1988) Biochem. J. 255, 721-724] and the implications with respect to the nature of their active sites are discussed.
| S-EPMC1133650 | biostudies-other
Project description:BackgroundIncreases in serum gamma-glutamyltransferase (GGT) activity have been reported in Thoroughbred (TB) racehorses and associated with maladaptation to training but the underlying etiology remains unknown.Hypothesis/objectivesClassify the etiology of high GGT syndrome in racing TBs by assessment of pancreatic enzymes, vitamin E concentrations, and both a candidate gene and whole genome association study. We hypothesized that a genetic variant resulting in antioxidant insufficiency or pancreatic dysfunction would be responsible for high GGT syndrome in TBs.AnimalsA total of 138 California racing TBs. Amylase: n = 31 affected (serum GGT activity ≥60 IU/L), n = 52 control (serum GGT activity <40 IU/L). Lipase: n = 19 affected, n = 35 control. Serum α-tocopherol concentrations: n = 32 affected, n = 46 control. Genome-wide association study (GWAS): 36 affected, 58 control. Whole genome sequencing: n = 5 affected, n = 5 control.MethodsBiochemical and vitamin analytes were compared among cohorts. A GWAS was performed and a subset of TBs underwent whole genome sequencing to interrogate candidate genes and positional genetic regions.ResultsSerum lipase and amylase activity and α-tocopherol concentrations did not differ between groups. No genetic variants were identified in 2 candidate genes (UGT1A1 and GGT1) that associated with the phenotype. Four single nucleotide polymorphisms (SNPs) approached a suggestive association with the phenotype (P = 2.15 × 10-5 ), defining a 100 kb region on chromosome 5 surrounding cluster of differentiation 1a (CD1A1), a transmembrane gene related to the major histocompatibility complex.Conclusions and clinical importanceAn underlying genetic etiology may exist for high GGT syndrome in racing TBs, similar to genetic disorders in humans.
| S-EPMC9708438 | biostudies-literature
Project description:ObjectivesGamma-glutamyltransferase (GGT) is a biomarker of liver disease and oxidative stress which was associated with all-cause and cardiovascular (CV) mortality in the general population and in patients with high risk conditions. This study aims at assessing whether oxLDL modifies the relationship between GGT, all-cause, and CV mortality in elderly individuals from the general population.DesignObservational longitudinal study.SettingPopulation-based cohort of older individuals (>65 years) free of liver disease.ParticipantsOne thousand and thirty-eight individuals from the Invecchiare in Chianti (InCHIANTI) study.MeasurementsSerum GGT level, oxidized low-density lipoprotein (oxLDL), CV comorbidities, all-cause and CV mortality.ResultsThe median age of the study population (n = 1,038) was 74 years (inter-quartile range: 69-79), 152 individuals (15%) had past CV events. During a median follow-up of 9 years, 401 individuals died, 168 of them (42%) for CV causes. In adjusted analyses, GGT predicted all-cause mortality (HR for 20 U/L increase in serum GGT: 1.11, 95% CI: 1.02-1.21, P = .02) and CV mortality (HR: 1.17, 95% CI: 1.03-1.33; P = .02). Furthermore, in an analysis for interaction circulating oxLDL amplified the effect of GGT on all-cause mortality (P = .003).ConclusionCirculating oxLDL amplifies the effect of GGT on mortality in the elderly. The mechanism for this association remains unknown and requires further research, including studying the potential role of GGT in oxidative stress. These results are consistent with the hypothesis of a causal role of GGT in the CV morbidity and mortality in older individuals and indicate that oxLDL plays a crucial role in the interpretation of the link between GGT and the risk of adverse clinical events in this population.
| S-EPMC5407291 | biostudies-literature
Project description:BackgroundGamma-glutamyltransferase (GGT) is a biomarker of liver injury. GGT has also been reported to be a marker of oxidative stress and a predictor of mortality in the general population. Hemodialysis (HD) patients suffer from oxidative stress. The aim of our study was to investigate the relationship between serum GGT levels and clinical outcomes in HD patients.MethodsA total of 1,634 HD patients were enrolled from the Clinical Research Center registry for end-stage renal disease, a prospective cohort in Korea. Patients were categorized into three groups by tertiles of serum GGT levels. The primary outcome was all-cause, cardiovascular, or infection-related mortality and hospitalization.ResultsDuring the median follow-up period of 30 months, the highest tertile of serum GGT levels had a significantly higher risk for all-cause mortality (hazard ratio (HR) 2.39, 95% confidence interval (CI), 1.55-3.69, P<0.001), cardiovascular mortality (HR 2.14, 95% CI, 1.07-4.26, P = 0.031) and infection-related mortality (HR 3.07, 95% CI, 1.30-7.25, P = 0.011) using tertile 1 as the reference group after adjusting for clinical variables including liver diseases. The highest tertile also had a significantly higher risk for first hospitalization (HR 1.22, 95% CI, 1.00-1.48, P = 0.048) and cardiovascular hospitalization (HR 1.42, 95% CI, 1.06-1.92, P = 0.028).ConclusionsOur data demonstrate that high serum GGT levels were an independent risk factor for all-cause, cardiovascular, and infection-related mortality, as well as cardiovascular hospitalization in HD patients. These findings suggest that serum GGT levels might be a useful biomarker to predict clinical outcomes in HD patients.
| S-EPMC4573328 | biostudies-literature
Project description:Gamma-glutamyltransferase (GGT) is an established marker for proliferative/apoptotic balance and has been associated with cancer risk and prognosis. The aim of this study was to evaluate the value of pre-treatment GGT serum levels as prognostic biomarker in patients with primary uterine leiomyosarcoma (ULMS). Data of women with ULMS were extracted from a multi-center database. Pre-treatment GGT serum levels were measured and patients assigned to predefined GGT risk groups. GGT values were correlated with clinico-pathological parameters and univariate and multivariable survival analyses were performed. A total of 44 patients with ULMS were analyzed. Mean (SD) pre-therapeutic GGT serum level was 33.8 (39.8) U/L. In Figo Stage I versus II-IV mean (SD) GGT values were 28.8 (34.0) U/l and 43.5 (49.2) U/l, respectively (p = 0.25). Five-year overall survival (OS) rates in ULMS patients with normal low versus higher GGT levels were 70% and 37%, respectively (p = 0.043). Univariate and multivariable analyses revealed that higher GGT serum levels (p = 0.043, p = 0.005) and high histological grade (p = 0.029, p = 0.012) were independently associated with impaired OS, respectively. Higher pre-treatment GGT serum levels were independently associated with unfavorable prognosis in women with ULMS. Thus, GGT seems to be a useful novel biomarker in ULMS.
| S-EPMC5028736 | biostudies-literature
Project description:L-γ-Glutamyl-p-nitroanilide (GPNA) is widely used to inhibit the glutamine (Gln) transporter ASCT2, but recent studies have demonstrated that it is also able to inhibit other sodium-dependent and independent amino acid transporters. Moreover, GPNA is a well known substrate of the enzyme γ-glutamyltransferase (GGT). Our aim was to evaluate the effect of GGT-mediated GPNA catabolism on cell viability and Gln transport. The GGT-catalyzed hydrolysis of GPNA produced cytotoxic effects in lung cancer A549 cells, resulting from the release of metabolite p-nitroaniline (PNA) rather than from the inhibition of Gln uptake. Interestingly, compounds like valproic acid, verapamil and reversan were able to increase the cytotoxicity of GPNA and PNA, suggesting a key role of intracellular detoxification mechanisms. Our data indicate that the mechanism of action of GPNA is more complex than believed, and further confirm the poor specificity of GPNA as an inhibitor of Gln transport. Different factors may modulate the final effects of GPNA, ranging from GGT and ASCT2 expression to intracellular defenses against xenobiotics. Thus, other strategies - such as a genetic suppression of ASCT2 or the identification of new specific inhibitors - should be preferred when inhibition of ASCT2 function is required.
| S-EPMC6351548 | biostudies-literature