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The thiols glutathione, cysteine, and homocysteine in human immunodeficiency virus (HIV) infection
Published in Ronald R. Watson, NUTRIENTS and FOODS in AIDS, 2017
F. Müller, P. Aukrust, A.M. Svardal, R.K. Berge, P.M. Ueland, S.S. Frøland
Figure 3.3 summarizes the reactions involved in the synthesis of glutathione. Reduced glutathione is synthesized intracellularly by the consecutive actions of γ-glutamylcysteine synthetase and glutathione synthetase utilizing adenosine triphosphate. The control point in the synthesis is γ-glutamylcysteine synthetase, which is subject to feedback inhibtion by reduced glutathione.27,28 Breakdown of glutathione is initiated by γ-glutamyl transpeptidase, which catalyses transfer of the γ-glutamyl group of glutathione to acceptors, e.g., amino acids, dipeptides, and H2O.11,28 Cystine is the most active amino acid acceptor, but other neutral amino acids are also acceptors (e.g., methionine and glutamate).10,11 Cysteinyl-glycine, formed in the transpeptidation reaction, is split by dipeptidases to cysteine and glycine, while the γ-glutamyl amino acids are substrates of γ-glutamyl cyclotransferase, which converts them into 5-oxiproline and the corresponding amino acids.11,29 Conversion of 5-oxiproline to glutamate is catalyzed by 5-oxiprolinase.11
Glutathione
Published in Ruth G. Alscher, John L. Hess, Antioxidants in Higher Plants, 2017
Alfred Hausladen, Ruth G. Alscher
Rüegsegger et al.53 found increased activities of glutathione synthetase when phytochelatin synthesis was stimulated by cadmium treatment or when glutathione synthesis was inhibited by treatment with the γ-glutamylcysteine synthetase inhibitor BSO. Since Cd2+ treatment and BSO both lead to a depletion of cellular GSH, the authors concluded that glutathione synthetase activity is regulated by GSH content. As GSH does not inhibit glutathione synthetase in vitro, mechanisms other than feedback inhibition appear to be involved.
Stress Proteins in Renal Ischemia
Published in John J. Lemasters, Constance Oliver, Cell Biology of Trauma, 2020
A relationship between glutathione (GSH) levels and the development of thermotolerance may exist. Most reports suggest that dramatic reductions in glutathione levels prevent the development of thermotolerance.71–74 Most studies show an increase in glutathione levels with the conditioning heat treatment.71–75 Some studies show a correlation between lowering GSH, decreasing thermotolerance, and decreased HSP levels.74 Other studies show that these correlations are not universal or simple. For example, Shrieve et al. studied thermotolerance in hamster fibroblasts and two heat-resistant variants.72 Despite different heat resistances, all cells showed similar GSH levels. A possible explanation of this result may be the fact that physiological concentrations of glutathione are much above the Km for enzymatic reactions involving glutathione. A GSH reduction to 10 to 30% of normal may be necessary before derangement of physiological reactions such as thermotolerance.76,77 However, a glutathione-synthetase-deficient mutant had GSH levels that were 6% of controls but could develop thermotolerance.75 Perhaps cellular glutathione levels are too crude a measurement. Organelle GSH levels in mitochondria or the endoplasmic reticulum may be the important factor.76,78 In addition, the type of glutathione within the organelle may be critically important. In the endoplasmic reticulum, reduced glutathione/disulfide glutathione ratios are 1:1 to 3:1 compared to total cellular GSH/GSSH ratios of 30:1 to 100:1.78
Borassus flabellifer Linn haustorium methanol extract mitigates fluoride-induced apoptosis by enhancing Nrf2/Haeme oxygenase 1 –dependent glutathione metabolism in intestinal epithelial cells
Published in Drug and Chemical Toxicology, 2022
Joice Tom Job, Rajakrishnan Rajagopal, Ahmed Alfarhan, Arunaksharan Narayanankutty
The cells were treated as described in section 2.4 in T-75 cm2 culture flasks and were collected by cell scrapers. The collected cells were then lysed using repeated freeze-thaw cycles. The lysate was then centrifuged at 10,000 rpm at 4 °C for 15 min; the clarified supernatant was used for the analysis of various biochemical parameters. Cellular antioxidant level such as reduced glutathione (GSH) was determined using standard protocols as described by Nair et al. (2016) and catalase activity was determined according to the protocols of Al-Oqail et al. (2020). Glutathione biosynthetic enzymes including γ-glutamyl cysteine synthetase (GCS) and glutathione synthetase (GS) were estimated as per standard methods described by Volohonsky et al. (2002). Enzymes involved in glutathione regeneration such as glutathione reductase (GR) (Mannervik 2001), glutathione-dependent detoxification enzymes such as glutathione-s-transferase (Moatamedi Pour et al.2014), and glutathione peroxidase (De Vega et al.2002) were also determined spectrophotometrically in terms of NADPH usage. Oxidative stress markers including lipid peroxidation in terms of thiobarbituric acid reactive substances (Chiu et al.2013) and conjugated dienes as per standard protocols (Narayanankutty et al.2016).
Glutathione synthetase deficiency: a novel mutation with femur agenesis
Published in Fetal and Pediatric Pathology, 2020
Ipek Guney Varal, Pelin Dogan, Orhan Gorukmez, Sevil Dorum, Arzu Akdag
Glutathione is an antioxidant that protects cells against damage by free radicals and is responsible for the detoxification of xenobiotics, membrane transportation, DNA synthesis, and metabolism. The glutathione synthetase (GSS) enzyme is responsible for glutathione synthesis via the γ-glutamyl cycle. When glutathione is not synthesized, levels of 5-oxoproline levels, a compound processed in the same cycle, are increased. GSS deficiency is a metabolic disease caused by different mutations in the GSS gene. It is inherited in an autosomal recessive manner and clinical manifestations may vary in severity (OMIM 601002). More than 80 cases have been reported worldwide [1]. The most common alterations of GSS deficiency include metabolic acidosis, hemolytic anemia, hyperbilirubinemia, neurological disorders and a susceptibility to sepsis [2,3]. These affected individuals will have high 5-oxoproline levels in urine and low GSS activity in erythrocytes or fibroblasts. Definitive diagnosis is established by identifying a GSS gene alteration. Recommended treatment includes acidosis management using sodium bicarbonate and antioxidant treatment using N-acetyl cysteine, vitamin C, and E [2,3].
5-Oxoproline concentrations in acute acetaminophen overdose
Published in Clinical Toxicology, 2020
Michael E. Mullins, Mary S. Jones, Robert D. Nerenz, Evan S. Schwarz, Dennis J. Dietzen
A limitation of the study is that 11 of 18 acute patients and all 5 late-presenting hepatic failure patients received IV N-acetylcysteine. Several authors assert that N-acetylcysteine may be a treatment for HAGMA with 5-oxoprolinemia in the setting of APAP use [4–8]. The proposed explanation is that glutathione inhibits gamma-glutamylcysteine synthetase (EC 6.3.2.2), the penultimate step in glutathione synthesis before glutathione synthetase (EC 6.3.2.3) in Figure 1. The product of this enzyme is gamma-glutamylcysteine which can either combine with glycine to form glutathione catalyzed by glutathione synthetase or convert to 5-oxoproline by gamma-glutamylcyclotransferase (EC 2.3.2.4). The proposed theory is that glutathione depletion releases the inhibition of gamma-glutamylcysteine synthetase and results in excess formation of gamma-glutamylcysteine, resulting in accumulation of 5-oxoproline.