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Human Erythroenzymopathies Of The Anaerobic Embden-Meyerhof Glycolytic And Associated Pathways
Published in Ronald L. Nagel, Genetically Abnormal Red Cells, 2019
Ernst R. Jaffé, William N. Valentine
The second phenotype of GSH-Syn deficiency involves a generalized deficiency of the enzyme,120-125 and hence of GSH itself. It is believed to result from mutations associated with absence of a gene product, either one catalytically inactive or one with extreme instability. In many tissues, GSH synthesis and utilization are linked by six enzyme-catalyzed reactions known collectively as the γ-glutamyl cycle.113 Normally, GSH largely controls its own synthesis by nonallosterically inhibiting γ-GC-Syn, acting, at least in part, as a competitive inhibitor with respect to glutamate.113 In the near absence of inhibitory GSH, γ-GC is synthesized unfettered. It accumulates in large amounts, and is converted to 5-oxoproline by the action of γ-glutamyl cyclotransferase. When 5-oxoproline is overproduced to the extent that it exceeds the capacity of 5-oxoprolinase to convert it to glutamate, the result is marked 5-oxoprolinuria, 5-oxoprolinemia, and severe metabolic acidosis. 5-oxoproline may reach concentrations of 3 to 6 mM in the plasma and cerebrospinal fluid.113 The severe deficiency syndrome thus causes a metabolic block in the synthesis of a compound acting as a feedback inhibitor of the formation of its immediate precursor, and interestingly, a metabolite derived from the latter is a major culprit in producing clinical manifestations.
Glutathione Synthesis
Published in Robert A. Greenwald, CRC Handbook of Methods for Oxygen Radical Research, 2018
The most highly purified preparation of γ-glutamylcysteine synthetase has been obtained from rat kidney.4-7 Rat kidney γ-glutamylcysteine synthetase has a molecular weight of about 104,000. It consists of two subunits of molecular weights about 73,000 and 27,700. The enzyme can be reversibly dissociated into its two subunits. The catalytic activity of the enzyme is associated with the heavy subunit. The function of the light subunit, which may be formed in the course of processing of the enzyme, is not yet known. γ-Glutamylcysteine synthetase is nonallosterically feedback-inhibited by glutathione. That glutathione normally regulates its own synthesis seems to explain observations on patients with severe glutathione synthetase deficiency.8,9 These patients have a marked deficiency of glutathione; they are unable to produce sufficient glutathione to feedback-inhibit γ-glutamylcysteine synthetase. Thus γ-glutamylcysteine is overproduced and is converted by the action of γ-glutamyl cyclotransferase to 5-oxoproline. The formation of the latter compound exceeds the capacity of 5-oxoprolinase and therefore large amounts of 5-oxoproline (an acid) accumulate in the body fluids and tissues, and are excreted in the urine. These patients experience severe acidosis, which requires constant therapy with bicarbonate. Although feedback inhibition of γ-glutamylcysteine synthetase10 seems to regulate the upper level of cellular glutathione, glutathione levels lower than maximal may be found because the levels of cysteine available for γ-glutamylcysteine synthesis may be limiting.
Metabolomic markers predictive of hepatic adaptation to therapeutic dosing of acetaminophen
Published in Clinical Toxicology, 2022
Brandon J. Sonn, Kennon J. Heard, Susan M. Heard, Angelo D’Alessandro, Kate M. Reynolds, Richard C. Dart, Barry H. Rumack, Andrew A. Monte
Investigating the subset subject cohort (n = 14), ASCA was used to identify major metabolome changes, specifically with four metabolites identified as being significant in this model (Figure 1(A)). This analysis allowed for a combined analysis based both on ALT class and by time series (days 0 vs. peak (day 7 or 10) vs. 16 vs. 31). Significant metabolites identified using ASCA were included using a combination of SPE and leverage (Figure 1(B)). As metabolites identified by a low SPE are associated with decreased prediction error within the developed model, a low SPE is desired to confirm their relevance in the model. Increased leverage for each metabolite highlights the importance and impact it has on the final model. Running a 1000 permutation test confirmed the significance of the model based on ALT class (p = <.05). Two metabolites involved within the glutathione metabolism pathway were significant: glycine and 5-oxoproline (Figure 1(C)). As well, there were two metabolites that were significant within the urea cycle: 5-l-glutamyl-l-glutamine and l-citrulline (Figure 1(D)). All of these metabolites displayed lower expression levels in the subjects that did not develop ALT elevations. This suggests that there is less glutathione and urea cycling within the subjects that did not experience an ALT elevation. Leverage and SPE values for each metabolite within this model can be found in Supplemental Table 2.
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
Pyroglutamic acid or 5-oxoproline (Figure 1) is a metabolite in the gamma-glutamyl cycle (Figure 2) [1]. Increased concentrations of 5-oxoproline (5-OP) can result from deranged glutathione metabolism. High anion gap metabolic acidosis (HAGMA) with measured 5-oxoproline concentration has occasionally followed acetaminophen (APAP) ingestions [1–3]. While recognized cases of 5-oxoprolinemia after APAP exposure appear rare, the prevalence and magnitude of 5-oxoprolinemia following potentially toxic APAP ingestion remain unknown [3].