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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 and Glutathione Derivatives: Possible Modulators of Ionotropic Glutamate Receptors
Published in Christopher A. Shaw, Glutathione in the Nervous System, 2018
Réka Janáky, Vince Varga, Zsolt Jenei, Pirjo Saransaari, Simo S. Oja
Glutathione is synthesized from its constituent amino acids and broken down via the γ-glutamyl cycle. The synthesis of GSH is catalyzed by γ-glutamylcysteine synthetase and glutathione synthetase, the former being the rate-limiting enzyme. The activity of both enzymes is under substrate and product (feedback) control. GSH is oxidized to GSSG by GSH peroxidase, and GSSG is reduced to GSH by glutathione reductase. The breakdown of glutathione is catalyzed by γ-glutamyl transferase, a membrane-bound enzyme that catalyzes the transfer of the γ-glutamyl moiety to free amino acids. γ-Glutamyl dipeptides are then split by γ-glutamyl cyclotransferase into its constituent amino acids and 5-oxoproline. The latter is further metabolized to glutamate by 5-oxoprolinase (Meister and Anderson 1983; Deneke and Fanburg 1989). The cellular and regional distribution of the enzymes involved in glutathione metabolism parallels that of glutathione (Philbert et al. 1991).
Glutathione
Published in Ruth G. Alscher, John L. Hess, Antioxidants in Higher Plants, 2017
Alfred Hausladen, Ruth G. Alscher
Whereas synthesis of GSH takes place both in the chloroplast and the extra-plastidic compartment, the GSH degrading enzymes γ-glutamylcyclotransferase52 and 5-oxoprolinase51 in tobacco suspension cultures are entirely cytosolic, based on the distribution of marker enzymes. However, this conflicts with the reported pH optima for these enzymes, which are between 8 and 10.5 (Table 1). The pH in the cytosol is about 7, and whereas γ-glutamylcyclotransferase retains some activity at this pH, 5-oxoprolinase is entirely inactive below pH 8.
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
The diagnosis of GSS deficiency is mostly established based on clinical manifestations and very high 5-oxoproline levels in blood and urine [8]. In the literature 5-oxoprolinuria is caused by both GSS deficiency or 5-oxoprolinase deficiency. 5-oxoprolinase deficient patients have normal acid–base status and do not have hemolytic anemia [1]. Transient metabolic acidosis and 5-oxoprolinuria may develop in adults due to the use of drugs, such as antibiotics, acetaminophen, and vigabatrin [9,10]. Metabolic acidosis and 5-oxoprolinuria accompanying hemolytic anemia can be observed in GSS deficiency. The present case was regarded as severe due to very high 5-oxoproline levels and the presence of persistent metabolic acidosis that led to dialysis, and to the neurological findings of follow-up investigations, including lethargy and hypotonicity. The level of 5-oxoproline was much higher in our patient compared to cases reported in the literature (170 times higher), which could be explained by the severity of the disease associated with poor neurological findings and the early mortality in our patient. Particularly in severely affected patients feeding deficiency, hypotonicity, convulsions and delayed psychomotor development can be observed. In accordance with the literature, feeding deficiency, hypotonicity and lethargy were manifestations of neurological symptoms in our case. Previously reported sonographic findings in GSS deficiency were nonspecific as frontoparietal white matter hyperintensity, atrophy of cerebral hemisphere, enlarged extra axial subarachnoid spaces, thin corpus callosum or enlarged subependymal pseudocysts which can be associated with metabolic and chromosomal disorders [1,2,6]. In our patient, CNS ultrasound revealed two extensively enlarged subependymal pseudocysts at the level of the lateral ventricles as well as increased echogenicity in the basal ganglia.
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
Our interpretation of the metabolic pathways conflicts with this view. First, most case reports of 5-oxoprolinemia occurred in therapeutic APAP dosing which should not have caused glutathione depletion. Second, cysteine is a substrate for the gamma-glutamyl cysteine synthetase, so the addition of another source of cysteine should increase gamma-glutamylcysteine production. Third, previous case reports have identified deficiencies of glutathione synthetase [9–12] or 5-oxoprolinase (EC 3.5.2.9) [13,14] as causes of 5-oxoprolinemia.
High anion gap metabolic acidosis induced by cumulation of ketones, L- and D-lactate, 5-oxoproline and acute renal failure
Published in Acta Clinica Belgica, 2018
Laura Heireman, Boris Mahieu, Mark Helbert, Wim Uyttenbroeck, Jan Stroobants, Marian Piqueur
5-Oxoproline-induced HAGMA is caused by disruption of the γ-glutamyl cycle associated with intake of paracetamol since its catabolism depletes glutathione, resulting in an increased activity of γ-glutamylcysteine synthetase [2]. This in turn leads to accumulation of γ-glutamylcysteine which is subsequently converted to 5-oxoproline when present in high concentrations [2]. However, glutathione stores become fully depleted only at high concentrations of paracetamol intake [3]. Therefore, 5-oxoproline accumulation may occur after an acute paracetamol overdose but it is seen more often after chronic intake of (sub)therapeutic doses of paracetamol in individuals predisposed to 5-oxoprolinemia [2,4]. Patients with glutathione synthetase deficiency are unable to replenish their already small glutathione stores during paracetamol catabolism [3]. Most cases of 5-oxoprolinemia are associated with combined intake of paracetamol and other drugs, including the antibiotics netilmycin and flucloxacillin, and the anticonvulsant vigabatrin [4–6]. These medications inhibit the oxidation of 5-oxoproline by 5-oxoprolinase and therefore, may provoke 5-oxoproline intoxication [4,6]. Other factors that have been shown to contribute to 5-oxoproline-induced acidosis in patients taking paracetamol are pregnancy, vegetarian diet and malnutrition [2,3,6–8]. These conditions are associated with deficiencies in glycine and cysteine, critical amino acids in the γ-glutamyl cycle, resulting in low glutathione synthesis [2,3]. 5-oxoproline-induced HAGMA occurs more frequently in women than in men, possibly due to sex-related differences in the paracetamol detoxification pathways [4]. Sepsis, another predisposing factor, may increase susceptibility to 5-oxoprolinuria by depleting glutathione stores. Furthermore, paracetamol is often administered in this setting as an antipyretic [6,9]. Chronic renal insufficiency and hepatic dysfunction (especially when related to chronic alcohol ingestion) are also associated with 5-oxoproline accumulation [6]. Renal failure causes diminished clearance of 5-oxoproline [10]. Glutathione synthesis is diminished in patients with uncontrolled type 2 diabetes mellitus due to decreased precursor availability. These patients are thus more prone to develop 5-oxoproline-induced acidosis [11].