China
Africa
Explore chapters and articles related to this topic
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.
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 synthetase deficiency is a metabolic disorder caused by different alterations such as missense/nonsense, splicing, small and gross deletions/insertions in the GSS gene. It manifests in the neonatal period with severe metabolic acidosis and increased 5-oxoproline levels, which are associated with neurological symptoms. When the γ-glutamyl cycle is modified due to GSS deficiency, negative feedback is lost, leading to an accumulation of γ-glutamyl cysteine and thereby an increase in 5-oxoproline via the γ-glutamyl cyclotransferase pathway [4,5]. The disease is classified into one of the three forms, depending on clinical severity: mild, moderate, or severe. In its mild form, the mutation affects enzyme stability and results in mild hemolytic anemia. In its moderate form, a decrease in glutathione levels in erythrocytes causes metabolic acidosis with an increased anion gap, in addition to hemolytic anemia. In severely affected patients, 5-oxoproline is increased in blood and urine, metabolic acidosis occurs, and tendencies toward infection and central nervous system disorders are observed [1,6]. In this report, our infant had hemolytic anemia, severe metabolic acidosis, neurological symptoms (lethargy, hypotonia) with central nervous system abnormalities, femur agenesis and a novel GSS gene mutation.
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].