Disease relevance of GSS

• The N-terminal sequence of gamma-GCS-GS is similar to Escherichia coli gamma-GCS, but the C-terminal sequence is an ATP-grasp domain more similar to d-Ala, d-Ala ligase than to any known GS [1].
• In Streptococcus agalactiae, GSH synthesis is catalyzed by a single enzyme, gamma-glutamylcysteine synthetase-glutathione synthetase (gamma-GCS-GS) [1].
• 5-Oxoprolinuria (pyroglutamic aciduria) resulting from glutathione synthetase (GSS) deficiency is an inherited autosomal recessive disorder characterized, in its severe form, by massive urinary excretion of 5-oxoproline, metabolic acidosis, haemolytic anaemia and central nervous system damage [2].
• Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction [3].
• Several episodes of neutropenia were observed in a child with glutathione synthetase deficiency (5-oxoprolinuria) [4].

Psychiatry related information on GSS

• This paper attempts to investigate empirically in 30 subjects some of the theoretical components related to individual differences that are thought by Gudjonsson & Clark (1986) to mediate interrogative suggestibility as measured by the Gudjonsson Suggestibility Scale (GSS; Gudjonsson, 1984a) [5].
• Ophthalmological, psychometric and therapeutic investigation in two sisters with hereditary glutathione synthetase deficiency (5-oxoprolinuria) [6].

High impact information on GSS

• We also characterized a fifth case, an homozygous missense mutation in the gene in an individual affected by a milder-form of the GSS deficiency, which is apparently restricted to erythrocytes and only associated with haemolytic anaemia [2].
• We identified seven mutations at the GSS locus on six alleles: one splice site mutation, two deletions and four missense mutations [2].
• Our data provide the first molecular genetic analysis of 5-oxoprolinuria and demonstrate that GSS deficiency with oxoprolinuria and GSS deficiency without 5-oxoprolinuria are caused by mutations in the same gene [2].
• Protection of granulocytes by vitamin E in glutathione synthetase deficiency [7].
• The administration of vitamin E (alpha-tocopherol) was found to improve polymorphonuclear leukocyte function in an infant with congenital deficiency of glutathione synthetase activity [7].

Chemical compound and disease context of GSS

• Glutathione synthetase-deficient lymphocytes and acetaminophen toxicity [8].
• These substitutions resulted in a strongly stimulated GSH accumulation in the transformed E. coli strain showing that these residues play a crucial role in the differential recognition of beta-alanine and glycine by hGSHS [9].
• To assess the activities of the two enzymes required for glutathione synthesis, gamma-glutamylcysteine synthetase and glutathione synthetase, in various forms of human cataracts [10].
• A 45-month-old girl with 5-oxoprolinuria (pyroglutamic aciduria), hemolysis, and marked glutathione depletion caused by deficiency of glutathione synthetase was followed before and during treatment with ascorbate or N-acetylcysteine [11].
• The glutathione synthase inhibitor, buthionine sulfoximine (BSO), specifically enhances the cytotoxic effects of treosulfan in human glioma cells [12].

Biological context of GSS

• The gene encoding human glutathione synthetase (GSS) maps to the long arm of chromosome 20 at band 11.2 [13].
• In the rat, GSS and GCL are regulated co-ordinately by oxidative stress, and induction of GSS further increases GSH synthetic capacity [14].
• It is postulated that missense mutations will account for the phenotype in the majority of patients with severe GS deficiency [3].
• A variety of structural alignment methods were applied and four highly conserved residues of human glutathione synthetase (Glu-144, Asn-146, Lys-305, and Lys-364) were identified in the binding site [15].
• 5. Southern blots of human genomic DNA hybridized with the glutathione synthetase cDNA revealed a relatively simple pattern of strongly hybridizing fragments, indicating the absence of a large gene family and suggesting that there may be only one glutathione synthetase gene in the human genome [16].

Anatomical context of GSS

• Analysis of somatic cell hybrids showed the human glutathione synthetase gene (GSS) to be located on chromosome 20, and this assignment has been refined to subband 20q11.2 using in situ hybridization [13].
• Oxidative damage to neutrophils in glutathione synthetase deficiency [4].
• Cultured fibroblasts from patients with GS deficiency have low levels of GSH, but instead accumulate gamma-GC [17].
• Addition of radial nerve factor (GSS) increased the yield of 1-MeA up to 19 times when radioactive L-methionine was substrate, but was ineffective with radioactive A [18].
• Optic nerves from CJD- and GSS-, and scrapie-infected mice and hamsters showed severe pathology [19].

Associations of GSS with chemical compounds

• Gamma-glutamylcysteine synthetase-glutathione synthetase: domain structure and identification of residues important in substrate and glutathione binding [1].
• Glutathione synthetase deficiency: is gamma-glutamylcysteine accumulation a way to cope with oxidative stress in cells with insufficient levels of glutathione [17]?
• Because 11,12-epoxyeicosatrienoic acid (11,12-EET) inhibits ENaC activity in the CCD (Wei Y, Lin DH, Kemp R, Yaddanapudi GSS, Nasjletti A, Falck JR, and Wang WH. J Gen Physiol 124: 719-727, 2004), we examined the role of 11,12-EET in mediating the effect of adenosine on ENaC [20].
• Reciprocal crosses of homozygous, diploid females and hemizygous, haploid males of strains GSS (susceptible) and AKITA (resistant) revealed that resistance to pyridaben and fenpyroximate was inherited incompletely dominant with slight differences between maternal and paternal inheritance [21].
• Extensive three-dimensional structural resemblances between biotin carboxylase and the ADP-forming peptide synthetases, represented by glutathione synthetase and D-Ala:D-Ala ligase, reveal a previously unsuspected evolutionary relationship between two major families of ADP-forming ligases [22].

Regulatory relationships of GSS

• Overexpression of either Nrf1 or Nrf2 induced the GSS promoter activity by 130 and 168% respectively [14].

Other interactions of GSS

• Two regions homologous to the NFE2 motif are demonstrated to be important for basal expression of human GSS, as mutation of these sites reduced the promoter activity by 66% [14].
• The recombinant protein exhibits glutathione synthetase activity and occurs as a homodimer [16].
• RESULTS: The expression of GPx-1, GPx-4, GSSG-R, GSH-S, SOD-1, CAT mRNA was not affected by a single LA treatment [23].
• Improved erythrocyte survival with high-dose vitamin E in chronic hemolyzing G6PD and glutathione synthetase deficiencies [24].
• Glutathione is synthesized from its constituent amino acids by the sequential action of gamma-glutamylcysteine synthetase (gamma-GCS) and GSH synthetase [25].

Analytical, diagnostic and therapeutic context of GSS

• Cell-free extracts of cultured fibroblasts from 9 patients with GS deficiency and 9 control subjects were analysed by HPLC for low-molecular-weight thiol compounds [17].
• Larvae of both strains, AKITA and UK-99, showed 1,100- and 480-fold resistance against pyridaben, 870- and 45-fold resistance against fenpyroximate, and 33- and 44-fold resistance against tebufenpyrad, respectively, in a foliar spray application bioassay compared with the susceptible strain GSS [21].
• On the other hand, GSH-S transferase, highly purified by affinity chromatography, had no inhibitory activity [26].
• Northern blot analysis with coding region probes revealed that in roots of Cd-exposed plants transcript amounts for OAS-TL and GSHS were only moderately increased, whereas gamma-ECS mRNA showed a stronger increase [27].
• RESULTS: Significant decreases in GSH levels and gamma-GCS activity but not GSH-S were observed in ND, HD and CAPD patients compared with controls [28].

References