Disease relevance of GSH2

• In the present report, we show that crude extracts of Streptococcus agalactiae catalyze the gamma-GCS and GS reactions and can synthesize GSH from its constituent amino acids [1].

High impact information on GSH2

• GSH is synthesized from its constituent amino acids by two ATP-dependent reactions catalyzed by gamma-glutamylcysteine synthetase and glutathione synthetase [2].
• Gamma-glutamylcysteine synthetase (gamma-GCS) and glutathione synthetase (GS), distinct enzymes that together account for glutathione (GSH) synthesis, have been isolated and characterized from several Gram-negative prokaryotes and from numerous eukaryotes including mammals, amphibians, plants, yeast, and protozoa [1].
• This novel bifunctional enzyme, referred to as gamma-GCS-GS, has been characterized in terms of catalytic activity, substrate specificity, and inhibition by GSH, cystamine, and transition state analog sulfoximines [1].
• The C terminus (360 amino acids) is, however, homologous to D-Ala, D-Ala ligase (24% identity; 38% similarity), an enzyme having the same protein fold as known GS proteins [1].
• The present study demonstrates that GSH2 expression is also regulated by Yap1p under oxidative stress-induced conditions [3].

Chemical compound and disease context of GSH2

• Glutathione synthesis in Streptococcus agalactiae. One protein accounts for gamma-glutamylcysteine synthetase and glutathione synthetase activities [1].

Biological context of GSH2

• In contrast to a strain deleted for GSH1, which lacks both GSH and gamma-Glu-Cys, the strain deleted for GSH2 was found to be unaffected in mitochondrial function as well as resistance to oxidative stress induced by hydrogen peroxide, tert-butyl hydroperoxide, and the superoxide anion [4].
• Glutathione synthetase activity in transformant carrying the GSH2 gene with multicopy plasmid increased approximately 4-fold [5].
• The GSH2 gene contained an open reading frame (1473 bp) with 491 amino acids, and molecular weight of the GSH2 gene product was calculated to be 55,812 [5].
• The gene was isolated as a 4.3-kb XbaI fragment that was capable of restoring GSH synthesis, heavy-metal resistance and cell proliferation when introduced into gsh2 mutant cells [6].
• The deduced amino acid sequence of P. falciparum GS shares only a moderate degree of identity with other known GSs, but the residues responsible for substrate and co-factor binding are almost all conserved, with the exception of the ones involved in gamma-glutamylcysteine binding [7].

Anatomical context of GSH2

• Antioxidants such as N,N',-diphenyl-p-phenylenediamine (DPPD), melatonin and vitamin E, and inhibitors of permeability transition of mitochondria, cyclosporin A and trifluoperazine, inhibited the LOOH-triggered cell death, while an inhibitor of glutathione synthetase, buthionine sulfoximine (BSO), enhanced the cell death by LOOH [8].

Associations of GSH2 with chemical compounds

• In contrast, strains deleted for GSH2, encoding the second step in GSH synthesis, grow poorly as the dipeptide intermediate, gamma-glutamylcysteine, can partially substitute for GSH [9].
• Glutathione (GSH) synthetase (Gsh2) catalyzes the ATP-dependent synthesis of GSH from gamma-glutamylcysteine (gamma-Glu-Cys) and glycine [4].
• GSH is synthesized by the action of two ATP-dependent enzymic steps, in which gamma-glutamylcysteine synthetase (gamma-GCS) catalyses the ligation of glutamate and cysteine and subsequently glutathione synthetase (GS) adds glycine to the dipeptide [7].
• We have determined structures of yeast glutathione synthase in two forms: unbound (2.3 A resolution) and bound to its substrate gamma-glutamylcysteine, the ATP analog AMP-PNP, and two magnesium ions (1.8 A resolution) [10].
• Growth studies showed that the most sensitive strains to 2-oxoaldehydes were the null mutants for GSH1 and GLO1, coding for glutathione synthase I and glyoxalase I respectively [11].

Other interactions of GSH2

• Both gsh1 and gsh2 mutants could acquire thermotolerance by mild heat-shock stress and induction of Hsp104p in both mutants was normal; however, mutant cells died faster by heat shock than their parental wild-type strain [12].
• The gsh2-deficient mutant, which accumulates gamma-glutamylcysteine (an intermediate of glutathione biosynthesis), was also sensitive to methylglyoxal compared with the isogenic wild type strain, although the growth arrest caused by methylglyoxal was partially restored by overexpression of the GLO1 gene [13].
• Glutathione synthase (GSH1) deletion led to decreased DHA survival in agreement with the glutathione cofactor requirement for the SFA1-encoded activity [14].

Analytical, diagnostic and therapeutic context of GSH2

• Sequence alignments of the proteins encoded by the cDNA clones for glutathione synthetase from Arabidopsis and S. pombe show that the Arabidopsis protein contains 200 extra amino acids at the N-terminus [15].

References