title: Glutathione is essential for early embryogenesis--analysis of a glutathione synthetase knockout mouse.
abstract: Glutathione (GSH) is present in all mammalian tissues and plays a crucial role in many cellular processes. The second and final step in the synthesis involves the formation of GSH from gamma-glutamylcysteine (γ-GC) and glycine and is catalyzed by glutathione synthetase (GS). GS deficiency is a rare autosomal recessive disorder, and is present in patients with a range of phenotypes, from mild hemolytic anemia and metabolic acidosis to severe neurologic disorders or even death in infancy. The substrate for GS, γ-GC, has been suggested as playing a protective role, by substituting for GSH as an antioxidant in GS deficient patients. To examine the role of GS and GSH metabolites in development, we generated mice deficient in GSH by targeted disruption of the GS gene (Gss). Homozygous mice died before embryonic day (E) 7.5, but heterozygous mice survived with no distinct phenotype. GS protein levels and enzyme activity, as well as GSH metabolites, were investigated in multiple tissues. Protein levels and enzyme activity of GS in heterozygous mice were diminished by 50%, while GSH levels remained intact. γ-GC could not be detected in any investigated tissue. These data demonstrate that GSH is essential for mammalian development, and GSH synthesis via GS is an indispensable pathway for survival.
authors.affiliation: Division of Pediatric Endocrinology, Department of Woman and Child Health, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-14186 Stockholm, Sweden. Andreas.Winkler@karolinska.se
authors.forename: Andreas
authors.initials: A
authors.lastname: Winkler
authors.forename: Runa
authors.initials: R
authors.lastname: Njålsson
authors.forename: Katarina
authors.initials: K
authors.lastname: Carlsson
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: Elgadi
authors.forename: Björn
authors.initials: B
authors.lastname: Rozell
authors.forename: Linu
authors.initials: L
authors.lastname: Abraham
authors.forename: Nuran
authors.initials: N
authors.lastname: Ercal
authors.forename: Zheng-Zheng
authors.initials: ZZ
authors.lastname: Shi
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lieberman
authors.forename: Agne
authors.initials: A
authors.lastname: Larsson
authors.forename: Svante
authors.initials: S
authors.lastname: Norgren
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D047108:Embryonic Development / Q000235:genetics*; D005978:Glutathione / Q000096:biosynthesis / Q000502:physiology*; D005981:Glutathione Synthase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress
chemical_list: D005981:Glutathione Synthase; D005978:Glutathione