TY - JOUR
T1 - Glutathione is essential for early embryogenesis - Analysis of a glutathione synthetase knockout mouse
AU - Winkler, Andreas
AU - Njålsson, Runa
AU - Carlsson, Katarina
AU - Elgadi, Abdelaziz
AU - Rozell, Björn
AU - Abraham, Linu
AU - Ercal, Nuran
AU - Shi, Zheng Zheng
AU - Lieberman, Michael W.
AU - Larsson, Agne
AU - Norgren, Svante
N1 - Funding Information:
These studies were supported by grants from the HRH Crown Princess Lovisa Society for Child Care, the Foundation in memory of Axel Tielman, the Swedish Society of Medicine, the Swedish Medical Research Council, the Society for Childcare, the Åke Wiberg Foundation, the Wera Ekström Foundation, the Sven Jerring Foundation, the Free Mason’s in Stockholm Foundation for Children’s Welfare, and the Swedish Research Council, which are gratefully acknowledged.
PY - 2011/8/19
Y1 - 2011/8/19
N2 - 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.
AB - 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.
KW - γ-Glutamylcysteine
KW - Glutathione
KW - Glutathione synthetase
KW - Glutathione synthetase deficiency
KW - Transgenic mice
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U2 - 10.1016/j.bbrc.2011.07.056
DO - 10.1016/j.bbrc.2011.07.056
M3 - Article
C2 - 21802407
AN - SCOPUS:80051781561
SN - 0006-291X
VL - 412
SP - 121
EP - 126
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 1
ER -