Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 412, Issue 1, Pages 121-126Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2011.07.056
Keywords
Glutathione; Glutathione synthetase; Glutathione synthetase deficiency; Transgenic mice; gamma-Glutamylcysteine
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Funding
- HRH Crown Princess Lovisa Society for Child Care
- Foundation in memory of Axel Tielman
- Swedish Society of Medicine
- Swedish Medical Research Council
- Society for Childcare
- Ake Wiberg Foundation
- Wera Ekstrom Foundation
- Sven Jerring Foundation
- Free Mason's in Stockholm Foundation for Children's Welfare
- Swedish Research Council
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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 (gamma-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, gamma-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. gamma-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. (C) 2011 Elsevier Inc. All rights reserved.
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