Abstract
Glutathione plays a crucial role in free radical scavenging, oxidative injury, and cellular homeostasis. Previously, we identified a non-synonymous polymorphism (P462S) in the gene encoding the catalytic subunit of glutamate-cysteine ligase (GCLC), the rate-limiting enzyme in glutathione biosynthesis. This polymorphism is present only in individuals of African descent. Presently, we report that this ethnic-specific polymorphism (462S) encodes an enzyme with significantly decreased in vitro activity when expressed by either a bacterial or mammalian cell expression system. In addition, overexpression of the 462P wild-type GCLC enzyme results in higher intracellular glutathione concentrations than overexpression of the 462S isoform. We also demonstrate that apoptotically stimulated mammalian cells overexpressing the 462S enzyme have increased caspase activation and increased DNA laddering compared to cells overexpressing the wild-type 462P enzyme. Finally, we genotyped several African and African-descent populations and demonstrate that the 462S polymorphism is in Hardy-Weinberg disequilibrium, with no individuals homozygous for the 462S polymorphism identified. These findings describe a glutathione production pathway polymorphism...Continue Reading
References
Sep 1, 1974·Archives of Internal Medicine·F RichardsC L Spurr
Jan 1, 1983·Annual Review of Biochemistry·A Meister, M E Anderson
May 1, 1996·European Journal of Immunology·T ChibaK Kikuchi
Jun 25, 1998·Archives of Biochemistry and Biophysics·Z Tu, M W Anders
Aug 7, 1998·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·C Ruwende, A Hill
May 11, 2000·Proceedings of the National Academy of Sciences of the United States of America·Z Z ShiM W Lieberman
Dec 19, 2000·Biochemical and Biophysical Research Communications·T P DaltonD W Nebert
Jun 26, 2002·Circulation·Shin-ichi NakamuraHisao Ogawa
Mar 29, 2003·Blood·David HamiltonGerald Batist
Jun 20, 2003·Analytical Biochemistry·Collin C WhiteTerrance J Kavanagh
Sep 6, 2003·Biological Chemistry·Yong-Won KwonJunji Yodoi
Mar 31, 2004·Molecular Genetics and Metabolism·Marshall L SummarGary Cunningham
May 5, 2007·Experimental and Clinical Endocrinology & Diabetes : Official Journal, German Society of Endocrinology [and] German Diabetes Association·L M BekrisA Lernmark
Oct 9, 2007·Proceedings of the National Academy of Sciences of the United States of America·René GysinKim Q Do
Nov 21, 2007·Haematologica·M Mañú PereiraJ L Vives Corrons
Citations
Jan 19, 2012·Toxicological Sciences : an Official Journal of the Society of Toxicology·Brooke N NakamuraUlrike Luderer
Oct 11, 2013·Toxicology Letters·Laura OrtizUlrike Luderer
Dec 3, 2013·Toxicology Letters·Laura OrtizUlrike Luderer
Dec 17, 2010·Neurotoxicology·Truc M LeMarshall L Summar
Dec 10, 2013·Free Radical Biology & Medicine·Rob van ZwietenDirk Roos
May 25, 2011·Free Radical Biology & Medicine·Sutapa MukhopadhyayPandu R Gangula
Nov 9, 2012·Cancer Research·Jinhwan LimUlrike Luderer