S37: Structural insights into glutathione homeostasis

Glutathione (GSH), γ-glutamylcysteinylglycine, is a low molecular weight thiol, central to maintenance of redox homeostasis.  Among its normal functions are the scavenging of reactive oxygen and nitrogen species, storage and transport of cysteine, leukotriene and prostaglandin biosynthesis, and regulation of enzyme activity via reduction of disulfide bonds and glutathionylation.  Disruption of glutathione metabolism is associated with the progression of AIDS, cancer, and neurodegenerative conditions such as Parkinson’s and Alzheimer’s disease.  Glutathione homeostasis is modulated to a large extent by two enzymes: glutamate cysteine ligase, which catalyzes the committed step in glutathione biosynthesis, and γ-glutamyltranspeptidase, which initiates glutathione reclamation.  Targeted disruption of either enzyme severely compromises fitness, underscoring the importance of this redox buffer.  In an attempt to understand how glutathione levels are dynamically regulated, we have initiated structural and functional studies of these two critical enzymes.  Examination of glutamate cysteine ligase and γ-glutamyltranspeptidase crystal structures reveals many of the details of catalysis and suggests possible mechanisms of post-translational regulation of enzymatic activity.