MECHANISTIC STUDIES OF GLUTATHIONE METABOLIC ENZYMES

University Of Chicago, Chicago IL

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Glutathione is a small tripeptide comprised of glutamate, cysteine, and glycine that is vital for normal cellular function. Glutathione is involved in numerous biological processes including the storage and transport of cysteine, as well as the biosynthesis of molecules involved in the inflammation response. However, its primary function appears to be in the maintenance of intracellular redox homeostasis by affording protection against reactive oxygen and nitrogen species. To attain a comprehensive understanding of glutathione homeostasis, further investigation of the glutathione metabolic enzymes at the protein level is required to complement ongoing studies of gene regulation. The proposed studies will focus on two enzymes: glutamate cysteine ligase (GCL) and γ-glutamyl transpeptidase (GGT), which catalyze the committed steps in glutathione biosynthesis and reclamation respectively. Previously, we have collected several data sets of H. pylori GGT (HpGT) in complex with various ligands. The current studies are focused on HpGT/inhibitor complexes. These structures will be used to aid in second generation inhibitor design. Recently, we determined the structure of yeast GCL by SAD using data collected on our in house system. We are requesting access to APS to collect high resolution data sets of the apoenzyme, various substrate complexes, and inhibitor bound structures. Each of these structures has been successfully solved by molecular replacement and the improved data that we will collect at the APS will aid in model refinement, analysis, and publication.