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. The Omega class Glutathione-S-Transferases (GSTO) are the most recently discovered members of this structural family. They display several atypical activities of interest. Principally, that they are major enzymes involved in human arsenic metabolism. Due to consumption of contaminated drinking water, this is a process potentiating carcinogenesis and heart disease in millions of people worldwide. The details of how its toxicity is mediated however, are still poorly understood. Additionally, the Omega GSTs display dehydroascorbate and thioltransferase activities, the latter of which may play a role in modulating the function of other enzymes. Indeed, the Omega GSTs are implicated in Ryanodine Receptor modulation, the early development of Alzheimers and Parkinsons disease and are the target of pharmaceuticals that inhibit inteleukin-1b secretion. Of the two functional proteins belonging to this class, the first has proven most amenable to crystallization. Interestingly it posses an additional activity not shared by its homologue, the detoxification of pesticide metabolites to acetophenones. We wish to crystallographically characterize the mechanistic details of this enzyme in order to gain a more fundamental understanding of the physiological phenomena with which it is associated.
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