STRUCT/FUNCT ANALYSIS OF ANTHRACYCLINE REDUCTION BY HUMAN CARBONYL REDUCTASE

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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. Structure/function analysis of anthracycline reduction by human carbonyl reductase Anthracyclines are a family of drugs commonly used to treat cancer. Though potent anti-tumor drugs, their use is limited due to potentially life-threatening cardiotoxicity. There is significant evidence that the toxic effects are due to an anthracycline alcohol metabolite that can form and accumulate in cardiac cells. One enzyme thought to be linked to the formation of this metabolite is carbonyl reductase (CR) This proposal seeks to define the function of CR with the long term goal of predicting the susceptibility of patients to anthracycline cardiotoxicity. The specific aims of this project are: 1) To characterize kinetically recombinant human carbonyl reductase; 2) To design and test inhibitors of recombinant human carbonyl reductase; 3) To crystallize recombinant human carbonyl reductase and determine its X-ray crystalline structure. Crystals of CR will be sent to Dr. Ramaswamy at the University of Iowa for further analysis and structure determination.