STRUCT/FUNCT ANALYSIS OF ANTHRACYCLINE REDUCTION BY HUMAN CARBONYL REDUCTASE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。人羰基还原酶还原蒽环类药物的结构/功能分析蒽环类药物是一类常用的治疗癌症的药物。虽然是有效的抗肿瘤药物，但由于潜在的危及生命的心脏毒性，它们的使用受到限制。有重要的证据表明，毒性作用是由于一种蒽环类酒精代谢物可以在心脏细胞中形成和积累。一种被认为与这种代谢物的形成有关的酶是羰基还原酶（CR）。该建议旨在确定CR的功能，并以预测患者对蒽环类药物心脏毒性的易感性为长期目标。本课题的具体目的是：1)对重组人羰基还原酶进行动力学表征；2)设计和测试重组人羰基还原酶抑制剂；3)重组人羰基还原酶结晶并测定其x射线晶体结构。CR晶体将被送到爱荷华大学的Ramaswamy博士进行进一步的分析和结构测定。

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.