Inosine Monophosphate Dehydrogenase

描述（由申请人提供）：肌苷单磷酸脱氢酶（IMPDH）酶催化鸟嘌呤核苷酸生物合成的限速步骤：将肌苷单磷酸（IMP）转化为单磷酸黄嘌呤（XMP），同时减少NAD。IMPDH控制鸟嘌呤核苷酸库的大小，而鸟嘌呤核苷酸库反过来又控制增殖和许多其他重要的细胞过程。IMPDH抑制剂具有抗增殖作用，使这种酶成为几乎所有疾病的药物靶点；特异性IMPDH抑制剂可用于免疫抑制、抗癌、抗病毒或抗菌化疗。我们已经证明，IMPDH在催化周期中期经历了一个大的构象变化，将酶从脱氢酶转化为水解酶，从而提供了一个独特的机会来研究构象动力学在催化中的作用。这种构象变化似乎也是药物选择性的主要决定因素。本提案概述了对IMPDH的机制和功能的研究。我们将描述解释IMPDH同工酶不同活性的结构特征。除了对设计同工酶特异性的IMPDH抑制剂至关重要外，这项工作将对理解酶催化的结构和功能之间的关系做出重要贡献。

DESCRIPTION (provided by applicant): Inosine monophosphate dehydrogenase (IMPDH) enzyme catalyzes the rate-limiting step in guanine nucleotide biosynthesis: the conversion of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with concomitant reduction of NAD. IMPDH controls the size of the guanine nucleotide pool, which in turn controls proliferation and many other important cellular processes. IMPDH inhibitors are antiproliferative, making the enzyme a drug target for virtually every disease; specific IMPDH inhibitors could be used as immunosuppressive, cancer, antiviral or antimicrobial chemotherapy. We have shown that IMPDH undergoes a large conformational change in mid-catalytic cycle that converts the enzyme from a dehydrogenase to a hydrolase, and thus presents a unique opportunity to investigate the role of conformational dynamics in catalysis. This conformational change also appears to be a major determinant of drug selectivity. This proposal outlines an investigation of the mechanism and function of IMPDH. We will delineate the structural features that account for the varied activities of IMPDH isozymes. In addition to being crucial for the design of isozyme-specific inhibitors of IMPDH, this work will be an important contribution to understanding the relationship between structure and function in enzyme catalysis.