Inosine Monophosphate Dehydrogenase

肌苷单磷酸脱氢酶

• 批准号: 6720721
• 负责人: Lizbeth K. Hedstrom
• 金额: $ 25.56万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6720721
• 关键词: X ray crystallography; alcohol dehydrogenase; catalyst; conformation; enzyme activity; enzyme mechanism; enzyme structure; inosine monophosphate; isozymes; potassium ion

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.

描述（由申请人提供）：肌苷单磷酸脱氢酶（IMPDH）催化鸟嘌呤核苷酸生物合成中的限速步骤：肌苷单磷酸（IMP）转化为黄苷单磷酸（XMP），伴随NAD还原。IMPDH控制鸟嘌呤核苷酸库的大小，这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，使该酶成为几乎所有疾病的药物靶标;特异性IMPDH抑制剂可用作免疫抑制剂、癌症、抗病毒或抗微生物化疗。我们已经表明，IMPDH经历了一个大的构象变化中的催化循环，将酶从脱氢酶的水解酶，从而提出了一个独特的机会，调查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。该提案概述了对人权事务国际法庭的机制和职能的调查。我们将描绘的结构特征，占不同的活动IMPDH同工酶。除了对IMPDH同工酶特异性抑制剂的设计至关重要之外，这项工作还将对理解酶催化中结构与功能之间的关系做出重要贡献。