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Structural characterization of the active flap of IMP dehydrogenase: A link between drug selectivity and catalytic efficiency.

机译:IMP脱氢酶活性瓣的结构表征:药物选择性和催化效率之间的联系。

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摘要

Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the oxidation of IMP to XMP with the reduction of NAD. The reaction is the rate-limiting step in de novo guanine nucleotide biosynthesis, which makes IMPDH a drug target in immunosuppressive, antiviral and antitumor chemotherapy.; Mycophenolic acid (MPA) is an IMPDH inhibitor widely used as an immunosuppressive agent in kidney transplantation. MPA specifically binds to the E-XMP* intermediate formed in the reaction pathway. Mammalian IMPDHs have higher affinity for MPA but lower kcat, while microbial isozymes have lower affinity for MPA but higher kcat. The selectivity of MPA is attributed to the accumulation of E-XMP* in the reaction, the affinity of the MPA binding site and an conformational change propagating from the nicotinamide subsite to the adenosine subsite of NAD site. A non-conserved distal flap in the active site appears to be important to the MPA affinity and IMPDH activity, so its movement may account for the unknown conformational change.; The goal of this thesis is to identify the structural basis of the conformational change that determines the MPA selectivity and the catalytic efficiency of IMPDH. We solved two x-ray crystal structures of the Tritrichomonas foetos IMPDH catalytic domain in complex with IMP and beta-Me-TAD and in complex with a transition state analog mizoribine 5'-monophosphate (MZP), respectively. The E·IMP·beta-Me-TAD structure defines the NAD site and reveals the structural difference of the adenosine end between microbial and mammalian IMPDHs. The binding of NAD also orients the active site loop for catalysis. However, the distal flap is disordered in the ternary complex. The E·MZP structure captures a closed conformation of the distal flap in the nicotinamide subsite, suggesting it competes for the same binding site with MPA. The conserved Arg-Tyr in the distal flap coordinates to MZP via a water molecule, suggesting it activates the water to hydrolyze the E-XMP* intermediate. Therefore, the distal flap controls both drug selectivity and catalytic efficiency of IMPDH by switching between the open and closed conformations.
机译:肌苷5'-单磷酸脱氢酶(IMPDH)催化IMP氧化为XMP,同时降低NAD。该反应是从头鸟嘌呤核苷酸生物合成中的限速步骤,使IMPDH成为免疫抑制,抗病毒和抗肿瘤化学治疗的药物靶标。麦考酚酸(MPA)是一种IMPDH抑制剂,在肾脏移植中被广泛用作免疫抑制剂。 MPA特异性结合在反应路径中形成的E-XMP *中间体。哺乳动物IMPDH对MPA的亲和力较高,但kcat较低,而微生物同工酶对MPA的亲和力较低,但kcat较高。 MPA的选择性归因于反应中E-XMP *的积累,MPA结合位点的亲和力以及从烟酰胺亚位点传播到NAD位点的腺苷亚位点的构象变化。活性部位远端皮瓣的非保守性似乎对MPA亲和力和IMPDH活性很重要,因此其运动可能是未知构象变化的原因。本文的目的是确定构象变化的结构基础,该构象变化决定了MPA的选择性和IMPDH的催化效率。我们解决了Tritrichomonas foetos IMPDH催化域的两个X射线晶体结构,分别与IMP和β-Me-TAD以及与过渡态类似物咪唑啉5'-单磷酸酯(MZP)形成复合物。 E·IMP·β-Me-TAD结构定义了NAD位点,揭示了微生物和哺乳动物IMPDH之间腺苷末端的结构差异。 NAD的结合也使活性位点环定向用于催化。但是,三叉复合体的远端皮瓣混乱。 E·MZP结构在烟酰胺亚位点捕获了远端皮瓣的闭合构象,表明它与MPA竞争相同的结合位点。远端皮瓣中保守的Arg-Tyr通过水分子与MZP配位,表明它激活水以水解E-XMP *中间体。因此,远端皮瓣通过在打开和关闭构象之间切换来控制IMPDH的药物选择性和催化效率。

著录项

  • 作者

    Gan, Lu.;

  • 作者单位

    Brandeis University.;

  • 授予单位 Brandeis University.;
  • 学科 Chemistry Biochemistry.; Chemistry Pharmaceutical.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 169 p.
  • 总页数 169
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;药物化学;
  • 关键词

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