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首页> 外文期刊>Chemistry: A European journal >Enzymatic Activity and Thermodynamic Stability of Biliverdin IXβ Reductase Are Maintained by an Active Site Serine
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Enzymatic Activity and Thermodynamic Stability of Biliverdin IXβ Reductase Are Maintained by an Active Site Serine

机译：BiliverdinIxβ还原酶的酶活性和热力学稳定性由活性位点丝氨酸维持

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摘要

Biliverdin reductase IXβ (BLVRB) is a crucial enzyme in heme metabolism. Recent studies in humans have identified a loss-of-function mutation (Ser111Leu) that unmasks a fundamentally important role in hematopoiesis. We have undertaken experimental and thermodynamic modeling studies to provide further insight into the role of the cofactor in substrate accessibility and protein folding properties regulating BLVRB catalytic mechanisms. Site-directed mutagenesis with molecular dynamic (MD) simulations establish the critical role of NAD(P)H-dependent conformational changes on substrate accessibility by forming the "hydrophobic pocket", along with identification of a single key residue (Arg35) modulating NADPH/NADH selectivity. Loop80 and Loop120 block the hydrophobic substrate binding pocket in apo BLVRB (open), whereas movement of these structures after cofactor binding results in the "closed" (catalytically active) conformation. Both enzymatic activity and thermodynamic stability are affected by mutation( s) involving Ser111, which is located in the core of the BLVRB active site. This work 1) elucidates the crucial role of Ser111 in enzymatic catalysis and thermodynamic stability by active site hydrogen bond network; 2) defines a dynamic model for apo BLVRB extending beyond the crystal structure of the binary BLVRB/NADP~+ complex; 3) provides a structural basis for the "encounter" and "equilibrium" states of the binary complex, which are regulated by NAD(P)H.
机译：Biliverdin还原酶IXβ（BLVRB）是血红素代谢的关键酶。最近的人类研究发现了功能丧失突变（Ser111Leu），使得非癌症在血液缺陷中的重要作用。我们已经采取了实验性和热力学建模研究，进一步了解辅助因子在底物可替代性和蛋白质折叠性能调节BLVRB催化机制的作用。具有分子动态（MD）模拟的部位导向诱变，通过形成“疏水口袋”，建立NAD（P）H依赖性构象变化对底物可访问性的关键作用，以及调制NADPH /的单个键残留物（ARG35）的鉴定NADH选择性。 Loop80和Loop120阻断APO BLVRB（OPEN）中的疏水基板结合袋，而在辅因子结合后这些结构的运动导致“闭合”（催化活性）构象。酶活性和热力学稳定性均受涉及SER111的突变的影响，该突变位于BLVRB活性位点的核心中。这项工作1）通过活性位点氢键网络阐明SER111在酶促催化和热力学稳定性中的关键作用; 2）定义了超出二元BLVRB / NADP〜+复合物的晶体结构的APO BLVRB的动态模型; 3）为二元复合物的“遇到”和“均衡”状态提供了由NAD（P）H调节的“遇到”和“平衡”状态的结构基础。

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  • 来源
    《Chemistry: A European journal》 |2017年第8期|共10页
  • 作者

    Wen-Ting Chu; Natasha M. Nesbitt; Dmitri V. Gnatenko; Zongdong Li; Beibei Zhang; Markus A. Seeliger; Seamus Browne; Timothy J. Mantle; Wadie F. Bahou; Jin Wang;

  • 作者单位

    State Key Laboratory of Electroanalytical Chemistry Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun Jilin 130022 (P. R. China);

    Department of Medicine Stony Brook University Stony Brook NY 11794 (USA);

    Department of Medicine Stony Brook University Stony Brook NY 11794 (USA);

    Department of Medicine Stony Brook University Stony Brook NY 11794 (USA);

    Department of Biochemistry and Cell Biology Stony Brook University Stony Brook NY 11794 (USA);

    Department of Pharmacological Sciences Stony Brook University Stony Brook NY 11794 (USA);

    Department of Biochemistry Trinity College Dublin 2 (Ireland);

    Department of Biochemistry Trinity College Dublin 2 (Ireland);

    Department of Medicine Stony Brook University Stony Brook NY 11794 (USA);

    State Key Laboratory of Electroanalytical Chemistry Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun Jilin 130022 (P. R. China);

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 应用化学;
  • 关键词

    cofactors; conformation analysis; enzyme catalysis; molecular dynamics; molecular modeling;

    机译：辅助因子;构象分析;酶催化;分子动力学;分子造型;

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