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首页> 外文学位 >Structural studies of three NAD(P)H-dependent enzymes involved in sugar metabolism: Mannitol dehydrogenase, xylose reductase, and lactate dehydrogenase.
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Structural studies of three NAD(P)H-dependent enzymes involved in sugar metabolism: Mannitol dehydrogenase, xylose reductase, and lactate dehydrogenase.

机译：糖代谢中涉及的三种NAD（P）H依赖酶的结构研究：甘露醇脱氢酶，木糖还原酶和乳酸脱氢酶。

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摘要

NAD(P)H-dependent oxidoreductases are important in all forms of metabolism. Sugar- and polyalcohol-specific dehydrogenase/reductases present good systems to study since their roles are well established. Despite the wealth of knowledge concerning NAD(P)H-dependent oxidoreductases, significant gaps exist in many areas. This work investigates catalytic mechanisms, features that confer specificity for cofactors and substrates, and molecular evolution in three enzymes. These enzymes have applications in medical diagnostics, chiral synthesis, biotechnology, and structure-assisted drug design.; Pseudomonas fluorescens mannitol 2-dehydrogenase (pfMDH), a secondary alcohol dehydrogenase, is the first member of the long-chain mannitol dehydrogenase family to be structurally characterized. pfMDH provides remarkable examples of both convergent and divergent evolution. The N-terminal domain includes a Rossmann fold and is involved in NAD+ binding while the C-terminal domain is primarily α-helical and promotes mannitol binding and catalysis. The reaction likely proceeds through an alkoxide intermediate whereby a lysine general base is assisted by two asparagines which precisely An unusual proton-transfer mechanism may return the lysine to its uncharged state.; The crystallographic study of Candida tenuis xylose reductase (ctXR) describes the structure of a family 2 aldo-keto reductase (AKR). Family 2 members are unusual in that many are homodimeric and efficiently utilize NADH in addition to NADPH. The (β/α)8-barrel monomers associate side-to-side via a highly-hydrated dimeric interface that may be required for protein stability. Apparently crucial for efficient NADH utilization is ctXR's ability to change the conformation of two loops as well as the presence of Glu227 on one of these loops. Residues that may be changed to improve biotechnological applications for the conversion of biomass into ethanol are delineated.; X-ray crystal structures of Toxoplasma gondii tachyzoite stage lactate dehydrogenase (LDH1) reveal active-site differences between parasitic and human isozymes. These amino-acid substitutions increase the hydrophobicity of LDH1's active site. As lactate dehydrogenase is necessary for growth of the parasite within human hosts, it presents an attractive target for drug design. The Met163 side chain displaces a conserved water molecule providing a structural explanation for the reduced substrate inhibition and increased catalytic efficiency with APAD+ observed in LDH1.
机译：NAD（P）H依赖的氧化还原酶在所有形式的代谢中都很重要。糖和多元醇特异性的脱氢酶/还原酶由于其作用已被很好地确立，因此是研究的良好系统。尽管有关NAD（P）H依赖的氧化还原酶的知识丰富，但在许多领域仍存在明显的差距。这项工作研究了催化机制，赋予辅因子和底物特异性的功能以及三种酶的分子进化。这些酶可用于医学诊断，手性合成，生物技术和结构辅助药物设计。荧光假单胞菌甘露醇2-脱氢酶（pfMDH）是一种仲醇脱氢酶，是长链甘露醇脱氢酶家族中第一个被结构表征的成员。 pfMDH提供了收敛和发散进化的杰出例子。 N端结构域包括Rossmann折叠，参与NAD + 结合，而C端结构域主要为α-螺旋，促进甘露醇结合和催化。该反应可能通过一种醇盐中间体进行，赖氨酸的一般碱由两种天冬酰胺辅助，这恰好是一种不寻常的质子转移机制可能使赖氨酸回到其不带电状态。 Candida tenuis 木糖还原酶（ctXR）的晶体学研究描述了家族2醛基酮还原酶（AKR）的结构。家庭2成员之所以与众不同，是因为许多成员是同型二聚体，除NADPH之外还有效利用了NADH。 （β/α） 8 -桶形单体通过高度水合的二聚体界面并排缔合，这可能是蛋白质稳定性所必需的。 ctXR改变两个环的构象以及其中一个环上存在Glu227的能力，显然对于有效利用NADH至关重要。描述了可以改变以改善生物技术应用以将生物质转化为乙醇的残留物。刚体弓形虫速殖子阶段乳酸脱氢酶（LDH1）的X射线晶体结构揭示了寄生和人类同工酶之间的活性位点差异。这些氨基酸取代增加了LDH1活性位点的疏水性。由于乳酸脱氢酶是人体宿主体内寄生虫生长所必需的，因此它为药物设计提出了有吸引力的目标。 Met163侧链取代了一个保守的水分子，为在LDH1中观察到的APAD + 减少的底物抑制和提高的催化效率提供了结构上的解释。

著录项

  • 作者

    Kavanagh, Kathryn Louise.;

  • 作者单位

    University of California, Davis.;

  • 授予单位 University of California, Davis.;
  • 学科 Chemistry Biochemistry.; Biology Molecular.; Biophysics General.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 138 p.
  • 总页数 138
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;分子遗传学;生物物理学;
  • 关键词

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