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首页> 外文期刊>Biochemistry >The Energy Landscape of 3-Deoxy-d-manno-octulosonate 8-Phosphate Synthase
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The Energy Landscape of 3-Deoxy-d-manno-octulosonate 8-Phosphate Synthase

机译：3-脱氧-d-甘露聚糖-八磺酸盐8-磷酸合酶的能量构象

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摘要

3-Deoxy-D-manno-octulosonate 8-phosphate (KDO8P) synthase catalyzes the condensation ofnarabinose 5-phosphate (A5P) and phosphoenolpyruvate (PEP) to form KDO8P, a key precursor in thenbiosynthesis of the endotoxin of Gram-negative bacteria. Earlier studies have established that the condensa-ntion occurs with a syn addition of water to the si side of C2PEPnand of C3PEPnto the re side of C1A5Pn. Twonstepwise mechanisms have been proposed for this reaction. One involves a transient carbanion intermediate,nformed by attack of water or a hydroxide ion on C2PEPn. The other involves a transient oxocarbeniumnzwitterionic intermediate, formed by direct attack of C3PEPnonto C1A5Pn, followed by reaction of water at C2.nIn both cases, the transient intermediates are expected to converge to a more stable tetrahedral intermediate,nwhich decays into KDO8P and inorganic phosphate. In this study we calculated the potential energy surfacesn(PESs) associated with all possible reaction paths in the active site of KDO8PS: the path involving a synnaddition of water to the si side of C2PEPnand of C3PEPnto the re side of C1A5Pn, with the PEP phosphate groupndeprotonated, has the lowest energy barrier (∼14 kcal/mol) and is strongly exoergonic (reaction energy ofn-38 kcal/mol). Consistent with the experimental observations, other potential reaction paths, like an antinaddition of water to the re side of C2PEPnor addition of C3PEPnto the si side of C1A5Pn, are associated with muchnhigher barriers. An important new finding of this study is that the lowest energy reaction path does notncorrespond to either one of the pure stepwisemechanisms proposed formerly but can be described instead as anpartially concerted reaction between PEP,A5P, and water. The success in using PESs to reproduce establishednfeatures of the reaction and to discriminate between different mechanisms suggests that this approach may benof general utility in the study of other enzymatic reactions.
机译：3-脱氧-D-甘露糖醛酸八磷酸酯（KDO8P）合酶催化萘糖5-磷酸酯（A5P）与磷酸烯醇丙酮酸（PEP）的缩合形成KDO8P，这是革兰氏阴性细菌内毒素生物合成的关键前体。较早的研究已经确定，冷凝是在C2PEPn的si侧和C3PEPn的si侧同时添加水的情况下发生的。已经提出了用于该反应的两个逐步机制。一种涉及瞬态碳负离子中间体，该中间体由水或氢氧根离子侵蚀C2PEPn形成。另一种涉及瞬态氧碳烯两性离子中间体，该中间体由C3PEPnon直接攻击C1A5Pn，然后在C2处发生水反应而形成。在两种情况下，均预期瞬态中间体会收敛为更稳定的四面体中间体，后者会分解为KDO8P和无机磷酸盐。在这项研究中，我们计算了与KDO8PS活性位点中所有可能的反应路径相关的势能面n（PESs）：该路径涉及水与C2PEPn的si侧和C3PEPn的同侧加到C1A5Pn的背面，以及PEP磷酸盐基团去质子化，具有最低的能垒（约14 kcal / mol），并且是强外能的（反应能为n-38 kcal / mol）。与实验观察结果一致，其他潜在的反应途径，例如向C2PEP的反侧添加水或向C1A5Pn的si侧添加C3PEPn，都与更高的势垒有关。这项研究的一个重要的新发现是，最低的能量反应路径与先前提出的任一纯逐步机理都不对应，但可以描述为PEP，A5P和水之间的部分协同反应。使用PES成功复制反应的既定特征并区分不同机制的成功表明，该方法可能在其他酶促反应的研究中不具有通用性。

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  • 来源
    《Biochemistry》 |2009年第49期|p.11706-11714|共9页
  • 作者

    Peng Tao Domenico L. Gatti and H. Bernhard Schlegel;

  • 作者单位

    ‡Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan 48201, and§Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202;

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