Proton-Shuttle-Assisted Heterolytic Carbon–Carbon Bond Cleavage and Formation
Proton-Shuttle-Assisted Heterolytic Carbon–Carbon Bond Cleavage and Formation
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DOI：
10.1021/acscatal.5b00079
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发表时间：
2015-03
期刊：
影响因子：
12.9
通讯作者：
Jingwei Zhou;Ruibo Wu;Binju Wang;Z. Cao;Honggao Yan;Y. Mo
中科院分区：
文献类型：
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作者：
Jingwei Zhou;Ruibo Wu;Binju Wang;Z. Cao;Honggao Yan;Y. Mo
DXP还原异构酶（DXR）催化1-脱氧-D-木酮糖-5-磷酸（DXP）转化为2-C-甲基-D-β-4-磷酸（MEP）是萜类化合物生物合成的关键步骤。这种MEP途径对于大多数致病细菌是必需的，但在人类中不存在，因此，它是开发新型抗生素的有吸引力的靶点。为此，关键是要阐明转换机制和确定过渡态，因为许多药物是过渡态类似物。在这里，我们进行了广泛的结合量子力学（密度泛函理论B3 LYP/6- 31 G *）和分子力学分子动力学模拟，以阐明催化机制。计算结果证实了DXP通过异裂C3-C4键断裂产生的两个亚稳态片段的瞬时存在，即1-丙烯-1，2-二醇和磷酸甘油醛，与最新的动力学同位素效应（KIE）实验符合雅阁。C3-C4键的异裂断裂和C2-C4键的形成是一个重要的过程。
The conversion of 1-deoxy-D-xylulose 5-phosphate (DXP) to 2-C-methyl-D-erythritol 4-phosphate (MEP) catalyzed by DXP reductoisomerase (DXR) is the committing step in the biosynthesis of terpenoids. This MEP pathway is essential for most pathogenic bacteria but absent in human, and thus, it is an attractive target for the development of novel antibiotics. To this end, it is critical to elucidate the conversion mechanism and identify the transition state, as many drugs are transition-state analogues. Here we performed extensive combined quantum mechanical (density functional theory B3LYP/6-31G*) and molecular mechanical molecular dynamics simulations to elucidate the catalytic mechanism. Computations confirmed the transient existence of two metastable fragments of DXP by the heterolytic C3–C4 bond cleavage, namely, 1-propene-1,2-diol and glycoaldehyde phosphate, in accord with the most recent kinetic isotope effect (KIE) experiments. Significantly, the heterolytic C3–C4 bond cleavage and C2–C4 bond formatio...