新型3-脱氧-d -甘露糖醛酸8-磷酸合酶抑制剂的结构设计。

Drug design and discovery Pub Date : 2003-01-01
Xingjue Xu, Jian Wang, Claude Grison, Sylvian Petek, Philippe Coutrot, Matthew R Birck, Ronald W Woodard, Domenico L Gatti
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引用次数: 0

摘要

3-脱氧- d -甘露糖醛酸8-磷酸(KDO8P)是KDO的磷酸化前体,是革兰氏阴性菌脂多糖的必需糖。KDO8P是由一种特定的合成酶(KDO8PS)通过浓缩5-磷酸阿拉伯糖(A5P)和磷酸烯醇丙酮酸(PEP)产生的,并释放无机磷酸盐。由于KDO8PS存在于细菌和植物中,但不存在于哺乳动物细胞中,并且使KDO8PS失活的突变也会阻断细胞复制,因此KDO8PS是设计通过阻断脂多糖生物合成的新型抗菌剂的有希望的靶点。以往的研究表明,一种模拟缩合反应中间体的化合物是一种良好的配体和有效的抑制剂。本文报道了该抑制剂的新衍生物与KDO8PS结合的晶体学研究。该酶与这些化合物的复合物结构,以及与PEP类似物,2-磷酸甘油酸(2-PGA)和z -甲基PEP的复合物结构,为设计新的KDO8PS抑制剂指明了未来的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Structure-based design of novel inhibitors of 3-deoxy-D-manno-octulosonate 8-phosphate synthase.

3-Deoxy-D-manno-octulosonate 8-phosphate (KDO8P) is the phosphorylated precursor of KDO, an essential sugar of the lipopolysaccharide of Gram negative bacteria. KDO8P is produced by a specific synthase (KDO8PS) by condensing arabinose 5-phosphate (A5P) and phosphoenolpyruvate (PEP), with release of inorganic phosphate. As KDO8PS is present in bacteria and plants, but not in mammalian cells, and mutations that inactivate KDO8PS also block cell replication, KDO8PS is a promising target for the design of new antimicrobials that act by blocking lipopolysaccharide biosynthesis. Previous studies have shown that a compound mimicking an intermediate of the condensation reaction is a good ligand and a powerful inhibitor. Here we report on the crystallographic investigation of the binding to KDO8PS of new derivatives of this original inhibitor. The structures of the enzyme in complex with these compounds, and also with the PEP analogs, 2-phosphoglyceric acid (2-PGA) and Z-methyl-PEP, point to future strategies for the design of novel inhibitors of KDO8PS.

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