Hydroxybenzaldoximes Are D-GAP-Competitive Inhibitors of E-coli 1-Deoxy-D-Xylulose-5-Phosphate Synthase
Hydroxybenzaldoximes Are D-GAP-Competitive Inhibitors of E-coli 1-Deoxy-D-Xylulose-5-Phosphate Synthase
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DOI：
10.1002/cbic.201500119
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发表时间：
2015-08-17
期刊：
影响因子：
3.2
通讯作者：
Meyers, Caren L. Freel
中科院分区：
文献类型：
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作者：
Bartee, David;Morris, Francine;Meyers, Caren L. Freel
1-脱氧-D-木酮糖-5-磷酸（DXP）合酶是病原菌和顶复门寄生虫中甲基异戊二烯磷酸途径中的第一个酶。在细菌病原体中，DXP位于代谢分支点，也作为维生素B1和B6生物合成的前体，维生素B1和B6对中枢代谢至关重要。在努力确定新的双底物类似物抑制剂，利用大的活性位点和不同的机制的DXP合酶，芳基混合肟的库的制备和评估。Trihydroxybenzaldoximes出现可逆的，低微摩尔的抑制剂，对D-甘油醛3-磷酸（D-GAP）的竞争性和对丙酮酸的非竞争性或非竞争性。羟基苯甲醛肟类化合物是第一类与D-GAP竞争的DXP合酶抑制剂，为研究DXP合酶的作用机制提供了新的工具，也为开发以类异戊二烯生物合成为靶点的抗菌药物提供了新的方向。
1-Deoxy-D-xylulose 5-phosphate (DXP) synthase is the first enzyme in the methylerythritol phosphate pathway to essential isoprenoids in pathogenic bacteria and apicomplexan parasites. In bacterial pathogens, DXP lies at a metabolic branch point, serving also as a precursor in the biosynthesis of vitamins B1 and B6, which are critical for central metabolism. In an effort to identify new bisubstrate analogue inhibitors that exploit the large active site and distinct mechanism of DXP synthase, a library of aryl mixed oximes was prepared and evaluated. Trihydroxybenzaldoximes emerged as reversible, low-micromolar inhibitors, competitive against D-glyceraldehyde 3-phosphate (D-GAP) and either uncompetitive or noncompetitive against pyruvate. Hydroxybenzaldoximes are the first class of D-GAP-competitive DXP synthase inhibitors, offering new tools for mechanistic studies of DXP synthase and a new direction for the development of antimicrobial agents targeting isoprenoid biosynthesis.