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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structure of 2C-methyl-D-erythritol 2,4-cyclodiphosphate synthase: An essential enzyme for isoprenoid biosynthesis and target for antimicrobial drug development
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Structure of 2C-methyl-D-erythritol 2,4-cyclodiphosphate synthase: An essential enzyme for isoprenoid biosynthesis and target for antimicrobial drug development

机译：2C-甲基-D-赤藓糖醇2,4-环二磷酸合酶的结构：类异戊二烯生物合成的必不可少的酶和抗菌药物开发的目标

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摘要

The crystal structure of the zinc enzyme Escherichia coli 2C-methyl-D-erythritol 2,4-cyclodiphosphate synthase in complex with cytidine 5′-diphosphate and Mn~(2+) has been determined to 1.8-A resolution. This enzyme is essential in E. coli and participates in the nonmeval-onate pathway of isoprenoid biosynthesis, a critical pathway present in some bacterial and apicomplexans but distinct from that used by mammals. Our analysis reveals a homotrimer, built around a β prism, carrying three active sites, each of which is formed in a cleft between pairs of subunits. Residues from two subunits recognize and bind the nucleotide in an active site that contains a Zn~(2+) with tetrahedral coordination. A Mn~(2+), with octahedral geometry, is positioned between the α and β phosphates acting in concert with the Zn~(2+) to align and polarize the substrate for catalysis. A high degree of sequence conservation for the enzymes from E. coli, Plasmodium falciparum, and Mycobacterium tuberculosis suggests similarities in secondary structure, subunit fold, quaternary structure, and active sites. Our model will therefore serve as a template to facilitate the structure-based design of potential antimicrobial agents targeting two of the most serious human diseases, tuberculosis and malaria.
机译：已确定锌酶大肠杆菌2C-甲基-D-赤藓糖醇2,4-环二磷酸合酶与胞苷5'-二磷酸和Mn〜（2+）的晶体结构为1.8-A分辨率。该酶在大肠杆菌中是必不可少的，并参与类异戊二烯生物合成的非甲羟戊酸途径，这是某些细菌和apicomplexans中存在的关键途径，但与哺乳动物使用的途径不同。我们的分析揭示了围绕三棱镜的同型三聚体，带有三个活性位点，每个活性位点在成对的亚基之间的缝隙中形成。来自两个亚基的残基识别并结合含有四面体配位的Zn〜（2+）的活性位点中的核苷酸。具有八面体几何形状的Mn〜（2+）位于与Zn〜（2+）协同作用的α和β磷酸酯之间，以对齐和极化要催化的底物。来自大肠杆菌，恶性疟原虫和结核分枝杆菌的酶的高度序列保守性表明二级结构，亚基折叠，四级结构和活性位点相似。因此，我们的模型将作为模板，促进针对两种最严重的人类疾病，结核病和疟疾的潜在抗菌剂的基于结构的设计。

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