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首页> 外文期刊>Journal of Molecular Biology >Structure of the Mycobacterium tuberculosis flavin dependent thymidylate synthase (MtbThyX) at 2.0 A resolution
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Structure of the Mycobacterium tuberculosis flavin dependent thymidylate synthase (MtbThyX) at 2.0 A resolution

机译：结核分枝杆菌黄素依赖性胸苷酸合酶（MtbThyX）在2.0 A分辨率下的结构

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摘要

A novel flavin-dependent thymidylate synthase was identified recently as an essential gene in many archaebacteria and some pathogenic eubacteria. This enzyme, ThyX, is a potential antibacterial drug target, since humans and most eukaryotes lack the thyX gene and depend upon the conventional thymidylate synthase (TS) for their dTMP requirements. We have cloned and overexpressed the thyX gene (Rv2754c) from Mycobacterium tuberculosis in Escherichia coli. The M. tuberculosis ThyX (MtbThyX) enzyme complements the E. coli X2913 strain that lacks its conventional TS activity. The crystal structure of the homotetrameric MtbThyX was determined in the presence of the cofactor FAD and the substrate analog, 5-bromo-2deoxyuridine-5 '-monophosphate (BrdUMP). In the active site, which is formed by three monomers, FAD is bound in an extended conformation with the adenosine ring in a deep pocket and BrdUMP in a closed conformation near the isoalloxazine ring. Structure-based mutational studies have revealed a critical role played by residues Lys165 and Arg168 in ThyX activity; possibly by governing access to the carbon atom to be methylated of a totally buried substrate dUMP. (c) 2005 Elsevier Ltd. All rights reserved.
机译：最近，一种新的黄素依赖性胸苷酸合酶被确定为许多古细菌和某些致病性真细菌的必需基因。这种酶ThyX是潜在的抗菌药物靶标，因为人类和大多数真核生物均缺乏thyX基因，并且依赖常规胸苷酸合酶（TS）满足dTMP的要求。我们已经从结核分枝杆菌的大肠杆菌中克隆并过表达thyX基因（Rv2754c）。结核分枝杆菌ThyX（MtbThyX）酶补充了缺乏常规TS活性的大肠杆菌X2913菌株。在辅助因子FAD和底物类似物5-溴-2-脱氧尿苷-5'-单磷酸酯（BrdUMP）的存在下，测定了同四聚体MtbThyX的晶体结构。在由三个单体形成的活性位点中，FAD以延伸的构象与深口袋中的腺苷环结合，而BrdUMP以闭合的构象结合在异四嗪环附近。基于结构的突变研究表明，残基Lys165和Arg168在ThyX活性中起着关键作用。可能是通过控制完全掩埋的底物dUMP接近要甲基化的碳原子来实现的。 （c）2005 Elsevier Ltd.保留所有权利。

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