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首页> 外文期刊>Journal of Molecular Biology >Crystal structures identify an atypical two-metal-ion mechanism for uridyltransfer in GlmU: Its significance to sugar nucleotidyl transferases
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Crystal structures identify an atypical two-metal-ion mechanism for uridyltransfer in GlmU: Its significance to sugar nucleotidyl transferases

机译：晶体结构确定了GlmU中的尿嘧啶转移的非典型的两个金属离子机制：它对糖核苷酸转移酶的意义。

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摘要

N-Acetylglucosamine-1-phosphate uridyltransferase (GlmU), exclusive to prokaryotes, is a bifunctional enzyme that synthesizes UDP-GlcNAc - an important component of the cell wall of many microorganisms. Uridyltransfer, one of the reactions it catalyzes, involves binding GlcNAc-1-P, UTP and Mg2 + ions; however, whether one or two ions catalyze this reaction remains ambiguous. Here, we resolve this using biochemical and crystallographic studies on GlmU from Mycobacterium tuberculosis (GlmUMtb) and identify a two-metal-ion mechanism (mechanism-B). In contrast to well-established two-metal mechanism (mechanism-A) for enzymes acting on nucleic acids, mechanism-B is distinct in the way the two Mg2 + ions (Mg2 + A and Mg2 + B) are positioned and stabilized. Further, attempts to delineate the roles of the metal ions in substrate stabilization, nucleophile activation and transition-state stabilization are presented. Interestingly, a detailed analysis of the available structures of sugar nucleotidyl transferases (SNTs) suggests that they too would utilize mechanism-B rather than mechanism-A. Based on this, SNTs could be classified into Group-I, which employs the two-metal mechanism-B as in GlmU, and Group-II that employs a variant one-metal mechanism-B, wherein the role of Mg2 + A is substituted by a conserved lysine. Strikingly, eukaryotic SNTs appear confined to Group-II. Recognizing these differences may be important in the design of selective inhibitors against microbial nucleotidyl transferases.
机译：N-乙酰基氨基葡萄糖-1-磷酸尿酸基转移酶（GlmU）是原核生物专有的，是一种双功能酶，可合成UDP-GlcNAc-UDP-GlcNAc-许多微生物细胞壁的重要组成部分。铀酰转移是它催化的反应之一，它涉及结合GlcNAc-1-P，UTP和Mg2 +离子。然而，是一个还是两个离子催化这一反应仍然是模棱两可的。在这里，我们使用来自结核分枝杆菌（GlmUMtb）的GlmU的生化和晶体学研究解决了这一问题，并确定了两种金属离子的机理（机理B）。与行之有效的作用于核酸的酶的双金属机理（机理A）相反，机理B在两个Mg2 +离子（Mg2 + A和Mg2 + B）的定位和稳定方式上是不同的。此外，提出了试图描述金属离子在底物稳定，亲核试剂活化和过渡态稳定中的作用的尝试。有趣的是，对糖核苷酸转移酶（SNT）可用结构的详细分析表明，它们也将利用机制B，而不是机制A。基于此，SNTs可以分为使用GlmU中采用双金属机制B的I组和使用替代单金属机制B的II组，其中Mg2 + A的作用被取代保守的赖氨酸。令人惊讶的是，真核SNT似乎仅限于II组。认识到这些差异对于设计针对微生物核苷酸转移酶的选择性抑制剂可能很重要。

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