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首页> 外文期刊>Biochemistry >The Mechanism of Acetyl Transfer Catalyzed by Mycobacterium tuberculosis GImU
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The Mechanism of Acetyl Transfer Catalyzed by Mycobacterium tuberculosis GImU

机译：结核分枝杆菌催化催化乙酰转移的机制

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摘要

The biosynthetic pathway of peptidoglycan is essential for Mycobacterium tuberculosis. We report here the acetyltransferase substrate specificity and catalytic mechanism of the bifunctional N-acetyltransferase/uridylyltransferase from M. tuberculosis (GlmU). This enzyme is responsible for the final two steps of the synthesis of UDP-N-acetylglucosamine, which is an essential precursor of peptidoglycan, from glucosamine 1-phosphate, acetyl-coenzyme A, and uridine 5'-triphosphate. GlmU utilizes ternary complex formation to transfer an acetyl from acetyl-coenzyme A to glucosamine 1-phosphate to form N-acetylglucosamine 1-phosphate. Steady-state kinetic studies and equilibrium binding experiments indicate that GlmU follows a steady-state ordered kinetic mechanism, with acetyl-coenzyme A binding first, which triggers a conformational change in GlmU, followed by glucosamine 1-phosphate binding. Coenzyme A is the last product to dissociate. Chemistry is partially rate-limiting as indicated by pH rate studies and solvent kinetic isotope effects. A novel crystal structure of a mimic of the Michaelis complex, with glucose 1-phosphate and acetyl-coenzyme A, helps us to propose the residues involved in deprotonation of glucosamine 1-phosphate and the loop movement that likely generates the active site required for glucosamine 1-phosphate to bind. Together, these results pave the way for the rational discovery of improved inhibitors against M. tuberculosis GlmU, some of which might become candidates for antibiotic discovery programs.
机译：肽聚糖的生物合成途径对于结核分枝杆菌是必不可少的。我们在此报道双官能N-乙酰转移酶/尿嘧啶基脲转移酶的乙酰转移酶底物特异性和催化机制来自汞型（GLMU）。该酶负责UDP-N-乙酰葡糖胺的合成的最后两个步骤，其是氨基葡萄糖1-磷酸酯，乙酰辅酶A和尿苷5'-三磷酸尿苷的必需前体。 GLMU利用三元复合物形成来从乙酰辅酶A中转移乙酰基至氨基葡萄糖1-磷酸酯以形成N-乙酰葡糖胺1-磷酸酯。稳态动力学研究和平衡结合实验表明，GLMU遵循稳态有序动力学机制，乙酰辅酶是结合的第一，其触发GLMU的构象变化，其次是氨基葡萄糖1-磷酸酯结合。辅酶A是解离的最后一件产品。化学是按pH速率研究和溶剂动力学同位素效应所表明的部分速率限制。具有葡萄糖1-磷酸盐和乙酰辅酶A的Michaelis络合物模拟的新型晶体结构有助于我们提出参与氨基葡萄糖1-磷酸酯的去质子化的残基和可能产生葡糖胺所需的活性位点的环运动1-磷酸盐结合。这些结果在一起铺平了改善抑制剂对肺癌的理性发现的方法，其中一些可能成为抗生素发现计划的候选人。

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