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首页> 外文期刊>Biochemistry >Crystal Structure of the Pantothenate Synthetase from Mycobacterium tuberculosis, Snapshots of the Enzyme in Action
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Crystal Structure of the Pantothenate Synthetase from Mycobacterium tuberculosis, Snapshots of the Enzyme in Action

机译：结核分枝杆菌泛酸合成酶的晶体结构，作用中的酶的快照

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摘要

Pantothenate synthetase (PS) from Mycobacterium tuberculosis represents a potential target for antituberculosis drugs.PS catalyzes the ATP-dependent condensation of pantoate and beta-alanine to form pantothenate.Previously,we determined the crystal structure of PS from M.tuberculosis and its complexes with AMPCPP,pantoate,and pantoyl adenylate.Here,we describe the crystal structure of this enzyme complexed with AMP and its last substrate,beta-alanine,and show that the phosphate group of AMP serves as an anchor for the binding of beta-alanine.This structure confirms that binding of beta-alanine in the active site cavity can occur only after formation of the pantoyl adenylate intermediate.A new crystal form was also obtained;it displays the flexible wall of the active site cavity in a conformation incapable of binding pantoate.Soaking of this crystal form with ATP and pantoate gives a fully occupied complex of PS with ATP.Crystal structures of these complexes with substrates,the reaction intermediate,and the reaction product AMP provide a step-by-step view of the PS-catalyzed reaction.A detailed reaction mechanism and its implications for inhibitor design are discussed.
机译：结核分枝杆菌的泛酸合成酶（PS）代表了抗结核药物的潜在靶标。PS催化泛酸和β-丙氨酸的ATP依赖性缩合反应形成泛酸。以前，我们测定了结核分枝杆菌及其复合物与PS的晶体结构。在这里，我们描述了这种与AMP及其最后一个底物β-丙氨酸复合的酶的晶体结构，并显示AMP的磷酸酯基团是结合β-丙氨酸的锚。这种结构证实了只有在泛酰腺苷酸中间体形成后才能在活性位腔中发生β-丙氨酸的结合，还获得了新的晶体形式;它以无法结合泛酸的构象显示活性位腔的柔性壁。用ATP和泛酸浸泡这种晶体形式，可以使PS和ATP完全占据复合物。这些复合物与底物的晶体结构，反应中间体和反应产物AMP提供了PS催化反应的逐步视图。详细讨论了反应机理及其对抑制剂设计的影响。

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