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首页> 外文期刊>Biochemistry >Substrate-Induced Closing of the Active Site Revealed by the Crystal Structure of Pantothenate Synthetase from Staphylococcus aureus
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Substrate-Induced Closing of the Active Site Revealed by the Crystal Structure of Pantothenate Synthetase from Staphylococcus aureus

机译：底物诱导的金黄色葡萄球菌泛酸合成酶晶体结构揭示的活性位点的关闭。

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摘要

Pantothenate synthetase (PS, EC 6.3.2.1) is the last enzyme in the pantothenate biosynthesisnpathway, a metabolic pathway identified as a potential target for new antimicrobials. PS catalyzes the ATP-ndependent condensation of pantoate and β-alanine to form pantothenate. Here we report the overexpression,npurification, enzyme assay, and tertiary structure of PS from Staphylococcus aureus. PS activity wasnexperimentally confirmed, indicating a kcat value comparable to those of enzymes from other organisms.nThe structures of the apoenzyme and the reaction intermediate (pantoyl adenylate; PA) complex werendetermined by X-ray crystallography to resolutions of 2.5 and 1.85 A, respectively. Structural analysisnindicated that the apoenzyme adopts an open and relatively mobile structure, while the complex structure isnclosed and entirely rigid. Structural comparison of the apoenzyme and the complex revealed how S. aureus PSnundergoes open/close conformational change, and also determined the key interactions with the adenine ringnof PA for a hinge bending domain closure. In the complex structure, PA and acetate are bound in the activensite. We suggest that the acetate mimics the substrate β-alanine. Therefore, the complex structure seems tonrepresent a catalytic state poised for in-line nucleophilic attack on PA. These data also offer an alternativenstrategy for designing novel compounds that selectively inhibit PS activity.
机译：泛酸合成酶（PS，EC 6.3.2.1）是泛酸生物合成途径中的最后一种酶，该代谢途径被确定为新抗菌药物的潜在靶标。 PS催化泛酸和β-丙氨酸的ATP非依赖性缩合形成泛酸。在这里我们报告金黄色葡萄球菌的PS的过表达，纯化，酶法测定和三级结构。实验上证实了PS的活性，表明其kcat值可与其他生物体的酶相当.n通过X射线晶体学确定脱辅酶的结构和反应中间体（泛酰腺苷酸; PA）复合物的分辨度分别为2.5和1.85 A.结构分析表明，脱辅酶采取开放且相对可移动的结构，而复杂的结构是封闭的且完全刚性的。脱辅酶和复合物的结构比较揭示了金黄色葡萄球菌PSn如何进行开/关构象变化，并且还确定了与PA的腺嘌呤环的关键相互作用，以进行铰链弯曲结构域闭合。在复杂的结构中，PA和乙酸盐结合在活性位点上。我们建议乙酸盐模拟底物β-丙氨酸。因此，复杂的结构似乎无法代表催化状态对PA的在线亲核攻击。这些数据也为设计选择性抑制PS活性的新型化合物提供了另一种策略。

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