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首页> 外文期刊>Biochemistry >Reinterpreting the mechanism of inhibition of mycobacterium tuberculosis d -alanine: D -alanine ligase by d -cycloserine
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Reinterpreting the mechanism of inhibition of mycobacterium tuberculosis d -alanine: D -alanine ligase by d -cycloserine

机译：d-环丝氨酸重新解释结核分枝杆菌d-丙氨酸的抑制机制：D-丙氨酸连接酶

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摘要

d-Cycloserine is a second-line drug approved for use in the treatment of patients infected with Mycobacterium tuberculosis, the etiologic agent of tuberculosis. The unique mechanism of action of d-cycloserine, compared with those of other clinically employed antimycobacterial agents, represents an untapped and exploitable resource for future rational drug design programs. Here, we show that d-cycloserine is a slow-onset inhibitor of MtDdl and that this behavior is specific to the M. tuberculosis enzyme orthologue. Furthermore, evidence is presented that indicates d-cycloserine binds exclusively to the C-terminal d-alanine binding site, even in the absence of bound d-alanine at the N-terminal binding site. Together, these results led us to propose a new model of d-alanine:d-alanine ligase inhibition by d-cycloserine and suggest new opportunities for rational drug design against an essential, clinically validated mycobacterial target.
机译：d-环丝氨酸是一种二线药物，已批准用于治疗被结核分枝杆菌（结核病的病原体）感染的患者。与其他临床使用的抗分枝杆菌药物相比，d-环丝氨酸的独特作用机制为未来的合理药物设计计划提供了未开发和可利用的资源。在这里，我们显示d-环丝氨酸是MtDdl的缓慢发作抑制剂，这种行为是结核分枝杆菌酶直向同源物特有的。此外，提供的证据表明，即使在N末端结合位点不存在结合的d-丙氨酸的情况下，d-环丝氨酸也仅与C末端d-丙氨酸结合位点结合。在一起，这些结果使我们提出了一种新的d-丙氨酸抑制模型：d-环丝氨酸抑制d-丙氨酸连接酶，并提出了针对必要的，经过临床验证的分枝杆菌靶点进行合理药物设计的新机会。

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