Mycobacterial Research Division, MRC National Institute for Medical Research , The Ridgeway, Mill Hill, London NW7 1AA, U.K.
Biochemistry. 2013 Oct 8;52(40):7145-9. doi: 10.1021/bi400839f. Epub 2013 Sep 25.
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.
D-环丝氨酸是一种二线药物，被批准用于治疗感染结核分枝杆菌（结核病的病原体）的患者。与其他临床使用的抗分枝杆菌药物相比，D-环丝氨酸独特的作用机制代表了未来合理药物设计项目中尚未开发和可利用的资源。在这里，我们表明 D-环丝氨酸是 MtDdl 的缓慢作用抑制剂，这种行为是特定于结核分枝杆菌酶的同系物的。此外，有证据表明 D-环丝氨酸专一地结合到 C 末端 D-丙氨酸结合位点，即使在 N 末端结合位点没有结合 D-丙氨酸的情况下也是如此。这些结果共同促使我们提出了 D-环丝氨酸抑制 D-丙氨酸：D-丙氨酸连接酶的新模型，并为针对重要的、经临床验证的分枝杆菌靶标进行合理药物设计提供了新的机会。
