来自美国威尔康乃尔医学院的研究人员发现用于治疗结核病的长达50年的药物——对氨基水杨酸(PAS)是叶酸代谢途径中的代谢抑制剂而非酶抑制剂。

-2013年1月4日《科学》

中文翻译


【题目】对氨基水杨酸充当结核杆菌叶酸代谢的错配底物

【译文】叶酸的合成途径是已证实的抗病原菌感染靶标,抗叶酸剂——对氨基水杨酸(PAS)是基于靶向药物开发策略,首次被引入到临床实践中的抗感染药物。50年后,PAS仍然是结核病的治疗药物。由于PAS在结构上类似二氢叶酸合成酶(DHPS)的底物——对氨基苯甲酸(PABA),因此人们假定PAS是根据这一原因来抑制结核杆菌(Mycobacterium tuberculosis)的DHPS的活性。然而本研究发现,由于DHPS的磺胺类抑制剂的胞内代谢,它们只能微弱地抑制结核杆菌。相比之下,PAS可充当DHPS的替代底物。在叶酸代谢中,DHPS催化PAS产生的产物会反过来抑制DHPS的活性,并且后续代谢步骤中的PAS衍生物都会与叶酸代谢酶的底物竞争,从而抑制这些酶的活性。叶酸代谢酶催化PAS产生的活跃型PAS衍生物是叶酸代谢的抑制剂,因此PAS可作为阻碍结核杆菌生长的前体药物。

英文原稿


[Title]: Para-Aminosalicylic Acid Acts as an Alternative Substrate of Folate Metabolism in Mycobacterium tuberculosis

[Authors]: Sumit Chakraborty, Todd Gruber, Clifton E. Barry III, Helena I. Boshoff, and Kyu Y. Rhee  

[Abstract]: Folate biosynthesis is an established anti-infective target, and the antifolate para-aminosalicylic acid (PAS) was one of the first anti-infectives introduced into clinical practice on the basis of target-based drug discovery. Fifty years later, PAS continues to be used to treat tuberculosis. PAS is assumed to inhibit dihydropteroate synthase (DHPS) in Mycobacterium tuberculosis by mimicking the substrate p-aminobenzoate (PABA). However, we found that sulfonamide inhibitors of DHPS inhibited growth of M. tuberculosis only weakly because of their intracellular metabolism. In contrast, PAS served as a replacement substrate for DHPS. Products of PAS metabolism at this and subsequent steps in folate metabolism inhibited those enzymes, competing with their substrates. PAS is thus a prodrug that blocks growth of M. tuberculosis when its active forms are generated by enzymes in the pathway they poison.

原文地址

http://www.sciencemag.org/content/339/6115/88.short

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