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Para-Aminosalicylic Acid Acts as an Alternative Substrate of Folate Metabolism in Mycobacterium tuberculosis

zhangxia111 添加于 2012/11/6 9:42:44  2735次阅读 | 0次推荐 | 3个评论

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 based on target-based drug discovery. Fifty years later, PAS continues in use for tuberculosis. PAS is assumed to inhibit dihydropteroate synthase (DHPS) in Mycobacterium tuberculosis (M. tuberculosis) by mimicking the substrate, p-aminobenzoate (PABA). However, we found that sulfonamide inhibitors of DHPS inhibited growth of M. tuberculosis only weakly due to their intracellular metabolism. PAS, by contrast, 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.

作 者:Sumit Chakraborty, Todd Gruber, Clifton E. Barry III, Helena I. Boshoff, Kyu Y. Rhee
期刊名称: Science
期卷页: 第卷 第期 ~页
学科领域:生命科学 » 细胞生物学 » 细胞呼吸与代谢
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原文链接:http://www.sciencemag.org/content/early/2012/10/31/science.1228980.abstract?sid=bdf702cf-228a-4c35-b637-3656926bff3c
DOI: 10.1126/science.1228980
ISBN: 0036-8075
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相关报道: http://paper.sciencenet.cn/htmlpaper/20131516114490727468.shtm
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发表评论人: [2013/1/6 22:43:18] 
这个链接是错的
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