The Dual Function of the Mycobacterium tuberculosis FadD32 Required for Mycolic Acid Biosynthesis
The Dual Function of the Mycobacterium tuberculosis FadD32 Required for Mycolic Acid Biosynthesis
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DOI：
10.1016/j.chembiol.2009.03.012
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发表时间：
2009-05-29
影响因子：
--
通讯作者：
Marrakchi, Hedia
中科院分区：
文献类型：
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作者：
Leger, Mathieu;Gavalda, Sabine;Marrakchi, Hedia
分枝杆菌酸是结核分枝杆菌细胞外膜的主要特异性脂质。它们的合成需要通过Pks 13使C-22-C-26脂肪酸与由FadD 32（分枝杆菌生长所必需的脂肪酰基-AMP连接酶）活化的C-50-C-60部分分枝菌酸缩合。生物化学和酶促方法的组合表明，FadD 32表现出相对长链脂肪酸的底物特异性。更重要的是，FadD 32催化合成的酰基-腺苷酸转移到特定的硫酯受体上，从而揭示了蛋白质酰基-ACP连接酶的功能。因此，FadD 32可能是一组M.结核病聚酮合酶相关的腺苷酸化酶具有这种活性。FadD 32的底物类似物不仅抑制酶活性，而且抑制分枝菌酸合成和分枝杆菌生长，为开发新型抗分枝杆菌剂开辟了途径。
Mycolic acids are major and specific lipids of Mycobacterium tuberculosis cell envelope. Their synthesis requires the condensation by Pks13 of a C-22-C-26 fatty acid with the C-50-C-60 meromycolic acid activated by FadD32, a fatty acyl-AMP ligase essential for mycobacterial growth. A combination of biochemical and enzymatic approaches demonstrated that FadD32 exhibits substrate specificity for relatively long-chain fatty acids. More importantly, FadD32 catalyzes the transfer of the synthesized acyl-adenylate onto specific thioester acceptors, thus revealing the protein acyl-ACP ligase function. Therefore, FadD32 might be the prototype of a group of M. tuberculosis polyketide-synthase-associated adenylation enzymes possessing such activity. A substrate analog of FadD32 inhibited not only the enzyme activity but also mycolic acid synthesis and mycobacterial growth, opening an avenue for the development of novel antimycobacterial agents.