Chalut Christian, Botella Laure, de Sousa-D'Auria Célia, Houssin Christine, Guilhot Christophe
Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique and Université P. Sabatier (Unité Mixte de Recherche 5089), 205 Route de Narbonne, 31077 Toulouse Cedex, France.
Proc Natl Acad Sci U S A. 2006 May 30;103(22):8511-6. doi: 10.1073/pnas.0511129103. Epub 2006 May 18.
Mycobacterium tuberculosis contains >20 enzymes that require activation by transfer of the 4'-phosphopantetheine moiety of CoA onto a conserved serine residue, a posttranslational modification catalyzed by 4'-phosphopantetheinyl transferases (PPTases). The modified proteins are involved in key metabolic processes such as cell envelope biogenesis and the production of virulence factors. We show that two PPTases conserved in all Mycobacterium spp. and in related genera activate two different subsets of proteins and are not functionally redundant. One enzyme, AcpS, activates the two fatty acid synthase systems of mycobacteria, whereas the other PPTase, PptT, acts on type-I polyketide synthases and nonribosomal peptide synthases, both of which are involved in the biosynthesis of virulence factors. We demonstrate that both PPTases are essential for Mycobacterium smegmatis viability and that PptT is required for the survival of Mycobacterium bovis bacillus Calmette-Guérin. These enzymes are thus central to the biology of mycobacteria and for mycobacterial pathogenesis and represent promising targets for new antituberculosis drugs.
结核分枝杆菌含有20多种需要通过将辅酶A的4'-磷酸泛酰巯基乙胺部分转移到保守的丝氨酸残基上而被激活的酶，这是一种由4'-磷酸泛酰巯基乙胺基转移酶（PPTases）催化的翻译后修饰。这些修饰后的蛋白质参与关键的代谢过程，如细胞壁生物合成和毒力因子的产生。我们发现，在所有分枝杆菌属物种以及相关属中保守的两种PPTases激活不同的蛋白质亚群，且在功能上并非冗余。一种酶AcpS激活分枝杆菌的两个脂肪酸合成酶系统，而另一种PPTase PptT作用于I型聚酮合酶和非核糖体肽合成酶，这两种酶都参与毒力因子的生物合成。我们证明这两种PPTases对耻垢分枝杆菌的生存能力至关重要，并且PptT是卡介苗（牛分枝杆菌卡介苗）存活所必需的。因此，这些酶对于分枝杆菌的生物学特性以及分枝杆菌致病机制至关重要，是新型抗结核药物有前景的靶点。
