Department of Structural Biology, Max-Planck-Institute of Biophysics, Max-von-Laue-Str. 3, 60438 Frankfurt, Germany.
Structure. 2013 Jul 2;21(7):1251-7. doi: 10.1016/j.str.2013.04.023. Epub 2013 Jun 6.
Antibiotic therapy in response to Mycobacterium tuberculosis infections targets de novo fatty acid biosynthesis, which is orchestrated by a 1.9 MDa type I fatty acid synthase (FAS). Here, we characterize M. tuberculosis FAS by single-particle cryo-electron microscopy and interpret the data by docking the molecular models of yeast and Mycobacterium smegmatis FAS. Our analysis reveals a porous barrel-like structure of considerable conformational variability that is illustrated by the identification of several conformational states with altered topology in the multienzymatic assembly. This demonstrates that the barrel-like structure of M. tuberculosis FAS is not just a static scaffold for the catalytic domains, but may play an active role in coordinating fatty acid synthesis. The conception of M. tuberculosis FAS as a highly dynamic assembly of domains revises the view on bacterial type I fatty acid synthesis and might inspire new strategies for inhibition of de novo fatty acid synthesis in M. tuberculosis.
针对结核分枝杆菌感染的抗生素治疗靶向从头脂肪酸生物合成，这是由一个 1.9 MDa 的 I 型脂肪酸合酶（FAS）协调的。在这里，我们通过单颗粒冷冻电子显微镜对结核分枝杆菌 FAS 进行了表征，并通过对接酵母和耻垢分枝杆菌 FAS 的分子模型对数据进行了解释。我们的分析揭示了一个多孔桶状结构，具有相当大的构象可变性，这通过鉴定多酶复合物中拓扑结构改变的几种构象状态得到了说明。这表明结核分枝杆菌 FAS 的桶状结构不仅仅是催化结构域的静态支架，它可能在协调脂肪酸合成中发挥积极作用。将结核分枝杆菌 FAS 视为高度动态的结构域组装，修改了对细菌 I 型脂肪酸合成的看法，并可能为抑制结核分枝杆菌中从头脂肪酸合成提供新的策略。
