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Structure. 2013 Jul 2;21(7):1251-7. doi: 10.1016/j.str.2013.04.023. Epub 2013 Jun 6.

Structure and conformational variability of the mycobacterium tuberculosis fatty acid synthase multienzyme complex.

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Department of Structural Biology, Max-Planck-Institute of Biophysics, Max-von-Laue-Str. 3, 60438 Frankfurt, Germany.


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.

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