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Journal Article

Structure and Conformational Variability of the Mycobacterium tuberculosis Fatty Acid Synthase Multienzyme Complex

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Enderle,  Mathias
Oesterhelt, Dieter / Membrane Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Grininger,  Martin
Oesterhelt, Dieter / Membrane Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Ciccarelli, L., Connell, S. R., Enderle, M., Mills, D. J., Vonck, J., & Grininger, M. (2013). Structure and Conformational Variability of the Mycobacterium tuberculosis Fatty Acid Synthase Multienzyme Complex. STRUCTURE, 21(7), 1251-1257. doi:10.1016/j.str.2013.04.023.


Cite as: https://hdl.handle.net/11858/00-001M-0000-0014-45EF-B
Abstract
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.