title: Structure and conformational variability of the mycobacterium tuberculosis fatty acid synthase multienzyme complex.
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.
authors.affiliation: Department of Structural Biology, Max-Planck-Institute of Biophysics, Max-von-Laue-Str. 3, 60438 Frankfurt, Germany.
authors.forename: Luciano
authors.initials: L
authors.lastname: Ciccarelli
authors.forename: Sean R
authors.initials: SR
authors.lastname: Connell
authors.forename: Mathias
authors.initials: M
authors.lastname: Enderle
authors.forename: Deryck J
authors.initials: DJ
authors.lastname: Mills
authors.forename: Janet
authors.initials: J
authors.lastname: Vonck
authors.forename: Martin
authors.initials: M
authors.lastname: Grininger
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000648:ultrastructure; D020134:Catalytic Domain; D020285:Cryoelectron Microscopy; D064429:Fatty Acid Synthases / Q000737:chemistry* / Q000648:ultrastructure; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000737:chemistry / Q000648:ultrastructure; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D040681:Structural Homology, Protein
chemical_list: D001426:Bacterial Proteins; D009097:Multienzyme Complexes; D064429:Fatty Acid Synthases