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Chem Biol. 2008 Apr;15(4):402-12. doi: 10.1016/j.chembiol.2008.03.007.

Separate entrance and exit portals for ligand traffic in Mycobacterium tuberculosis FabH.

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Department of Chemistry, Portland State University, Portland, OR 97207, USA.


Mycobacterium tuberculosis FabH initiates type II fatty acid synthase-catalyzed formation of the long chain (C(16)-C(22)) acyl-coenzyme A (CoA) precursors of mycolic acids, which are major constituents of the bacterial cell envelope. Crystal structures of M. tuberculosis FabH (mtFabH) show the substrate binding site to be a buried, extended L-shaped channel with only a single solvent access portal. Entrance of an acyl-CoA substrate through the solvent portal would require energetically unfavorable reptational threading of the substrate to its reactive position. Using a class of FabH inhibitors, we have tested an alternative hypothesis that FabH exists in an "open" form during substrate binding and product release, and a "closed" form in which catalysis and intermediate steps occur. This hypothesis is supported by mass spectrometric analysis of the product profile and crystal structures of complexes of mtFabH with these inhibitors.

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