Crystal structure of Mycobacterium tuberculosis FadB2 implicated in mycobacterial β-oxidation


The intracellular pathogen Mycobacterium tuberculosis is the causative agent of tuberculosis, which is a leading cause of mortality worldwide. The survival of M. tuberculosis in host macrophages through long-lasting periods of persistence depends, in part, on breaking down host cell lipids as a carbon source. The critical role of fatty-acid catabolism in this organism is underscored by the extensive redundancy of the genes implicated in β-oxidation (∼100 genes). In a previous study, the enzymology of the M. tuberculosisl-3-hydroxyacyl-CoA dehydrogenase FadB2 was characterized. Here, the crystal structure of this enzyme in a ligand-free form is reported at 2.1 Å resolution. FadB2 crystallized as a dimer with three unique dimer copies per asymmetric unit. The structure of the monomer reveals a dual Rossmann-fold motif in the N-terminal domain, while the helical C-terminal domain mediates dimer formation. Comparison with the CoA- and NAD + -bound human orthologue mitochondrial hydroxyacyl-CoA dehydrogenase shows extensive conservation of the residues that mediate substrate and cofactor binding. Superposition with the multi-catalytic homologue M. tuberculosis FadB, which forms a trifunctional complex with the thiolase FadA, indicates that FadB has developed structural features that prevent its self-association as a dimer. Conversely, FadB2 is unable to substitute for FadB in the tetrameric FadA–FadB complex as it lacks the N-terminal hydratase domain of FadB. Instead, FadB2 may functionally (or physically) associate with the enoyl-CoA hydratase EchA8 and the thiolases FadA2, FadA3, FadA4 or FadA6 as suggested by interrogation of the STRING protein-network database.

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Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences
Funding Information: GSB acknowledges support from a Personal Research Chair from Mr James Bardrick and a Royal Society Wolfson Research Merit Award. We thank Diamond Light Source for access to synchrotron beamlines (BAG MX14692) and their staff for support during experiments
Additional Information: © 2019 The Authors. Published under an open-access Creative Commons Attribution (CC-BY) Licence. Acta Cryst. (2019). D75, 101-108 Funding: This work is supported by funding from the Medical Research Council (MRC; MR/S000542/1).
Uncontrolled Keywords: l-3-hydroxyacyl-CoA dehydrogenase,mycobacterial β-oxidation,Mycobacterium tuberculosis,X-ray crystallography,3-Hydroxyacyl CoA Dehydrogenases/chemistry,Enoyl-CoA Hydratase/metabolism,Oxidation-Reduction,Humans,Protein Multimerization,Protein Binding,Crystallography, X-Ray,Mycobacterium tuberculosis/enzymology,Structural Biology
Publication ISSN: 2059-7983
Last Modified: 08 Dec 2023 11:18
Date Deposited: 20 Sep 2019 07:59
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
http://10.1107/ ... /mn5119sup1.pdf (Related URL)
PURE Output Type: Article
Published Date: 2019-01-01
Accepted Date: 2018-12-04
Authors: Cox, Jonathan A.G. (ORCID Profile 0000-0001-5208-4056)
Taylor, Rebecca C.
Brown, Alistair K.
Attoe, Samuel
Besra, Gurdyal S.
Fütterer, Klaus



Version: Published Version

License: Creative Commons Attribution

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