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

DOI: 10.1107/S2059798318017242 DOI Help

Authors: Jonathan A. G. Cox (University of Birmingham) , Rebecca C. Taylor (University of Birmingham) , Alistair K. Brown (University of Birmingham) , Samuel Attoe (University of Birmingham) , Gurdyal S. Besra (University of Birmingham) , Klaus Fütterer (University of Birmingham)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acta Crystallographica Section D Structural Biology , VOL 75 , PAGES 101 - 108

State: Published (Approved)
Published: January 2019
Diamond Proposal Number(s): 14692

Open Access Open Access

Abstract: 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. tuberculosis L-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.

Journal Keywords: Mycobacterium tuberculosis; L-3-hydroxyacyl-CoA dehydrogenase; mycobacterial β-oxidation; X-ray crystallography

Diamond Keywords: Tuberculosis (TB); Bacteria

Subject Areas: Biology and Bio-materials

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 23/01/2019 14:33


Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)