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Crystal structure of Mycobacterium tuberculosis FadB2 implicated in mycobacterial β‐oxidation
Author(s) -
Cox Jonathan A. G.,
Taylor Rebecca C.,
Brown Alistair K.,
Attoe Samuel,
Besra Gurdyal S.,
Fütterer Klaus
Publication year - 2019
Publication title -
acta crystallographica section d
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.374
H-Index - 138
ISSN - 2059-7983
DOI - 10.1107/s2059798318017242
Subject(s) - mycobacterium tuberculosis , dehydrogenase , dimer , thiolase , biology , biochemistry , nad+ kinase , protein structure , oxidoreductase , hydrolase , enzyme , chemistry , tuberculosis , medicine , organic chemistry , pathology
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.