6hrd | pdb_00006hrd
Crystal structure of M. tuberculosis FadB2 (Rv0468)
Structural highlights
FunctionFADB2_MYCTU Catalyzes the NAD-dependent oxidation of beta-hydroxybutyryl-CoA to acetoacetyl-CoA in vitro at pH 10. Also catalyzes the reverse reaction albeit in a lower pH range of 5.5-6.5. The reverse reaction is able to use NADPH as well as NADH.[1] Publication Abstract from PubMedThe 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 beta-oxidation ( approximately 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 A 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. Crystal structure of Mycobacterium tuberculosis FadB2 implicated in mycobacterial beta-oxidation.,Cox JAG, Taylor RC, Brown AK, Attoe S, Besra GS, Futterer K Acta Crystallogr D Struct Biol. 2019 Jan 1;75(Pt 1):101-108. doi: , 10.1107/S2059798318017242. Epub 2019 Jan 8. PMID:30644849[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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