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

Jonathan A.G. Cox, Rebecca C. Taylor, Alistair K. Brown, Samuel Attoe, Gurdyal S. Besra, Klaus Fütterer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)101-108
Number of pages8
JournalActa Crystallographica Section D: Structural Biology
Issue numberPt 1
Publication statusPublished - 1 Jan 2019

Bibliographical note

© 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).


  • 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


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