The intracellular growth restricted (igr) operon in M. tuberculosis is required for in vivo growth and the igr knockout strain has a cholesterol-sensitive phenotype.  We identified two new structural-functional motifs for catalysis of �-oxidation with steroid substrates in the igr operon.  All known acyl-CoA dehydrogenases form homotetrameric or homdimeric assemblies.  In Mtb, FadE28 and FadE29 form a heterotetrameric a2�2 acyl-CoA dehydrogenase.  Mao-C like (R)-enoyl-CoA hydratases also typically form homodimers.  In contrast, Mtb, Rv3541c and Rv3542c form an unusual dimer of heterodimers as evidenced by our crystal structure of the complex.  We have undertaken a fuller bioinformatic analysis of the Mtb genome, and we have successfully identified additional heteromeric complexes that are encoded by cholesterol-regulated genes.  The structures of these M. tuberculosis enzymes are unique to bacteria and provide entry to targeted inhibition in the presence of host �-oxidation enzymes.

Unusual heterotetramic structural motifs employed by <i>M. tuberculosis</i> in sterol metabolism

245th National Meeting (2013)

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Unusual heterotetramic structural motifs employed by M. tuberculosis in sterol metabolism