4X28

Crystal structure of the ChsE4-ChsE5 complex from Mycobacterium tuberculosis

Summary for 4X28

• Entry DOI: 10.2210/pdb4x28/pdb
• Descriptor: Acyl-CoA dehydrogenase, DIHYDROFLAVINE-ADENINE DINUCLEOTIDE, ... (4 entities in total)
• Functional Keywords: dehydrogenase, oxidoreductase
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv); More
• Total number of polymer chains: 4
• Total formula weight: 168552.81

Authors

Guja, K.E.,Yang, M.,Sampson, N.,Garcia-Diaz, M. (deposition date: 2014-11-26, release date: 2015-02-18, Last modification date: 2024-10-23)

Primary citation

Yang, M.,Lu, R.,Guja, K.E.,Wipperman, M.F.,St Clair, J.R.,Bonds, A.C.,Garcia-Diaz, M.,Sampson, N.S.
Unraveling Cholesterol Catabolism in Mycobacterium tuberculosis: ChsE4-ChsE5 alpha 2 beta 2 Acyl-CoA Dehydrogenase Initiates beta-Oxidation of 3-Oxo-cholest-4-en-26-oyl CoA.
Acs Infect Dis., 1:110-125, 2015

PubMed Abstract: The metabolism of host cholesterol by () is an important factor for both its virulence and pathogenesis, although how and why cholesterol metabolism is required is not fully understood. uses a unique set of catabolic enzymes that are homologous to those required for classical β-oxidation of fatty acids but are specific for steroid-derived substrates. Here, we identify and assign the substrate specificities of two of these enzymes, ChsE4-ChsE5 (Rv3504-Rv3505) and ChsE3 (Rv3573c), that carry out cholesterol side chain oxidation in Steady-state assays demonstrate that ChsE4-ChsE5 preferentially catalyzes the oxidation of 3-oxo-cholest-4-en-26-oyl CoA in the first cycle of cholesterol side chain β-oxidation that ultimately yields propionyl-CoA, whereas ChsE3 specifically catalyzes the oxidation of 3-oxo-chol-4-en-24-oyl CoA in the second cycle of β-oxidation that generates acetyl-CoA. However, ChsE4-ChsE5 can catalyze the oxidation of 3-oxo-chol-4-en-24-oyl CoA as well as 3-oxo-4-pregnene-20-carboxyl-CoA. The functional redundancy of ChsE4-ChsE5 explains the in vivo phenotype of the knockout strain of ; the loss of ChsE1-ChsE2 can be compensated for by ChsE4-ChsE5 during the chronic phase of infection. The X-ray crystallographic structure of ChsE4-ChsE5 was determined to a resolution of 2.0 Å and represents the first high-resolution structure of a heterotetrameric acyl-CoA dehydrogenase (ACAD). Unlike typical homotetrameric ACADs that bind four flavin adenine dinucleotide (FAD) cofactors, ChsE4-ChsE5 binds one FAD at each dimer interface, resulting in only two substrate-binding sites rather than the classical four active sites. A comparison of the ChsE4-ChsE5 substrate-binding site to those of known mammalian ACADs reveals an enlarged binding cavity that accommodates steroid substrates and highlights novel prospects for designing inhibitors against the committed β-oxidation step in the first cycle of cholesterol side chain degradation by .

PubMed: 26161441
DOI: 10.1021/id500033m

Experimental method

X-RAY DIFFRACTION (1.99 Å)