7LG9

ChsB1

Summary for 7LG9

• Entry DOI: 10.2210/pdb7lg9/pdb
• Descriptor: 3-ketoacyl-ACP reductase (2 entities in total)
• Functional Keywords: short-chain type alcohol dehydrogenase/reductase hydroxyacyl-coa dehydrogenase, oxidoreductase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 65529.39

Authors

Yuan, T.,Werman, J.M.,Yin, X.,Yang, M.,Garcia-Diaz, M.,Sampson, N.S. (deposition date: 2021-01-19, release date: 2021-04-21, Last modification date: 2023-10-18)

Primary citation

Yuan, T.,Werman, J.M.,Yin, X.,Yang, M.,Garcia-Diaz, M.,Sampson, N.S.
Enzymatic beta-Oxidation of the Cholesterol Side Chain in Mycobacterium tuberculosis Bifurcates Stereospecifically at Hydration of 3-Oxo-cholest-4,22-dien-24-oyl-CoA.
Acs Infect Dis., 7:1739-1751, 2021

PubMed Abstract: The unique ability of (Mtb) to utilize host lipids such as cholesterol for survival, persistence, and virulence has made the metabolic pathway of cholesterol an area of great interest for therapeutics development. Herein, we identify and characterize two genes from the Cho-region (genomic locus responsible for cholesterol catabolism) of the Mtb genome, (Rv3538) and (Rv3502c). Their protein products catalyze two sequential stereospecific hydration and dehydrogenation steps in the β-oxidation of the cholesterol side chain. ChsH3 favors the 22 hydration of 3-oxo-cholest-4,22-dien-24-oyl-CoA in contrast to the previously reported EchA19 (Rv3516), which catalyzes formation of the (22)-hydroxy-3-oxo-cholest-4-en-24-oyl-CoA from the same enoyl-CoA substrate. ChsB1 is stereospecific and catalyzes dehydrogenation of the ChsH3 product but not the EchA19 product. The X-ray crystallographic structure of the ChsB1 apo-protein was determined at a resolution of 2.03 Å, and the holo-enzyme with bound NAD cofactor was determined at a resolution of 2.21 Å. The homodimeric structure is representative of a classical NAD-utilizing short-chain type alcohol dehydrogenase/reductase, including a Rossmann-fold motif, but exhibits a unique substrate binding site architecture that is of greater length and width than its homologous counterparts, likely to accommodate the bulky steroid substrate. Intriguingly, Mtb utilizes hydratases from the MaoC-like family in sterol side-chain catabolism in contrast to fatty acid β-oxidation in other species that utilize the evolutionarily distinct crotonase family of hydratases.

PubMed: 33826843
DOI: 10.1021/acsinfecdis.1c00069

Experimental method

X-RAY DIFFRACTION (2.03 Å)