ArticleThe Journal of biological chemistry2010
Characterization of a carbon-carbon hydrolase from Mycobacterium tuberculosis involved in cholesterol metabolism.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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44 citing papers in PubMed, 109 citations in OpenAlex.
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- Impaired fatty acid import or catabolism in macrophages restricts intracellular growth ofeLife · 2025Article
- Impaired fatty acid import or catabolism in macrophages restricts intracellular growth ofbioRxiv : the preprint server for biology · 2025Article
- Genome-wide screen of Mycobacterium tuberculosis-infected macrophages revealed GID/CTLH complex-mediated modulation of bacterial growth.Nature communications · 2024Article
- The expanding boundaries of sphingolipid lysosomal storage diseases; insights from Niemann-Pick disease type C.Biochemical Society transactions · 2023Review
- The unusual convergence of steroid catabolic pathways inProceedings of the National Academy of Sciences of the United States of America · 2022Article
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- Degradation of Bile Acids by Soil and Water Bacteria.Microorganisms · 2021Review
- Different genome-wide transcriptome responses of Nocardioides simplex VKM Ac-2033D to phytosterol and cortisone 21-acetate.BMC biotechnology · 2021Article
- Whole genome sequencing analysis of a dexamethasone-degrading Burkholderia strain CQ001.Medicine · 2019Article
- Review
- Genome-wide response on phytosterol in 9-hydroxyandrostenedione-producing strain of Mycobacterium sp. VKM Ac-1817D.BMC biotechnology · 2019Article
- Comprehensive Comparative Analysis of Cholesterol Catabolic Genes/Proteins in Mycobacterial Species.International journal of molecular sciences · 2019Article
- Metabolites Involved in Aerobic Degradation of the A and B Rings of Estrogen.Applied and environmental microbiology · 2019Article
- Cholesterol and fatty acids grease the wheels of Mycobacterium tuberculosis pathogenesis.Pathogens and disease · 2018Review
- Cyclipostins and Cyclophostin analogs as promising compounds in the fight against tuberculosis.Scientific reports · 2017Article
- Investigation of the mycobacterial enzyme HsaD as a potential novel target for anti-tubercular agents using a fragment-based drug design approach.British journal of pharmacology · 2017Article
- Cholesterol metabolism: a potential therapeutic target in Mycobacteria.British journal of pharmacology · 2017Review
- The Minimal Unit of Infection: Mycobacterium tuberculosis in the Macrophage.Microbiology spectrum · 2016Review
- Pathogenic mycobacteria achieve cellular persistence by inhibiting the Niemann-Pick Type C disease cellular pathway.Wellcome open research · 2016Article
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
Abstract
In the recently identified cholesterol catabolic pathway of Mycobacterium tuberculosis, 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoate hydrolase (HsaD) is proposed to catalyze the hydrolysis of a carbon-carbon bond in 4,5-9,10-diseco-3-hydroxy-5,9,17-tri-oxoandrosta-1(10),2-diene-4-oic acid (DSHA), the cholesterol meta-cleavage product (MCP) and has been implicated in the intracellular survival of the pathogen. Herein, purified HsaD demonstrated 4-33 times higher specificity for DSHA (k(cat)/K(m) = 3.3 +/- 0.3 x 10(4) m(-1) s(-1)) than for the biphenyl MCP 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid (HOPDA) and the synthetic analogue 8-(2-chlorophenyl)-2-hydroxy-5-methyl-6-oxoocta-2,4-dienoic acid (HOPODA), respectively. The S114A variant of HsaD, in which the active site serine was substituted with alanine, was catalytically impaired and bound DSHA with a K(d) of 51 +/- 2 mum. The S114A.DSHA species absorbed maximally at 456 nm, 60 nm red-shifted versus the DSHA enolate. Crystal structures of the variant in complex with HOPDA, HOPODA, or DSHA to 1.8-1.9 Aindicate that this shift is due to the enzyme-induced strain of the enolate. These data indicate that the catalytic serine catalyzes tautomerization. A second role for this residue is suggested by a solvent molecule whose position in all structures is consistent with its activation by the serine for the nucleophilic attack of the substrate. Finally, the alpha-helical lid covering the active site displayed a ligand-dependent conformational change involving differences in side chain carbon positions of up to 6.7 A, supporting a two-conformation enzymatic mechanism. Overall, these results provide novel insights into the determinants of specificity in a mycobacterial cholesterol-degrading enzyme as well as into the mechanism of MCP hydrolases.
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