ArticleThe Journal of biological chemistry2009
The Structure of Mycobacterium tuberculosis CYP125: molecular basis for cholesterol binding in a P450 needed for host infection.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed, 114 citations in OpenAlex.
- Article
- Structure-Function Analysis ofInternational journal of molecular sciences · 2025Article
- Fragment-Based Development of Small Molecule Inhibitors TargetingJournal of medicinal chemistry · 2025Article
- Structure Based Discovery of Inhibitors of CYP125 and CYP142 from Mycobacterium tuberculosis.Chemistry (Weinheim an der Bergstrasse, Germany) · 2023Article
- Evolutionary pathways for deep-sea adaptation in marine planktonicFrontiers in microbiology · 2023Article
- Roles of cysteine in the structure and metabolic function ofRSC advances · 2022Article
- An Unprecedented Number of Cytochrome P450s Are Involved in Secondary Metabolism inMicroorganisms · 2022Article
- Gene expression profile analysis and target gene discovery of Mycobacterium tuberculosis biofilm.Applied microbiology and biotechnology · 2021Article
- Ancient Bacterial ClassInternational journal of molecular sciences · 2021Article
- Characterization of CYP125A13, the First Steroid C-27 Monooxygenase fromJournal of microbiology and biotechnology · 2020Article
- IpdE1-IpdE2 Is a Heterotetrameric Acyl Coenzyme A Dehydrogenase That Is Widely Distributed in Steroid-Degrading Bacteria.Biochemistry · 2020Article
- Microbial transformation of cholesterol: reactions and practical aspects-an update.World journal of microbiology & biotechnology · 2019Review
- Evaluation of Luminogenic Substrates as Probe Substrates for Bacterial Cytochrome P450 Enzymes: Application toSLAS discovery : advancing life sciences R & D · 2019Article
- Review
- Function, essentiality, and expression of cytochrome P450 enzymes and their cognate redox partners in Mycobacterium tuberculosis: are they drug targets?Applied microbiology and biotechnology · 2019Review
- Linking cytochrome P450 enzymes from Mycobacterium tuberculosis to their cognate ferredoxin partners.Applied microbiology and biotechnology · 2018Article
- Bacterial steroid hydroxylases: enzyme classes, their functions and comparison of their catalytic mechanisms.Applied microbiology and biotechnology · 2018Review
- Overexpression of cytochrome p450 125 in Mycobacterium: a rational strategy in the promotion of phytosterol biotransformation.Journal of industrial microbiology & biotechnology · 2018Article
- Potential drug targets in the Mycobacterium tuberculosis cytochrome P450 system.Journal of inorganic biochemistry · 2018Review
- Cholesterol metabolism: a potential therapeutic target in Mycobacteria.British journal of pharmacology · 2017Review
1 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
We report characterization and the crystal structure of the Mycobacterium tuberculosis cytochrome P450 CYP125, a P450 implicated in metabolism of host cholesterol and essential for establishing infection in mice. CYP125 is purified in a high spin form and undergoes both type I and II spectral shifts with various azole drugs. The 1.4-A structure of ligand-free CYP125 reveals a "letterbox" active site cavity of dimensions appropriate for entry of a polycyclic sterol. A mixture of hexa-coordinate and penta-coordinate states could be discerned, with water binding as the 6th heme-ligand linked to conformation of the I-helix Val(267) residue. Structures in complex with androstenedione and the antitubercular drug econazole reveal that binding of hydrophobic ligands occurs within the active site cavity. Due to the funnel shape of the active site near the heme, neither approaches the heme iron. A model of the cholesterol CYP125 complex shows that the alkyl side chain extends toward the heme iron, predicting hydroxylation of cholesterol C27. The alkyl chain is in close contact to Val(267), suggesting a substrate binding-induced low- to high-spin transition coupled to reorientation of the latter residue. Reconstitution of CYP125 activity with a redox partner system revealed exclusively cholesterol 27-hydroxylation, consistent with structure and modeling. This activity may enable catabolism of host cholesterol or generation of immunomodulatory compounds that enable persistence in the host. This study reveals structural and catalytic properties of a potential M. tuberculosis drug target enzyme, and the likely mode by which the host-derived substrate is bound and hydroxylated.
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