ArticleThe Journal of biological chemistry2008
Characterization of active site structure in CYP121. A cytochrome P450 essential for viability of Mycobacterium tuberculosis H37Rv.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed.
- Azole chroman-4-one, tetralone and chromen-4-one derivatives: synthesis, Mycobacterium tuberculosis CYP121A1 enzyme inhibition and antimycobacterial activity.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Article
- 3-(Pyridine-3-ylmethylene)chroman-4-one and tetralone derivatives: synthesis,RSC medicinal chemistry · 2026Article
- Active Site Residues Contribute to the Multistep Dynamics of Dicyclotyrosine Bound to CYP121A1 ofBiochemistry · 2025Article
- Fragment-Based Development of Small Molecule Inhibitors TargetingJournal of medicinal chemistry · 2025Article
- Insights into Active Site Cysteine Residues inInternational journal of molecular sciences · 2025Review
- Structure-Function Analysis of the EssentialInternational journal of molecular sciences · 2024Article
- Article
- In Situ Structural Observation of a Substrate- and Peroxide-Bound High-Spin Ferric-Hydroperoxo Intermediate in the P450 Enzyme CYP121.Journal of the American Chemical Society · 2023Article
- Biological and Sensing Applications of a Few 1,3,4-Oxadiazole Based Donor-Acceptor Systems.Journal of fluorescence · 2023Article
- Synthesis, biological evaluation and computational studies of pyrazole derivatives asRSC medicinal chemistry · 2022Article
- Glycosylated Flavonoid Compounds as Potent CYP121 Inhibitors ofBiomolecules · 2022Article
- A new strategy for hit generation: Novel in cellulo active inhibitors of CYP121A1 from Mycobacterium tuberculosis via a combined X-ray crystallographic and phenotypic screening approach (XP screen).European journal of medicinal chemistry · 2022Article
- Structure-Activity Relationship and Mode-Of-Action Studies Highlight 1-(4-Biphenylylmethyl)-1H-imidazole-Derived Small Molecules as Potent CYP121 Inhibitors.ChemMedChem · 2021Article
- Activation modes in biocatalytic radical cyclization reactions.Journal of industrial microbiology & biotechnology · 2021Review
- Modifications of diketopiperazines assembled by cyclodipeptide synthases with cytochrome PApplied microbiology and biotechnology · 2021Review
- Surface hydrophobics mediate functional dimerization of CYP121A1 of Mycobacterium tuberculosis.Scientific reports · 2021Article
- Anti-Tubercular Properties of 4-Amino-5-(4-Fluoro-3- Phenoxyphenyl)-4Antibiotics (Basel, Switzerland) · 2020Article
- Substrate-Assisted Hydroxylation andACS catalysis · 2020Article
- 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
- Synthesis and biological evaluation of novel cYY analogues targeting Mycobacterium tuberculosis CYP121A1.Bioorganic & medicinal chemistry · 2019Article
Corrections and comments
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Authors and funding
15 authors.
Funding
Abstract
Mycobacterium tuberculosis (Mtb) cytochrome P450 gene CYP121 is shown to be essential for viability of the bacterium in vitro by gene knock-out with complementation. Production of CYP121 protein in Mtb cells is demonstrated. Minimum inhibitory concentration values for azole drugs against Mtb H37Rv were determined, the rank order of which correlated well with Kd values for their binding to CYP121. Solution-state spectroscopic, kinetic, and thermodynamic studies and crystal structure determination for a series of CYP121 active site mutants provide further insights into structure and biophysical features of the enzyme. Pro346 was shown to control heme cofactor conformation, whereas Arg386 is a critical determinant of heme potential, with an unprecedented 280-mV increase in heme iron redox potential in a R386L mutant. A homologous Mtb redox partner system was reconstituted and transported electrons faster to CYP121 R386L than to wild type CYP121. Heme potential was not perturbed in a F338H mutant, suggesting that a proposed P450 superfamily-wide role for the phylogenetically conserved phenylalanine in heme thermodynamic regulation is unlikely. Collectively, data point to an important cellular role for CYP121 and highlight its potential as a novel Mtb drug target.
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Registered trials
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