Cytochrome P450 monooxygenases are versatile heme-thiolate enzymes that catalyze a wide range of reactions. Self-sufficient cytochrome P450 enzymes contain the redox partners in a single polypeptide chain. Here, we present the crystal structure of full-length CYP116B46, a self-sufficient P450. The continuous polypeptide chain comprises three functional domains, which align well with the direction of electrons traveling from FMN to the heme through the [2Fe-2S] cluster. FMN and the [2Fe-2S] cluster are positioned closely, which facilitates efficient electron shuttling. The edge-to-edge straight-line distance between the [2Fe-2S] cluster and heme is approx. 25.3 A. The role of several residues located between the [2Fe-2S] cluster and heme in the catalytic reaction is probed in mutagenesis experiments. These findings not only provide insights into the intramolecular electron transfer of self-sufficient P450s, but are also of interest for biotechnological applications of self-sufficient P450s. Self-sufficient cytochrome P450 monooxygenases, which contain all redox partners in a single polypeptide chain, are of interest for biotechnological applications. Here, the authors present the crystal structure of full-length Thermobispora bispora CYP116B46 and discuss the potential electron transfer pathway.

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Structural insight into the electron transfer pathway of a self-sufficient P450 monooxygenase.

Inspiration from Nature: Influence of Engineered Ligand Scaffolds and Auxiliary Factors on the Reactivity of Biomimetic Oxidants

Supporting data for the article "Fragment-based approaches to the development of Mycobacterium tuberculosis CYP121 inhibitors", published in the Journal of Medicinal Chemistry, 2016. LCMS, HRMS, IR and NMR spectra from the characterisation of compounds reported in the Experimental Methods section of the article are provided as PDFs. Isothermal titration calorimetry enthalpy plots and data fitting for compounds reported in Table 2 of the article are provided as PDFs. Data for human cytochrome P450 inhibition studies with compounds 19a, 25a and 26a provided as a PDF.

Research data supporting "Fragment-based approaches to the development of Mycobacterium tuberculosis CYP121 inhibitors"

The human cytochrome P450 (CYP) enzymes CYP3A4 and CYP3A5 metabolize most drugs and have high similarities in their structure and substrate preference. Whereas CYP3A4 is predominantly expressed in the liver, CYP3A5 is upregulated in cancer, contributing to drug resistance. Selective inhibitors of CYP3A5 are, therefore, critical to validating it as a therapeutic target. Here we report clobetasol propionate (clobetasol) as a potent and selective CYP3A5 inhibitor identified by high-throughput screening using enzymatic and cell-based assays. Molecular dynamics simulations suggest a close proximity of clobetasol to the heme in CYP3A5 but not in CYP3A4. UV-visible spectroscopy and electron paramagnetic resonance analyses confirmed the formation of an inhibitory type I heme-clobetasol complex in CYP3A5 but not in CYP3A4, thus explaining the CYP3A5 selectivity of clobetasol. Our results provide a structural basis for selective CYP3A5 inhibition, along with mechanistic insights, and highlight clobetasol as an important chemical tool for target validation.

Clobetasol Propionate Is a Heme-Mediated Selective Inhibitor of Human Cytochrome P450 3A5.

Potential drug targets in the Mycobacterium tuberculosis cytochrome P450 system.

Structural Characterization and Ligand/Inhibitor Identification Provide Functional Insights into the Mycobacterium tuberculosis Cytochrome P450 CYP126A1.

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Structural Characterization and Ligand/Inhibitor Identification Provide Functional Insights into the Mycobacterium tuberculosis Cytochrome P450 CYP126A1.