Homology models of human all-trans retinoic acid metabolizing enzymes CYP26B1 and CYP26B1 spliced variant.

Patricia Saenz-Méndez, Ali Ateia Elmabsout, Helena Sävenstrand, Mohamed Khalid Alhaj Awadalla, Åke Strid, Allan Sirsjö, Leif A Eriksson

Journal: Journal of chemical information and modeling 2013;52(10):2631-7

PMID: 22985482

Full Text on American Chemical Society View on PubMed

Abstract

Homology models of CYP26B1 (cytochrome P450RAI2) and CYP26B1 spliced variant were derived using the crystal structure of cyanobacterial CYP120A1 as template for the model building. The quality of the homology models generated were carefully evaluated, and the natural substrate all-trans-retinoic acid (atRA), several tetralone-derived retinoic acid metabolizing blocking agents (RAMBAs), and a well-known potent inhibitor of CYP26B1 (R115866) were docked into the homology model of full-length cytochrome P450 26B1. The results show that in the model of the full-length CYP26B1, the protein is capable of distinguishing between the natural substrate (atRA), R115866, and the tetralone derivatives. The spliced variant of CYP26B1 model displays a reduced affinity for atRA compared to the full-length enzyme, in accordance with recently described experimental information.

Address: Computational Chemistry and Biology Group, Facultad de Química, UdelaR, 11800 Montevideo, Uruguay.

DOI: 10.1021/ci300264u

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MeSH Terms: Alternative Splicing, Bacterial Proteins, Benzothiazoles, Crystallography, X-Ray, Cytochrome P-450 Enzyme System, Enzyme Inhibitors, Humans, Isoenzymes, Molecular Docking Simulation, Retinoic Acid 4-Hydroxylase, Structural Homology, Protein, Synechocystis, Tetralones, Thermodynamics, Tretinoin, Triazoles