Abstract
A new CYP26A1 homology model was built based on the crystal structure of cyanobacterial CYP120A1. The model quality was examined for stereochemical accuracy, folding reliability, and absolute quality using a variety of different bioinformatics tools. Furthermore, the docking capabilities of the model were assessed by docking of the natural substrate all-trans-retinoic acid (atRA), and a group of known azole- and tetralone-based CYP26A1 inhibitors. The preferred binding pose of atRA suggests the (4S)-OH-atRA metabolite production, in agreement with recently available experimental data. The distances between the ligands and the heme group iron of the enzyme are in agreement with corresponding distances obtained for substrates and azole inhibitors for other cytochrome systems. The calculated theoretical binding energies agree with recently reported experimental data and show that the model is capable of discriminating between natural substrate, strong inhibitors (R116010 and R115866), and weak inhibitors (liarozole, fluconazole, tetralone derivatives).
Highlights
Retinoic acid (RA) is the most active metabolite of vitamin A, which mediates the biological functions of the vitamin
Five CYP26A1 homology models have been presented in enzyme inhibitor docking studies [29,30,31,32,33]
Structures, we found that CYP26A1 shares 33% sequence identity with 2VE3 which is the highest score to a known structure
Summary
Retinoic acid (RA) is the most active metabolite of vitamin A (retinol), which mediates the biological functions of the vitamin. Upon RA binding to the nuclear retinoic acid receptor (RAR), RAR heterodimerizes with the nuclear retinoid X receptor (RXR). The resulting dimer interacts with specific DNA retinoic acid response element (RARE) located in the promoter regions of RA target genes [2]. RA is intracellularly synthesized from retinol via two oxidation steps involving oxidation of retinol to retinal and further oxidation to RA by a group of retinol and retinal dehydrogenases, respectively. The endogenously synthesized RA is chemically found in different geometric isomers including 9-cis-RA, 11-cis-RA, 13-cis-RA, (9Z,13Z)-RA, and the chemically most stable structure all-trans RA (atRA) [3]. When atRA is synthesized, it either binds to the nuclear receptor or undergoes degradation to more polar derivatives by a group of cytochrome P450 oxidase (CYP)
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