Identification of Tazarotenic Acid as the First Xenobiotic Substrate of Human Retinoic Acid Hydroxylase CYP26A1 and CYP26B1

Autor: Robert S. Foti, Alex Zelter, Leslie J. Dickmann, Brian Buttrick, Nina Isoherranen, Philippe Diaz, Dominique Douguet
Přispěvatelé: Amgen Inc. USA, University of Washington [Seattle], University of Montana, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)
Rok vydání: 2016
Předmět:
Models
Molecular
0301 basic medicine
Receptors
Retinoic Acid
Stereochemistry
Metabolite
Molecular Sequence Data
Retinoic acid
Tretinoin
[CHIM.THER]Chemical Sciences/Medicinal Chemistry
Metabolism
Transport
and Pharmacogenomics
Substrate Specificity
Xenobiotics
03 medical and health sciences
CYP26A1
chemistry.chemical_compound
Cytochrome P-450 Enzyme System
Catalytic Domain
Humans
Amino Acid Sequence
Heme
ComputingMilieux_MISCELLANEOUS
Pharmacology
chemistry.chemical_classification
biology
Nicotinic Acids
Cytochrome P450
Active site
Retinoic Acid 4-Hydroxylase
[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences
Kinetics
030104 developmental biology
Enzyme
Pharmaceutical Preparations
chemistry
Biochemistry
embryonic structures
biology.protein
Molecular Medicine
[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
Xenobiotic
[CHIM.CHEM]Chemical Sciences/Cheminformatics
Zdroj: Journal of Pharmacology and Experimental Therapeutics
Journal of Pharmacology and Experimental Therapeutics, American Society for Pharmacology and Experimental Therapeutics, 2016, 357 (2), pp.281-292. ⟨10.1124/jpet.116.232637⟩
ISSN: 1521-0103
0022-3565
DOI: 10.1124/jpet.116.232637
Popis: Cytochrome P450 (CYP) 26A1 and 26B1 are heme-containing enzymes responsible for metabolizing all-trans retinoic acid (at-RA). No crystal structures have been solved, and therefore homology models that provide structural information are extremely valuable for the development of inhibitors of cytochrome P450 family 26 (CYP26). The objectives of this study were to use homology models of CYP26A1 and CYP26B1 to characterize substrate binding characteristics, to compare structural aspects of their active sites, and to support the role of CYP26 in the metabolism of xenobiotics. Each model was verified by dockingat-RA in the active site and comparing the results to known metabolic profiles ofat-RA. The models were then used to predict the metabolic sites of tazarotenic acid with results verified by in vitro metabolite identification experiments. The CYP26A1 and CYP26B1 homology models predicted that the benzothiopyranyl moiety of tazarotenic acid would be oriented toward the heme of each enzyme and suggested that tazarotenic acid would be a substrate of CYP26A1 and CYP26B1. Metabolite identification experiments indicated that CYP26A1 and CYP26B1 oxidatively metabolized tazarotenic acid on the predicted moiety, with in vitro rates of metabolite formation by CYP26A1 and CYP26B1 being the highest across a panel of enzymes. Molecular analysis of the active sites estimated the active-site volumes of CYP26A1 and CYP26B1 to be 918 Å(3)and 977 Å(3), respectively. Overall, the homology models presented herein describe the enzyme characteristics leading to the metabolism of tazarotenic acid by CYP26A1 and CYP26B1 and support a potential role for the CYP26 enzymes in the metabolism of xenobiotics.
Databáze: OpenAIRE
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