Functional properties and substrate characterization of human CYP26A1, CYP26B1, and CYP26C1 expressed by recombinant baculovirus in insect cells

Helvig, Christian; Taimi, Mohammed; Cameron, Don; Jones, Glenville; Petkovich, Martin

doi:10.1016/j.vascn.2011.08.005

Cited by 16 publications

(15 citation statements)

References 25 publications

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“…With the evidence suggesting intratesticular RA is formed within the tissue and assuming no interindividual differences in the clearance of intratesticular RA, a correlation between the RA synthesis rate and the measured intratesticular RA is expected. The reason intratesticular 13-cis RA correlated with ALDH1A activity and at RA did not, may be due to the fact 13-cis RA is a poor substrate for CYP26 enzymes compared with at RA ( 47 ). Therefore, interindividual differences in CYP26 expression are more likely to affect the intratesticular concentration of at RA.…”

Section: Figmentioning

confidence: 95%

Importance of ALDH1A enzymes in determining human testicular retinoic acid concentrations

Arnold

Kent

Hogarth

et al. 2015

Journal of Lipid Research

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Section: Figmentioning

confidence: 95%

Importance of ALDH1A enzymes in determining human testicular retinoic acid concentrations

Arnold

Kent

Hogarth

et al. 2015

Journal of Lipid Research

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“…CYP26A1 was the first member of the CYP26 family to be identified, characterized and cloned (22,23). CYP26B1 has 41% amino acid identity with CYP26A1 but similar functional activity (24,25). In subsets of vascular and immune cells, interference with CYP26 has profound effects on atRA levels (26)(27)(28), and increased levels of endogenous atRA result in induction of a number of retinoid-responsive genes in vascular cells (27).…”

Section: Introductionmentioning

confidence: 99%

A CYP26B1 Polymorphism Enhances Retinoic Acid Catabolism and May Aggravate Atherosclerosis

Krivospitskaya

Elmabsout

Sundman

et al. 2012

Mol Med

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All-trans retinoic acid, controlled by cytochrome P450, family 26 (CYP26) enzymes, potentially has beneficial effects in atherosclerosis treatment. This study investigates CYP26 subfamily B, polypeptide 1 (CYP26B1) in atherosclerosis and the effects of a genetic polymorphism in CYP26B1 on retinoid catabolism. We found that CYP26B1 mRNA was induced by retinoic acid in human atherosclerotic arteries, and CYP26B1 and the macrophage marker CD68 were colocalized in human atherosclerotic lesions. In mice, Cyp26B1 mRNA was higher in atherosclerotic arteries than in normal arteries. Databases were queried for nonsynonymous CYP26B1 single nucleotide polymorphisms (SNPs) and rs2241057 selected for further studies. Constructs of the CYP26B1 variants were created and used for production of purified proteins and transfection of macrophagelike cells. The minor variant catabolized retinoic acid with significantly higher efficiency, indicating that rs2241057 is functional and suggesting reduced retinoid availability in tissues with the minor variant. rs2241057 was investigated in a Stockholm Coronary Atherosclerosis Risk Factor (SCARF) subgroup. The minor allele was associated with slightly larger lesions, as determined by angiography. In summary, this study identifies the first CYP26B1 polymorphism that alters CYP26B1 capacity to metabolize retinoic acid. CYP26B1 was expressed in macrophage-rich areas of human atherosclerotic lesions, induced by retinoic acid and increased in murine atherosclerosis. Taken together, the results indicate that CYP26B1 capacity is genetically regulated and suggest that local CYP26B1 activity may influence atherosclerosis.

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“…The CYP26 family of cytochrome P450 (CYP26A1, CYP26B1, and CYP26C1) has been identified as being responsible for the metabolism of at-RA and its metabolites (Ray et al, 1997;Taimi et al, 2004;Guengerich, 2006;Lee et al, 2007;Lutz et al, 2009;Thatcher and Isoherranen, 2009;Helvig et al, 2011;Ross and Zolfaghari, 2011;Nelson et al, 2013). To date, however, no known xenobiotic compounds have been identified as substrates of CYP26A1 or CYP26B1, the two most characterized CYP26 isoforms.…”

Section: Discussionmentioning

confidence: 99%

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

Foti¹,

Isoherranen²,

Zelter³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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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 docking at-RA in the active site and comparing the results to known metabolic profiles of at-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.

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Functional properties and substrate characterization of human CYP26A1, CYP26B1, and CYP26C1 expressed by recombinant baculovirus in insect cells

Cited by 16 publications

References 25 publications

Importance of ALDH1A enzymes in determining human testicular retinoic acid concentrations

Importance of ALDH1A enzymes in determining human testicular retinoic acid concentrations

A CYP26B1 Polymorphism Enhances Retinoic Acid Catabolism and May Aggravate Atherosclerosis

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

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