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Identification, modeling and ligand affinity of early deuterostome CYP51s, and functional characterization of recombinant zebrafish sterol 14α-demethylase / Ann Michelle Stanley Morrison; Jared V. Goldstone; David C. Lamb; Akira Kubota; Benjamin Lemaire; John J. Stegeman

Biochimica et Biophysica Acta (BBA) - General Subjects, Volume: 1840, Issue: 6, Pages: 1825 - 1836

Swansea University Author: Lamb, David

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Abstract

Sterol 14α-demethylase (cytochrome P450 51, CYP51, P45014DM) is a microsomal enzyme that in eukaryotes catalyzes formation of sterols essential for cell membrane function and as precursors in biosynthesis of steroid hormones. Functional properties of CYP51s are unknown in non-mammalian deuterostomes...

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Published in: Biochimica et Biophysica Acta (BBA) - General Subjects
ISSN: 03044165
Published: 2014
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URI: https://cronfa.swan.ac.uk/Record/cronfa31515
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Abstract: Sterol 14α-demethylase (cytochrome P450 51, CYP51, P45014DM) is a microsomal enzyme that in eukaryotes catalyzes formation of sterols essential for cell membrane function and as precursors in biosynthesis of steroid hormones. Functional properties of CYP51s are unknown in non-mammalian deuterostomes. Molecular phylogeny positioned S. purpuratus CYP51 at the base of the deuterostome clade. In zebrafish, CYP51 is expressed in all organs examined, most strongly in intestine. The recombinant protein bound lanosterol and catalyzed 14α-demethylase activity, at 3.2 nmol/min/nmol CYP51. The binding of azoles to zebrafish CYP51 gave KS (dissociation constant) values of 0.26 μM for ketoconazole and 0.64 μM for propiconazole. Displacement of carbon monoxide also indicated zebrafish CYP51 has greater affinity for ketoconazole. Docking to homology models showed that lanosterol docks in fish and sea urchin CYP51s with an orientation essentially the same as in mammalian CYP51. Docking of ketoconazole indicates it would inhibit fish and sea urchin CYP51s. Biochemical and computational analyses are consistent with lanosterol being a substrate for early deuterostome CYP51s. The results expand the phylogenetic view of animal CYP51, with evolutionary, environmental and therapeutic implications.
Keywords: sterol demthylase; cytochrome P450; zebrafish; evolution
College: Swansea University Medical School
Issue: 6
Start Page: 1825
End Page: 1836