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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 Lamb Orcid Logo, Akira Kubota, Benjamin Lemaire, John J. Stegeman

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

Swansea University Author: David Lamb Orcid Logo

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DOI (Published version): 10.1016/j.bbagen.2013.12.009

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: 2013
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URI: https://cronfa.swan.ac.uk/Record/cronfa31515
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fullrecord <?xml version="1.0"?><rfc1807><datestamp>2019-08-18T16:50:35.0095221</datestamp><bib-version>v2</bib-version><id>31515</id><entry>2016-12-18</entry><title>Identification, modeling and ligand affinity of early deuterostome CYP51s, and functional characterization of recombinant zebrafish sterol 14&#x3B1;-demethylase</title><swanseaauthors><author><sid>1dc64e55c2c28d107ef7c3db984cccd2</sid><ORCID>0000-0001-5446-2997</ORCID><firstname>David</firstname><surname>Lamb</surname><name>David Lamb</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2016-12-18</date><deptcode>BMS</deptcode><abstract>Sterol 14&#x3B1;-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 14&#x3B1;-demethylase activity, at 3.2 nmol/min/nmol CYP51. The binding of azoles to zebrafish CYP51 gave KS (dissociation constant) values of 0.26 &#x3BC;M for ketoconazole and 0.64 &#x3BC;M 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.</abstract><type>Journal Article</type><journal>Biochimica et Biophysica Acta (BBA) - General Subjects</journal><volume>1840</volume><journalNumber>6</journalNumber><paginationStart>1825</paginationStart><paginationEnd>1836</paginationEnd><publisher/><issnPrint>03044165</issnPrint><keywords>sterol demthylase; cytochrome P450; zebrafish; evolution</keywords><publishedDay>19</publishedDay><publishedMonth>12</publishedMonth><publishedYear>2013</publishedYear><publishedDate>2013-12-19</publishedDate><doi>10.1016/j.bbagen.2013.12.009</doi><url>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118742/pdf/nihms584470.pdf</url><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm/><lastEdited>2019-08-18T16:50:35.0095221</lastEdited><Created>2016-12-18T17:42:18.3308314</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Ann Michelle Stanley</firstname><surname>Morrison</surname><order>1</order></author><author><firstname>Jared V.</firstname><surname>Goldstone</surname><order>2</order></author><author><firstname>David</firstname><surname>Lamb</surname><orcid>0000-0001-5446-2997</orcid><order>3</order></author><author><firstname>Akira</firstname><surname>Kubota</surname><order>4</order></author><author><firstname>Benjamin</firstname><surname>Lemaire</surname><order>5</order></author><author><firstname>John J.</firstname><surname>Stegeman</surname><order>6</order></author></authors><documents/><OutputDurs/></rfc1807>
spelling 2019-08-18T16:50:35.0095221 v2 31515 2016-12-18 Identification, modeling and ligand affinity of early deuterostome CYP51s, and functional characterization of recombinant zebrafish sterol 14α-demethylase 1dc64e55c2c28d107ef7c3db984cccd2 0000-0001-5446-2997 David Lamb David Lamb true false 2016-12-18 BMS 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. Journal Article Biochimica et Biophysica Acta (BBA) - General Subjects 1840 6 1825 1836 03044165 sterol demthylase; cytochrome P450; zebrafish; evolution 19 12 2013 2013-12-19 10.1016/j.bbagen.2013.12.009 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118742/pdf/nihms584470.pdf COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2019-08-18T16:50:35.0095221 2016-12-18T17:42:18.3308314 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Ann Michelle Stanley Morrison 1 Jared V. Goldstone 2 David Lamb 0000-0001-5446-2997 3 Akira Kubota 4 Benjamin Lemaire 5 John J. Stegeman 6
title Identification, modeling and ligand affinity of early deuterostome CYP51s, and functional characterization of recombinant zebrafish sterol 14α-demethylase
spellingShingle Identification, modeling and ligand affinity of early deuterostome CYP51s, and functional characterization of recombinant zebrafish sterol 14α-demethylase
David Lamb
title_short Identification, modeling and ligand affinity of early deuterostome CYP51s, and functional characterization of recombinant zebrafish sterol 14α-demethylase
title_full Identification, modeling and ligand affinity of early deuterostome CYP51s, and functional characterization of recombinant zebrafish sterol 14α-demethylase
title_fullStr Identification, modeling and ligand affinity of early deuterostome CYP51s, and functional characterization of recombinant zebrafish sterol 14α-demethylase
title_full_unstemmed Identification, modeling and ligand affinity of early deuterostome CYP51s, and functional characterization of recombinant zebrafish sterol 14α-demethylase
title_sort Identification, modeling and ligand affinity of early deuterostome CYP51s, and functional characterization of recombinant zebrafish sterol 14α-demethylase
author_id_str_mv 1dc64e55c2c28d107ef7c3db984cccd2
author_id_fullname_str_mv 1dc64e55c2c28d107ef7c3db984cccd2_***_David Lamb
author David Lamb
author2 Ann Michelle Stanley Morrison
Jared V. Goldstone
David Lamb
Akira Kubota
Benjamin Lemaire
John J. Stegeman
format Journal article
container_title Biochimica et Biophysica Acta (BBA) - General Subjects
container_volume 1840
container_issue 6
container_start_page 1825
publishDate 2013
institution Swansea University
issn 03044165
doi_str_mv 10.1016/j.bbagen.2013.12.009
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118742/pdf/nihms584470.pdf
document_store_str 0
active_str 0
description 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.
published_date 2013-12-19T03:38:31Z
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score 11.03559

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