Cytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis.

Persistent Link:
http://hdl.handle.net/10150/618983
Title:
Cytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis.
Author:
Ačimovič, Jure; Goyal, Sandeep; Košir, Rok; Goličnik, Marko; Perše, Martina; Belič, Ales; Urlep, Žiga; Guengerich, F Peter; Rozman, Damjana
Affiliation:
Univ Arizona, Dept Chem & Biochem
Issue Date:
2016
Publisher:
NATURE PUBLISHING GROUP
Citation:
Cytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis. 2016, 6:28462 Sci Rep
Journal:
Scientific reports
Rights:
This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Collection Information:
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
Abstract:
Cholesterol synthesis is among the oldest metabolic pathways, consisting of the Bloch and Kandutch-Russell branches. Following lanosterol, sterols of both branches are proposed to be dedicated to cholesterol. We challenge this dogma by mathematical modeling and with experimental evidence. It was not possible to explain the sterol profile of testis in cAMP responsive element modulator tau (Crem τ) knockout mice with mathematical models based on textbook pathways of cholesterol synthesis. Our model differs in the inclusion of virtual sterol metabolizing enzymes branching from the pathway. We tested the hypothesis that enzymes from the cytochrome P450 (CYP) superfamily can participate in the catalysis of non-classical reactions. We show that CYP enzymes can metabolize multiple sterols in vitro, establishing novel branching points of cholesterol synthesis. In conclusion, sterols of cholesterol synthesis can be oxidized further to metabolites not dedicated to production of cholesterol. Additionally, CYP7A1, CYP11A1, CYP27A1, and CYP46A1 are parts of a broader cholesterol synthesis network.
Note:
Open Access Journal
ISSN:
2045-2322
PubMed ID:
27334049
DOI:
10.1038/srep28462
Version:
Final published version
Sponsors:
Slovene Research Agency [P1-0104]; US National Institutes of Health [R37 CA090426]; Slovene Human Resources Development and Scholarship Fund
Additional Links:
http://www.nature.com/articles/srep28462

Full metadata record

DC FieldValue Language
dc.contributor.authorAčimovič, Jureen
dc.contributor.authorGoyal, Sandeepen
dc.contributor.authorKošir, Roken
dc.contributor.authorGoličnik, Markoen
dc.contributor.authorPerše, Martinaen
dc.contributor.authorBelič, Alesen
dc.contributor.authorUrlep, Žigaen
dc.contributor.authorGuengerich, F Peteren
dc.contributor.authorRozman, Damjanaen
dc.date.accessioned2016-08-27T00:59:23Z-
dc.date.available2016-08-27T00:59:23Z-
dc.date.issued2016-
dc.identifier.citationCytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis. 2016, 6:28462 Sci Repen
dc.identifier.issn2045-2322-
dc.identifier.pmid27334049-
dc.identifier.doi10.1038/srep28462-
dc.identifier.urihttp://hdl.handle.net/10150/618983-
dc.description.abstractCholesterol synthesis is among the oldest metabolic pathways, consisting of the Bloch and Kandutch-Russell branches. Following lanosterol, sterols of both branches are proposed to be dedicated to cholesterol. We challenge this dogma by mathematical modeling and with experimental evidence. It was not possible to explain the sterol profile of testis in cAMP responsive element modulator tau (Crem τ) knockout mice with mathematical models based on textbook pathways of cholesterol synthesis. Our model differs in the inclusion of virtual sterol metabolizing enzymes branching from the pathway. We tested the hypothesis that enzymes from the cytochrome P450 (CYP) superfamily can participate in the catalysis of non-classical reactions. We show that CYP enzymes can metabolize multiple sterols in vitro, establishing novel branching points of cholesterol synthesis. In conclusion, sterols of cholesterol synthesis can be oxidized further to metabolites not dedicated to production of cholesterol. Additionally, CYP7A1, CYP11A1, CYP27A1, and CYP46A1 are parts of a broader cholesterol synthesis network.en
dc.description.sponsorshipSlovene Research Agency [P1-0104]; US National Institutes of Health [R37 CA090426]; Slovene Human Resources Development and Scholarship Funden
dc.language.isoenen
dc.publisherNATURE PUBLISHING GROUPen
dc.relation.urlhttp://www.nature.com/articles/srep28462en
dc.rightsThis work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/en
dc.titleCytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis.en
dc.typeArticleen
dc.contributor.departmentUniv Arizona, Dept Chem & Biochemen
dc.identifier.journalScientific reportsen
dc.description.noteOpen Access Journalen
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
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