Cytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis.
Author
Ačimovič, JureGoyal, Sandeep
Košir, Rok
Goličnik, Marko
Perše, Martina
Belič, Ales
Urlep, Žiga
Guengerich, F Peter
Rozman, Damjana
Affiliation
Univ Arizona, Dept Chem & BiochemIssue Date
2016
Metadata
Show full item recordPublisher
NATURE PUBLISHING GROUPCitation
Cytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis. 2016, 6:28462 Sci RepJournal
Scientific reportsRights
Copyright © The Author(s) 2016. This work is licensed under a Creative Commons Attribution 4.0 International License.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 JournalISSN
2045-2322PubMed ID
27334049Version
Final published versionSponsors
Slovene Research Agency [P1-0104]; US National Institutes of Health [R37 CA090426]; Slovene Human Resources Development and Scholarship FundAdditional Links
http://www.nature.com/articles/srep28462ae974a485f413a2113503eed53cd6c53
10.1038/srep28462
Scopus Count
Collections
Except where otherwise noted, this item's license is described as Copyright © The Author(s) 2016. This work is licensed under a Creative Commons Attribution 4.0 International License.
Related articles
- Cholesterol hydroperoxides as substrates for cholesterol-metabolizing cytochrome P450 enzymes and alternative sources of 25-hydroxycholesterol and other oxysterols.
- Authors: van Lier JE, Mast N, Pikuleva IA
- Issue date: 2015 Sep 14
- Novel sterols synthesized via the CYP27A1 metabolic pathway.
- Authors: Pikuleva I, Javitt NB
- Issue date: 2003 Dec 1
- Circadian rhythm of cholesterol synthesis in mouse liver: a statistical analysis of the post-squalene metabolites in wild-type and Crem-knock-out mice.
- Authors: Ačimovič J, Košir R, Kastelec D, Perše M, Majdič G, Rozman D, Košmelj K, Goličnik M
- Issue date: 2011 May 20
- The role of cytochrome P450 in the regulation of cholesterol biosynthesis.
- Authors: Gibbons GF
- Issue date: 2002 Dec