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Cytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis
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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917857/ https://www.ncbi.nlm.nih.gov/pubmed/27334049 http://dx.doi.org/10.1038/srep28462 |
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author | Ačimovič, Jure Goyal, Sandeep Košir, Rok Goličnik, Marko Perše, Martina Belič, Ales Urlep, Žiga Guengerich, F. Peter Rozman, Damjana |
author_facet | Ačimovič, Jure Goyal, Sandeep Košir, Rok Goličnik, Marko Perše, Martina Belič, Ales Urlep, Žiga Guengerich, F. Peter Rozman, Damjana |
author_sort | Ačimovič, Jure |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4917857 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-49178572016-06-27 Cytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis Ačimovič, Jure Goyal, Sandeep Košir, Rok Goličnik, Marko Perše, Martina Belič, Ales Urlep, Žiga Guengerich, F. Peter Rozman, Damjana Sci Rep Article 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. Nature Publishing Group 2016-06-23 /pmc/articles/PMC4917857/ /pubmed/27334049 http://dx.doi.org/10.1038/srep28462 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ 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/ |
spellingShingle | Article Ačimovič, Jure Goyal, Sandeep Košir, Rok Goličnik, Marko Perše, Martina Belič, Ales Urlep, Žiga Guengerich, F. Peter Rozman, Damjana Cytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis |
title | Cytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis |
title_full | Cytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis |
title_fullStr | Cytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis |
title_full_unstemmed | Cytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis |
title_short | Cytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis |
title_sort | cytochrome p450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917857/ https://www.ncbi.nlm.nih.gov/pubmed/27334049 http://dx.doi.org/10.1038/srep28462 |
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