Cytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis
| Autor: | Marko Goličnik, Jure Acimovic, Rok Košir, Žiga Urlep, Martina Perše, Aleš Belič, Damjana Rozman, F. Peter Guengerich, Sandeep Goyal |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine CAMP-Responsive Element Modulator Biology Cholesterol 7 alpha-hydroxylase Article Gas Chromatography-Mass Spectrometry Cyclic AMP Response Element Modulator Lanosterol Mice 03 medical and health sciences chemistry.chemical_compound Cytochrome P-450 Enzyme System Testis CYP27A1 Animals Humans education Mice Knockout education.field_of_study Multidisciplinary 030102 biochemistry & molecular biology Cholesterol Cholesterol side-chain cleavage enzyme Cytochrome P450 Models Theoretical Recombinant Proteins Sterol Rats Sterols 030104 developmental biology Biochemistry chemistry biology.protein lipids (amino acids peptides and proteins) Oxidation-Reduction |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep28462 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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