Cytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis.
Guengerich, F Peter
AffiliationUniv Arizona, Dept Chem & Biochem
MetadataShow full item record
PublisherNATURE PUBLISHING GROUP
CitationCytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis. 2016, 6:28462 Sci Rep
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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.
NoteOpen Access Journal
VersionFinal published version
SponsorsSlovene Research Agency [P1-0104]; US National Institutes of Health [R37 CA090426]; Slovene Human Resources Development and Scholarship Fund
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