title: Cytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis.
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.
authors.affiliation: Center for Functional Genomics and Bio-Chips, Faculty of Medicine, University of Ljubljana, Zaloška 4, SI-1000 Ljubljana, Slovenia.|Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia.
authors.forename: Jure
authors.initials: J
authors.lastname: Ačimovič
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, United States.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Goyal
authors.affiliation: Center for Functional Genomics and Bio-Chips, Faculty of Medicine, University of Ljubljana, Zaloška 4, SI-1000 Ljubljana, Slovenia.|Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia.
authors.forename: Rok
authors.initials: R
authors.lastname: Košir
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia.
authors.forename: Marko
authors.initials: M
authors.lastname: Goličnik
authors.affiliation: Medical Experimental Centre, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Zaloška 4, SI-1000 Ljubljana, Slovenia.
authors.forename: Martina
authors.initials: M
authors.lastname: Perše
authors.affiliation: Faculty of Electrical Engineering, University of Ljubljana, Slovenia.
authors.forename: Ales
authors.initials: A
authors.lastname: Belič
authors.affiliation: Center for Functional Genomics and Bio-Chips, Faculty of Medicine, University of Ljubljana, Zaloška 4, SI-1000 Ljubljana, Slovenia.|Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia.
authors.forename: Žiga
authors.initials: Ž
authors.lastname: Urlep
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, United States.
authors.forename: F Peter
authors.initials: FP
authors.lastname: Guengerich
authors.affiliation: Center for Functional Genomics and Bio-Chips, Faculty of Medicine, University of Ljubljana, Zaloška 4, SI-1000 Ljubljana, Slovenia.|Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia.
authors.forename: Damjana
authors.initials: D
authors.lastname: Rozman
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis*; D051786:Cyclic AMP Response Element Modulator / Q000172:deficiency / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007810:Lanosterol / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008962:Models, Theoretical; D010084:Oxidation-Reduction; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification; D013261:Sterols / Q000032:analysis / Q000378:metabolism; D013737:Testis / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D013261:Sterols; D051786:Cyclic AMP Response Element Modulator; D007810:Lanosterol; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol