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.

Disrupting Hepatocyte Cyp51 from Cholesterol Synthesis Leads to Progressive Liver Injury in the Developing Mouse and Decreases RORC Signalling

“…7c) were recently proposed as strong RORC agonists11. Elevated levels of lathosterol and 7-dehydrocholesterol might support the existence of a shunt pathway, as previously proposed by us2223 and others24.…”

“…Hepatic cholesterol intermediates (including LAN) generally correlate with their plasma concentration, but not in the case of DHL24. This suggested that DHL might be metabolized in a shunt pathway as most recently confirmed by us39, or might be exported to the bile, which still awaits experimental confirmation. The former option is enticing as it offers an explanation as to why we found no decrease in sterol intermediates immediately before their conversion to cholesterol in H Cyp51 −/− mice (e.g.…”

Isotope-Labeling Studies Support the Electrophilic Compound I Iron Active Species, FeO3+, for the Carbon–Carbon Bond Cleavage Reaction of the Cholesterol Side-Chain Cleavage Enzyme, Cytochrome P450 11A1

“…Doing the most relevant experiments has not been possible with P450 11A1, in that the only types of labeling experiments possible with the substrate cholesterol are described here and the ability to catalyze other reactions is limited. 27 P450 11A1 does catalyze a number of other reactions, particularly with vitamin D, 42,43 but none of these involve the formation of carbonyls. Reactions with other P450s can be considered, e.g.…”

Selective oxidation of aliphatic C–H bonds in alkylphenols by a chemomimetic biocatalytic system

“…Putatively, 5′a could be oxidized in one of the methyl groups to generate a diol intermediate (5′c), which could then lose a single carbon unit by the C-C bond cleavage during further oxidation, generating 2′b and a molecule of formaldehyde. This mechanism is not uncommon in the reactions of cholesterol side chain cleavage (39,40). For example, the transformation from cholesterol to pregnenolone depends on the cleavage of C20,C22 carbon-carbon bond catalyzed by CYP11A1 (41).…”