Compound I is the reactive intermediate in the first monooxygenation step during conversion of cholesterol to pregnenolone by cytochrome P450scc: EPR/ENDOR/cryoreduction/annealing studies
Open accessAbstract
Cytochrome P450scc (CYP11A1) catalyzes conversion of cholesterol (CH) to pregnenolone, the precursor to all steroid hormones. This process proceeds via three sequential monooxygenation reactions: two stereospecific hydroxylations with formation first of 22R-hydroxycholesterol (22-HC) and then 20α,22R-dihydroxycholesterol (20,22-DHC), followed by C20-C22 bond cleavage. Herein we have employed EPR and ENDOR spectroscopy to characterize the intermediates in the first hydroxylation step by 77 K radiolytic one-electron cryoreduction and subsequent annealing of the ternary oxy-cytochrome P450scc-cholesterol complex. This approach is fully validated by the demonstration that the cryoreduced ternary complex of oxy-P450scc-CH is catalytically competent and hydroxylates cholesterol to form 22-HC with no detectable formation of 20-HC, just as occurs under physiological conditions. Cryoreduction of the ternary complex trapped at 77 K produces predominantly the hydroperoxy-ferriheme P450scc intermediate, along with a minor fraction of peroxo-ferriheme intermediate that converts into a new hydroperoxo-ferriheme species at 145 K. This behavior reveals that the distal pocket of the parent oxy-P450scc-cholesterol complex exhibits an efficient proton delivery network, with an ordered water molecule H-bonded to the distal oxygen of the dioxygen ligand. During annealing of the hydroperoxy-ferric P450scc intermediates at 185 K, they convert to the primary product complex in which CH has been converted to 22-HC. In this process, the hydroperoxy-ferric intermediate decays with a large solvent kinetic isotope effect, as expected when proton delivery to the terminal O leads to formation of Compound I (Cpd I). (1)H ENDOR measurements of the primary product formed in deuterated solvent show that the heme Fe(III) is coordinated to the 22R-O(1)H of 22-HC, where the (1)H is derived from substrate and exchanges to D after annealing at higher temperatures. These observations establish that Cpd I is the agent that hydroxylates CH, rather than the hydroperoxy-ferric heme.
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Recent high-resolution temporal enzymatic work indicates that transient cholesterol hydroperoxyl serves as reaction intermediates.
“Recent high-resolution temporal enzymatic work further indicates that transient cholesterol hydroperoxyl serves as reaction intermediates (48, 49), further supporting the sequential oxidative cleavage model of this enzyme.”
From Adrenal Mitochondria and Steroidogenesis: From Individual Proteins to Functional Protein Assemblies (2016) · cites this paper as [48]
The Discussion (‘Hydroxylation of Cholesterol’; page not available in our copy) identifies transient hydroperoxy-ferriheme intermediates during cholesterol hydroxylation. It does not identify a cholesterol hydroperoxyl intermediate: the hydroperoxy group is bound to the enzyme’s heme, and the paper concludes that Compound I is the active hydroxylating species. (LLM, conf=0.84)
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- Authors
- Davydov, R., Gilep, A. A., Strushkevich, N. V., Usanov, S. A., & Hoffman, B. M.
- Affiliations
- Northwestern University (US)
- Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 220141 Minsk, Kuprevicha 5, Belarus
- University of Toronto (CA)
- National Academy of Sciences of Belarus (BY)
- Corresponding author
- Usanov, Sergey A.
- Hoffman, Brian M.
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2012-10-05
- Volume
- 134
- Issue
- 41
- Pages
- 17149-17156
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC3491644
- OpenAlex
- W2049338973
- Cited by
- 49
- References
- 41
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 6 · 2022: 2 · 2021: 2 · 2020: 4 · 2019: 2 · 2018: 2 · 2017: 5 · 2016: 5 · 2015: 9 · 2014: 5
- FWCI
- 2.45
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL13531, R01HL013531)
- Topics
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Physical Sciences › Energy › Renewable Energy, Sustainability and the Environment › Metalloenzymes and iron-sulfur proteins
- Keywords
- cytochrome P450scc, CYP11A1, cholesterol, pregnenolone, monooxygenation, compound I, hydroxycholesterol, 22R-hydroxycholesterol, steroidogenesis, proton delivery, solvent kinetic isotope effect, electron spin resonance, ENDOR spectroscopy
- MeSH terms
- Cholesterol, Cholesterol Side-Chain Cleavage Enzyme, Electron Spin Resonance Spectroscopy, Ferric Compounds, Ferrous Compounds, Models, Molecular, Oxidation-Reduction, Oxygen, Pregnenolone
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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