Human cytochrome P450scc (CYP11A1) catalyzes epoxide formation with ergosterol
Open accessAbstract
Cytochrome P450scc (P450scc) catalyzes the cleavage of the side chain of both cholesterol and the vitamin D(3) precursor, 7-dehydrocholesterol. The aim of this study was to test the ability of human P450scc to metabolize ergosterol, the vitamin D(2) precursor, and define the structure of the major products. P450scc incorporated into the bilayer of phospholipid vesicles converted ergosterol to two major and four minor products with a k(cat) of 53 mol · min(-1) · mol P450scc(-1) and a K(m) of 0.18 mol ergosterol/mol phospholipid, similar to the values observed for cholesterol metabolism. The reaction of ergosterol with P450scc was scaled up to make enough of the two major products for structural analysis. From mass spectrometry, NMR, and comparison of the NMR data to that for similar molecules, we determined the structures of the two major products as 20-hydroxy-22,23-epoxy-22,23-dihydroergosterol and 22-keto-23-hydroxy-22,23-dihydroergosterol. Molecular modeling and nuclear Overhauser effect (or enhancement) spectroscopy spectra analysis helped to establish the configurations at C20, C22, and C23 and determine the final structures of major products as 22R,23S-epoxyergosta-5,7-diene-3β,20α-diol and 3β,23S-dihydroxyergosta-5,7-dien-22-one. It is likely that the formation of the second product is through a 22,23-epoxy (oxirane) intermediate followed by C22 hydroxylation with the formation of strained 22-hydroxy-22,23-epoxide (oxiranol), which is immediately transformed to the more stable α-hydroxyketone. Molecular modeling of ergosterol into the P450scc crystal structure positioned the ergosterol side chain consistent with formation of the above products. Thus, we have shown that P450scc efficiently catalyzes epoxide formation with ergosterol giving rise to novel epoxy, hydroxy, and keto derivatives, without causing cleavage of the side chain.
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Ergosterol can be metabolized by CYP11A1 but without side chain cleavage.
“Ergosterol, another Δ7 sterol that is the major membrane sterol in fungi, can also be metabolized by CYP11A1 but unlike 7DHC, no cleavage of the side chain occurs”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [44]
Human CYP11A1 catalyzes epoxidation of the C22-C23 double bond and hydroxylation at C20 of ergosterol, generating 20-hydroxy-22,23-epoxy-22,23-dihydroergosterol as a major metabolite.
“Human CYP11A1 was found to catalyze epoxidation of the C22 C23 double bond as well as hydroxylation of the ergosterol side chain at C20, generating 20-hydroxy-22,23-epoxy-22,23-dihydroergosterol as a major metabolite”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [44]
Unlike ergosterol, vitamin D2 does not undergo epoxidation of the C22-C23 double bond by CYP11A1.
“unlike ergosterol [44], no epoxidation of the double bond between C22 and C23 occurs for vitamin D2”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [44]
Catalytic activity of CYP11A1 on non-traditional substrates such as vitamin D and ergosterol does not result in side chain cleavage, but involves sequential hydroxylations of the side chain including at C17.
“Importantly, catalytic activity on non-traditional substrates such as vitamin D and ergosterol does not result in side chain cleavage, but involves sequential hydroxylations of the side chain including at C17 [[10,24–30], and see below].”
From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [10]
The activity of CYP11A1 is affected by substrate structure: sterols with steroidal or Δ7-steroidal structures undergo side chain cleavage following hydroxylations at C22 and C20, whereas vitamin D metabolism involves sequential hydroxylations starting at C20 without cleavage.
“The activity of CYP11A1 is affected by the structure of the substrate with sterols having steroidal or Δ7-steroidal structures undergoing side chain cleavage following hydroxylations at C22 and C20. In contrast, metabolism of vitamin D involves sequential hydroxylations that start at C20 but do not lead to cleavage.”
From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [10]
Molecular modeling using the crystal structure of CYP11A1 predicts that other intermediates of cholesterol synthesis could also serve as substrates for CYP11A1.
“Molecular modeling using the crystal structure of CYP11A1 predicts that other intermediates of cholesterol synthesis could also serve as substrates for CYP11A1.”
From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [10]
Purified human CYP11A1 acts on ergosterol, with no cleavage of the side chain due to the C22 double bond; the C22=C23 double bond undergoes epoxidation to produce 20-hydroxy-22,23-epoxy-22,23-dihydroergosterol, and the other major product is 22-keto-23-hydroxy-22,23-dihydroergosterol.
“Purified human CYP11A1 acts on the fungal membrane sterol, ergosterol, also available through the diet. No cleavage of the side chain occurs due to the presence of the double bond at C22. Rather, the C22=C23 double bond undergoes epoxidation to produce 20-hydroxy-22,23-epoxy-22,23-dihydroergosterol. The other major product is 22-keto-23-hydroxy-22,23-dihydroergosterol.”
From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [10]
The catalytic efficiency for metabolism of ergosterol by human CYP11A1 is the same as that for cholesterol.
“The catalytic efficiency for the metabolism of ergosterol by human CYP11A1 is the same as that for cholesterol [10].”
From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [10]
CYP11A1 favors initial hydroxylation of vitamin D3 at C20 over C22 (or C23), with 20(OH)D3 as the first and major metabolite.
“Subsequent enzymatic analysis revealed that CYP11A1 favors initial hydroxylation of D3 at C20 over C22 (or C23), with 20(OH)D3 representing the first and major metabolite.”
From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [10]
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References 42 · Cited by 32
- Authors
- Tuckey, R. C., Nguyen, M. N., Chen, J., Slominski, A. T., Baldisseri, D. M., Tieu, E. W., Zjawiony, J. K., & Li, W.
- Affiliations
- The University of Western Australia (AU)
- University of Tennessee Health Science Center (US)
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 40
- Issue
- 3
- Pages
- 436-444
- ISSN
- 0090-9556 (ISSN-L)
- PMC
- PMC3286270
- OpenAlex
- W2127919481
- Cited by
- 32
- References
- 42
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 4 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 1 · 2016: 2 · 2015: 7 · 2014: 5 · 2013: 2 · 2012: 3
- FWCI
- 1.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (University of Western Australia) (submittedVersion)
- Funders
- National Institutes of Health (1s10od010678-01)
- Health Science Center, University of Tennessee
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR052190)
- National Center for Research Resources (S10RR026377)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- CYP11A1, cytochrome P450scc, ergosterol, epoxidation, cholesterol side-chain cleavage
- MeSH terms
- Cholesterol Side-Chain Cleavage Enzyme, Dehydrocholesterols, Epoxy Compounds, Ergocalciferols, Ergosterol, Ethylene Oxide, Humans, Hydroxylation, Kinetics, Magnetic Resonance Spectroscopy, Phospholipids, Mass Spectrometry
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