Catalytic modulation of human cytochromes P450 17A1 and P450 11B2 by phospholipid
Open accessAbstract
Unlike most of the drug-metabolizing cytochrome P450s, microsomal P450 17A1 and mitochondrial P450 11B2 catalyze sequential multi-step reactions in steroid biosynthesis. The membrane phospholipid composition might be one parameter that modulates the efficiency and processivity of specific pathways. Here we systematically examined the effects of physiologically relevant phospholipids on the catalysis of purified P450 17A1, P450 11B2, and P450 11B1 in reconstituted assay systems. Both dioleoylphosphatidylcholine (DOPC, 18:1) and dilauroylphosphatidylcholine (DLPC, 12:0) were found to be very efficient in reconstituting 17-hydroxylase and 1720-lyase reactions of P450 17A1. Phosphatidylethanolamine (PE) specifically enhanced 1720-lyase activity up to 2.4-fold in the presence of phosphatidylcholine. On the other hand, P450 11B2-catalyzed production of aldosterone from 11-deoxycorticosterone was very low and from 18-hydroxycorticosterone nil, implying low processivity. DOPC or cardiolipin, which is exclusively located in the inner mitochondrial membrane, maximized aldosterone yield. In sharp contrast, reconstitution of homologous P450 11B1 with DOPC significantly decreased corticosterone formation without affecting the synthesis of 18-hydroxycorticosterone. The intrinsic fluorescence of P450 17A1 and 11B2 increased in the presence of DOPC, DLPC and PE. Acrylamide quenching studies showed that PE decreased solvent accessibility for tryptophan in P450 17A1, as did 20:4 PC or 18:2 PC for P450 11B2. A moderately positive correlation between the proportion of high-spin substrate-bound species and catalytic activity was only observed in the presence of phosphatidylcholines with low-temperature phase transition. These results demonstrate the potential for phospholipids to regulate the activity of steroidogenic P450 activities and thereby steroid hormone biosynthetic pathways.
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Although enzyme function in vitro appears to be similar, clinical observations suggest that patients carrying the P30L allele are somewhat more symptomatic, straddling the border between SV and NC forms of CAH.
“Although enzyme function in vitro appears to be similar (111), clinical observations suggest that patients carrying the P30L allele are somewhat more symptomatic, straddling the border between SV and NC forms of CAH (213,222).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [111]
The Results and Discussion passages concern how phospholipids affect P450 17A1 and P450 11B2 activity, not the P30L allele. Searches for P30L, CYP21A2, and congenital adrenal hyperplasia found no passage addressing either comparable in-vitro enzyme function or the clinical severity attributed to P30L carriers. The cited paper's copy therefore does not verify this claim. (LLM, conf=0.76)
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The Action of Cytochromeb5on CYP2E1 and CYP2C19 Activities Requires Anionic Residues D58 and D65
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Cytochrome P450 Reconstitution Systems
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“For mitochondrial P450s, CL was reported to induce activation of P450 11A1 via a decrease in Km (39); conversely, CL inhibited P450 11B1 via an increase in Km and a decrease in Vmax (40).”
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“Lipid-P450 interactions have been suggested to maintain the active conformation of the protein (54), to affect the binding of P450 to POR for efficient electron transfer (55), and to facilitate the binding of hydrophobic substrates (56).”
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Hepatocyte‐specific Selenoi deficiency predisposes mice to hepatic steatosis and obesity
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- Authors
- Peng, H.-M., Barlow, C., & Auchus, R. J.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Auchus, Richard J.
- Venue
- The Journal of Steroid Biochemistry and Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 181
- Pages
- 63-72
- ISSN
- 0960-0760 (ISSN-L)
- PMC
- PMC5992074
- OpenAlex
- W2789295608
- Cited by
- 14
- References
- 60
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 2 · 2021: 2 · 2020: 2 · 2019: 1
- FWCI
- 0.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Steroid Biochemistry and Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01-GM086596)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- cytochrome P450 17A1, phospholipids, steroidogenesis, membrane lipid composition, aldosterone biosynthesis, corticosterone synthesis, 18-hydroxycorticosterone, phosphatidylethanolamine, phosphatidylcholine, cardiolipin, intrinsic fluorescence, lipid phase transition, enzyme processivity, reconstituted enzyme system
- MeSH terms
- Catalysis, Humans, Membrane Lipids, Oxidation-Reduction, Phospholipids, Steroid 17-alpha-Hydroxylase, Cytochrome P-450 CYP11B2
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