Control of androgen biosynthesis in the human through the interaction of Arg347 and Arg358 of CYP17 with cytochrome b5
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The lyase activity of human CYP17 (17α-hydroxylase-17,20-lyase also P-450c17 or P-45017α) is greatly dependent on the presence of cytochrome b5, and this effect has been ascribed an important regulatory role [Lee-Robichaud, Wright, Akhtar and Akhtar (1995) Biochem. J. 308, 901–908]. This facet was further investigated by site-directed mutagenesis of selected basic residues of human CYP17. The purified mutant proteins were subjected to detailed kinetic analysis. It was found that the mutation of Lys83, Arg347 and Arg358 produced proteins that were deficient in their responsiveness to cytochrome b5, and the effect was most pronounced for the two arginine mutants (Arg347 → His and Arg358 → Gln) which have been found in male patients suffering from genital ambiguity. These residues are invoked to mediate protein–protein interaction between cytochrome b5 and CYP17, which ‘awakens ’ the lyase activity of the enzyme required for androgen formation.
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Some of the actions of cytochrome b5 in experimental systems can be observed with apo-cytochrome b5 or Mn2+-b5 (which do not transfer electrons), including the stimulation of 17,20-lyase activity of human P450c17.
“Indeed, some of the actions of cytochrome b 5 in experimental systems can be observed with apo-cytochrome b 5 (345) or Mn ϩ2 -b 5 (284) (which do not transfer electrons), including the stimulation of 17,20-lyase activity of human P450c17 (189, 232).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [284]
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The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders
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Pitfalls in characterizing P450c17 mutations associated with isolated 17,20 lyase deficiency
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- Authors
- LEE-ROBICHAUD, P., AKHTAR, M. E., & AKHTAR, M.
- Affiliations
- University of Southampton (GB)
- Department of Biochemistry, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, U.K.
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 1998-06-01
- Volume
- 332
- Issue
- 2
- Pages
- 293-296
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1219480
- OpenAlex
- W2418321979
- Semantic Scholar
- 183bdee22a2bbbf67459b3eec673692ec58b742d
- Cited by
- 54
- References
- 25
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 3 · 2019: 1 · 2018: 1 · 2017: 4 · 2016: 4 · 2015: 4 · 2014: 3 · 2013: 1 · 2012: 1
- FWCI
- 0.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Keywords
- CYP17, cytochrome b5, androgen production, 17α-hydroxylase/17,20-lyase, protein-protein interaction, site-directed mutagenesis, enzyme kinetics, congenital adrenal hyperplasia, ambiguous genitalia, steroidogenesis regulation
- MeSH terms
- Androgens, Arginine, Electron Transport, Genital Diseases, Male, Humans, 17-alpha-Hydroxypregnenolone, Kinetics, Male, Pregnenolone, Recombinant Proteins, Spectrum Analysis, Steroid 17-alpha-Hydroxylase, Cytochromes b5, Mutagenesis, Site-Directed
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