Recombinant CYP11B Genes Encode Enzymes that Can Catalyze Conversion of 11-Deoxycortisol to Cortisol, 18-Hydroxycortisol, and 18-Oxocortisol1
Abstract
CYP11B1 (11beta-hydroxylase) and CYP11B2 (aldosterone synthase) are 93% identical mitochondrial enzymes that both catalyze 11beta-hydroxylation of steroid hormones. CYP11B2 has the additional 18-hydroxylase and 18-oxidase activities required for conversion of 11-deoxycorticosterone to aldosterone. These two additional C18 conversions can be catalyzed by CYP11B1 if serine-288 and valine-320 are replaced by the corresponding CYP11B2 residues, glycine and alanine. Here we show that such a hybrid enzyme also catalyzes conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. These latter two steroids are present at elevated levels in individuals with glucocorticoid suppressible hyperaldosteronism (GSH) and some forms of primary aldosteronism. Their production by the recombinant CYP11B enzyme is enhanced by substitution of further amino acids encoded in exons 4, 5, and 6 of CYP11B2. A converted CYP11B1 gene, containing these exons from CYP11B2, would be regulated like CYP11B1, yet encode an enzyme with the activities of CYP11B2, thus causing GSH or essential hypertension. In a sample of 103 low renin hypertensive patients, 218 patients with primary aldosteronism, and 90 normotensive individuals, we found a high level of conversion of CYP11B genes and four cases of GSH caused by unequal crossing over but no gene conversions of the type expected to cause GSH.
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The adrenal zona fasciculata does not express angiotensin II receptors or P450c11AS, but expresses MC2R and P450c11β, which cannot convert 18-hydroxycorticosterone to aldosterone and has minimal capacity to convert corticosterone to 18-hydroxycorticosterone.
“By contrast, the adrenal zona fasciculata does not express angiotensin II receptors or P450c11AS, but instead expresses MC2R (the ACTH receptor) and P450c11, which cannot convert 18-hydroxycorticoste-rone to aldosterone and has minimal capacity to convert corticosterone to 18-hydroxycorticosterone (458).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [458]
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The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders
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“CYP11B1 also has the capacity to hydroxylate C18 of 11-deoxycorticosterone or corticosterone to form 18-hydroxycorticosterone (62); however, it cannot catalyze the oxidation of the 18-hydroxy group to form aldosterone.”
BackgroundMonogenic disorders of adrenal steroidogenesis
Baranowski, E. S., Arlt, W., & Idkowiak, J. (2018) · Hormone Research in Paediatrics · doi:10.1159/000488034 · Cited by 79 · see citing works
Glucocorticoid-remediable aldosteronism
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Measurement of 18-hydroxycorticosterone during adrenal vein sampling for primary aldosteronism
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- Authors
- Mulatero, P., Curnow, K. M., Aupetit-Faisant, B., Foekling, M., Gomez-Sanchez, C., Veglio, F., Jeunemaitre, X., Corvol, P., & Pascoe, L.
- Affiliations
- Inserm (FR)
- Harry S. Truman Memorial Veterans' Hospital (US)
- University of Turin (IT)
- Corresponding author
- Pascoe, L.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 1998-11
- Volume
- 83
- Issue
- 11
- Pages
- 3996-4001
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2018602574
- Cited by
- 88
- References
- 25
- Citations by year
- 2023: 1 · 2021: 3 · 2020: 4 · 2019: 4 · 2018: 3 · 2017: 2 · 2016: 4 · 2015: 8 · 2014: 3 · 2013: 3 · 2012: 3
- FWCI
- 2.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Keywords
- CYP11B1, CYP11B2, 11β-hydroxylase, aldosterone synthase, 11-deoxycortisol, cortisol, 18-hydroxycortisol, 18-oxocortisol, primary aldosteronism, essential hypertension, low-renin hypertension, unequal crossover, gene conversion, hybrid enzymes, steroid hydroxylation
- MeSH terms
- Catalysis, Cortodoxone, Gene Conversion, Genetic Code, Genetic Testing, Humans, Hydrocortisone, Hyperaldosteronism, Hypertension, Renin, Steroid 11-beta-Hydroxylase, Case-Control Studies, Cytochrome P-450 CYP11B2
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