The product of the CYP11B2 gene is required for aldosterone biosynthesis in the human adrenal cortex
Open accessAbstract
The steroid 11 beta-hydroxylase (P450c11) enzyme is responsible for the conversion of 11-deoxycortisol to cortisol in the zona fasciculata of the adrenal cortex. Animal studies have suggested that this enzyme or a closely related isozyme is also responsible for the successive 11 beta- and 18-hydroxylation and 18-oxidation of deoxycorticosterone required for aldosterone synthesis in the zona glomerulosa. There are two distinct 11 beta-hydroxylase genes in man, CYP11B1 and CYP11B2, which are predicted to encode proteins with 93% amino acid identity. We used a sensitive assay based on the polymerase chain reaction to analyze the expression of the CYP11B1 and B2 genes. Transcripts of CYP11B1 were detected at high levels in surgical specimens of normal adrenals and also in an aldosterone-secreting adrenal tumor. Transcripts of CYP11B2 were found at low levels in normal adrenals, but at a much higher level in the aldosterone-secreting tumor. CYP11B2 mRNA levels were increased in cultured zona glomerulosa cells by physiological levels of angiotensin-II. The entire coding regions of both CYP11B1 and B2 cDNAs were cloned from the tumor mRNA. Expression of these cDNAs in cultured COS-1 cells demonstrated that the CYP11B1 product could only 11 beta-hydroxylate 11-deoxycortisol or deoxycorticosterone, whereas the CYP11B2 product could also 18-hydroxylate cortisol or corticosterone. A small amount of aldosterone was synthesized from deoxycorticosterone only in cells expressing CYP11B2 cDNA. These data demonstrate that the product of CYP11B2 is required for the final steps in the synthesis of aldosterone.
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Severe defects can impair all P450c11AS activities, leading to the clinical phenotype of CMOI deficiency, whereas P450c11β provides 11β-hydroxylase activity in the zona fasciculata.
“Thus, severe defects can impair all P450c11AS activities, leading to the clinical phenotype of CMOI deficiency (456), whereas P450c11 provides 11-hydroxylase activity in the zona fasciculata.”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [456]
The 'Predicted Effects of Mutations Involving CYP11B1 and CYP11B2' section links defects in CYP11B2 to impaired aldosterone synthesis. But it predicts corticosterone methyloxidase-II deficiency from inactivating mutations, not the CMOI phenotype attributed to this citation, and does not say that severe defects impair all P450c11AS activities. No page number is available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredP450c11AS is found only in the zona glomerulosa, where it has 11β-hydroxylase, 18-hydroxylase, and 18-methyl oxidase (aldosterone synthase) activities; thus, P450c11AS is able to catalyze all the reactions needed to convert DOC to aldosterone.
“The less abundant isozyme, P450c11AS, is found only in the zona glomerulosa, where it has 11-hydroxylase, 18-hydroxylase, and 18-methyl oxidase (aldosterone synthase) activities; thus, P450c11AS is able to catalyze all the reactions needed to convert DOC to aldosterone (455-457).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [456]
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Experimental — accuracy not yet measuredCYP11B2 catalyzes the sequential 11β-hydroxylation of 11-deoxycorticosterone, the hydroxylation of C18, and the subsequent oxidation of C18 to yield the C18 aldehyde group of aldosterone.
“This last reaction is catalyzed by CYP11B2, which is able to catalyze the sequential 11β-hydroxylation of 11-deoxycorticosterone, the hydroxylation of C18 and the subsequent oxidation of C18 to yield the C18 aldehyde group of aldosterone (Figure 2) (63–65).”
From Adrenal Mitochondria and Steroidogenesis: From Individual Proteins to Functional Protein Assemblies (2016) · cites this paper as [64]
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- Authors
- Curnow, K. M., Tusie-Luna, M.-T., Pascoe, L., Natarajan, R., Gu, J.-L., Nadler, J. L., & White, P. C.
- Affiliations
- City Of Hope National Medical Center (US)
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 1991-10
- Volume
- 5
- Issue
- 10
- Pages
- 1513-1522
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W2073280986
- Semantic Scholar
- 87d88f16a63b0b511fab93307ca6b66fcb1ec1ce
- Cited by
- 362
- References
- 28
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 5 · 2023: 8 · 2022: 6 · 2021: 9 · 2020: 4 · 2019: 3 · 2018: 6 · 2017: 6 · 2016: 14 · 2015: 12 · 2014: 10 · 2013: 13 · 2012: 7
- FWCI
- 10.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Irma T. Hirschl Trust
- National Institutes of Health (5r01dk039721-12, 5r01dk042169-12)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-37867, DK42169, DK-39721)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- CYP11B2, CYP11B1, aldosterone biosynthesis, 11β-hydroxylase, 18-hydroxylation, zona glomerulosa, zona fasciculata, angiotensin II, deoxycorticosterone, cortisol, adrenal cortex
- MeSH terms
- Adrenal Cortex, Adrenal Cortex Neoplasms, Aldosterone, Animals, Base Sequence, Cell Line, Cells, Cultured, Cloning, Molecular, Exons, Humans, Hydroxysteroid Dehydrogenases, Molecular Sequence Data, Plasmids, RNA, Messenger, Transcription, Genetic, Transfection, Zona Glomerulosa, Polymerase Chain Reaction, Mutagenesis, Site-Directed, 11-beta-Hydroxysteroid Dehydrogenases
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