Biology:Aldosterone synthase

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Aldosterone synthase, also called steroid 18-hydroxylase, corticosterone 18-monooxygenase or P450C18, is a steroid hydroxylase cytochrome P450 enzyme involved in the biosynthesis of the mineralocorticoid aldosterone and other steroids. The enzyme catalyzes sequential hydroxylations of the steroid angular methyl group at C18 after initial 11β-hydroxylation (the enzyme has steroid 18-hydroxylase activity as well as steroid 11 beta-hydroxylase activity). It is encoded by the CYP11B2 gene in humans.

Aldosterone synthase is a protein which is only expressed in the zona glomerulosa[1] of the adrenal cortex and is primarily regulated by the renin–angiotensin system.[2] It is the sole enzyme capable of synthesizing aldosterone in humans and plays an important role in electrolyte balance and blood pressure.[3]

Genetics

Aldosterone synthase is encoded on chromosome 8q22[1] by the CYP11B2 gene.[1] The gene contains 9 exons and spans roughly 7000 base pairs of DNA.[1] CYP11B2 is closely related with CYP11B1. The two genes show 93% homology to each other and are both encoded on the same chromosome.[4] Research has shown that calcium ions activate transcription factors at CYP11B2 through well defined interactions at the 5'-flanking region of CYP11B2.[1]

Aldosterone synthase is a member of the cytochrome P450 superfamily of enzymes.[5] The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids.

Function

Aldosterone synthase is the enzyme that has steroid 18-hydroxylase activity as well as steroid 11 beta-hydroxylase activity. The 18-hydroxylase activity consists in catalyzing sequential hydroxylations of the steroid angular methyl group at C18.

Whereas steroid 11β-hydroxylase (encoded by CYP11B1 gene) only catalyzes hydroxylation at position 11 beta (mainly of 11-deoxycorticosterone and 11-deoxycortisol), aldosterone synthase (encoded by CYP11B2 gene) catalyzes the synthesis of aldosterone from deoxycorticosterone, a process that successively requires hydroxylation at positions 11 beta and 18 and oxidation at position 18.[6]

Adrenocorticotropic hormone is assumed to play a role in the regulation of aldosterone synthase likely through stimulating the synthesis of 11-deoxycorticosterone which is the initial substrate of the enzymatic action in aldosterone synthase.[7]

Renin–angiotensin system schematic showing aldosterone activity on the right

Metabolism

Biosynthetic pathway of aldosterone starting with progesterone

Aldosterone synthase converts 11-deoxycorticosterone to corticosterone, to 18-hydroxycorticosterone, and finally to aldosterone:

In human metabolism the biosynthesis of aldosterone largely depends on the metabolism of cholesterol. Cholesterol is metabolized in what is known as the early pathway of aldosterone synthesis[8] and is hydroxylated becoming (20R,22R)-dihydroxycholesterol which is then metabolized as a direct precursor to pregnenolone. Pregnenolone can then followed one of two pathways which involve the metabolism of progesterone or the testosterone and estradiol biosynthesis. Aldosterone is synthesized by following the metabolism of progesterone.

In the potential case where aldosterone synthase is not metabolically active the body accumulates 11-deoxycorticosterone. This increases salt retention leading to increased hypertension.[9]

Substrates

Aldosterone synthase shows different catalytic activity during metabolism of its substrates.[3] Here are some of the substrates, grouped by catalytic activity of the enzyme:

Methyl oxidase deficiency

Lack of metabolically active aldosterone synthase leads to corticosterone methyl oxidase deficiency type I and II. The deficiency is characterized clinically by salt-wasting, failure to thrive, and growth retardation.[16] The in-active proteins are caused by the autosomal recessive inheritance of defective CYP11B2 genes in which genetic mutations destroy the enzymatic activity of aldosterone synthase.[16] Deficient aldosterone synthase activity results in impaired biosynthesis of aldosterone while corticosterone in the zona glomerulosa is excessively produced in both corticosterone methyl oxidase deficiency type I and II. The corticosterone methyl oxidase deficiencies both share this effect however type I causes an overall deficiency of 18-hydroxycorticosterone while type II overproduces it.[16]

Enzymatic inhibition

Inhibition of aldosterone synthase is currently being investigated as a medical treatment for hypertension, heart failure, and renal disorders.[17] Deactivation of enzymatic activity reduces aldosterone concentrations in plasma and tissues which decreases mineralocorticoid receptor-dependent and independent effects in cardiac vascular and renal target organs.[17] Inhibition has shown to decrease plasma and urinary aldosterone concentrations by 70 - 80%, rapid hypokalaemia correction, moderate decrease of blood pressure, and an increase plasma renin activity in patients who are on a low-sodium diet.[17] Ongoing medical research is focusing on the synthesis of second-generation aldosterone synthase inhibitors to create an ideally selective inhibitor as the current, orally delivered, LCl699 has shown to be non-specific to aldosterone synthase.[17]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "The regulation of aldosterone synthase expression". Molecular and Cellular Endocrinology 217 (1–2): 67–74. March 2004. doi:10.1016/j.mce.2003.10.011. PMID 15134803. 
  2. ↑ "Disorders of the aldosterone synthase and steroid 11beta-hydroxylase deficiencies". Hormone Research 51 (5): 211–22. 1999. doi:10.1159/000023374. PMID 10559665. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 "Structural insights into aldosterone synthase substrate specificity and targeted inhibition". Molecular Endocrinology 27 (2): 315–24. February 2013. doi:10.1210/me.2012-1287. PMID 23322723. 
  4. ↑ "Characterization of two genes encoding human steroid 11 beta-hydroxylase (P-450(11) beta)". The Journal of Biological Chemistry 264 (35): 20961–7. December 1989. doi:10.1016/S0021-9258(19)30030-4. PMID 2592361. 
  5. ↑ "CYP11B2". http://ghr.nlm.nih.gov/gene/CYP11B2. 
  6. ↑ "Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency". Proceedings of the National Academy of Sciences of the United States of America 89 (11): 4996–5000. June 1992. doi:10.1073/pnas.89.11.4996. PMID 1594605. Bibcode: 1992PNAS...89.4996P. 
  7. ↑ "Site of stimulation of aldosterone biosynthesis by angiotensin and potassium". The Journal of Clinical Investigation 51 (6): 1413–8. June 1972. doi:10.1172/JCI106937. PMID 4336939. 
  8. ↑ "Aldosterone biosynthesis, regulation, and classical mechanism of action". Heart Failure Reviews 10 (1): 7–13. January 2005. doi:10.1007/s10741-005-2343-3. PMID 15947886. 
  9. ↑ "CYP11B1". Genetics Home Reference. U.S. National Library of Medicine. Sep 2013. https://ghr.nlm.nih.gov/gene/CYP11B1. 
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 "The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway". The Journal of Steroid Biochemistry and Molecular Biology 178: 203–212. April 2018. doi:10.1016/j.jsbmb.2017.12.014. PMID 29277707. 
  11. ↑ "The regulation of aldosterone synthase expression". Molecular and Cellular Endocrinology 217 (1–2): 67–74. March 2004. doi:10.1016/j.mce.2003.10.011. PMID 15134803. 
  12. ↑ "DIAGNOSIS OF ENDOCRINE DISEASE: 18-Oxocortisol and 18-hydroxycortisol: is there clinical utility of these steroids?". European Journal of Endocrinology 178 (1): R1–R9. January 2018. doi:10.1530/EJE-17-0563. PMID 28904009. 
  13. ↑ "Studies on the origin of circulating 18-hydroxycortisol and 18-oxocortisol in normal human subjects". The Journal of Clinical Endocrinology and Metabolism 89 (9): 4628–33. September 2004. doi:10.1210/jc.2004-0379. PMID 15356073. 
  14. ↑ "Biosynthesis of 18-hydroxytestosterone in the human foetal liver". European Journal of Biochemistry 9 (3): 402–5. June 1969. doi:10.1111/j.1432-1033.1969.tb00622.x. PMID 4307594. 
  15. ↑ "Expression of CYP11B2 in Aldosterone-Producing Adrenocortical Adenoma: Regulatory Mechanisms and Clinical Significance". The Tohoku Journal of Experimental Medicine 240 (3): 183–190. November 2016. doi:10.1620/tjem.240.183. PMID 27853054. 
  16. ↑ 16.0 16.1 16.2 "Hereditary defect in biosynthesis of aldosterone: aldosterone synthase deficiency 1964-1997". The Journal of Clinical Endocrinology and Metabolism 82 (11): 3525–8. November 1997. doi:10.1210/jcem.82.11.4399. PMID 9360501. 
  17. ↑ 17.0 17.1 17.2 17.3 "Aldosterone synthase inhibition in humans". Nephrology, Dialysis, Transplantation 28 (1): 36–43. January 2013. doi:10.1093/ndt/gfs388. PMID 23045428. 

Further reading

External links



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