aldosterone synthase

{{Short description|Protein-coding gene in the species Homo sapiens}}

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 {{gene|CYP11B2}} gene in humans.

Aldosterone synthase is a protein which is only expressed in the zona glomerulosa{{cite journal | vauthors = Bassett MH, White PC, Rainey WE | title = The regulation of aldosterone synthase expression | journal = Molecular and Cellular Endocrinology | volume = 217 | issue = 1–2 | pages = 67–74 | date = March 2004 | pmid = 15134803 | doi = 10.1016/j.mce.2003.10.011 | s2cid = 43133280 }} of the adrenal cortex and is primarily regulated by the renin–angiotensin system.{{cite journal | vauthors = Peter M, Dubuis JM, Sippell WG | title = Disorders of the aldosterone synthase and steroid 11beta-hydroxylase deficiencies | journal = Hormone Research | volume = 51 | issue = 5 | pages = 211–22 | year = 1999 | pmid = 10559665 | doi = 10.1159/000023374 | doi-broken-date = 3 December 2024 | s2cid = 24182379 }} It is the sole enzyme capable of synthesizing aldosterone in humans and plays an important role in electrolyte balance and blood pressure.{{cite journal | vauthors = Strushkevich N, Gilep AA, Shen L, Arrowsmith CH, Edwards AM, Usanov SA, Park HW | title = Structural insights into aldosterone synthase substrate specificity and targeted inhibition | journal = Molecular Endocrinology | volume = 27 | issue = 2 | pages = 315–24 | date = February 2013 | pmid = 23322723 | pmc = 5417327 | doi = 10.1210/me.2012-1287 }}

Genetics

Aldosterone synthase is encoded on chromosome 8q22 by the CYP11B2 gene. The gene contains 9 exons and spans roughly 7000 base pairs of DNA. CYP11B2 is closely related with CYP11B1. The two genes show 93% homology to each other and are both encoded on the same chromosome.{{cite journal | vauthors = Mornet E, Dupont J, Vitek A, White PC | title = Characterization of two genes encoding human steroid 11 beta-hydroxylase (P-450(11) beta) | journal = The Journal of Biological Chemistry | volume = 264 | issue = 35 | pages = 20961–7 | date = December 1989 | doi = 10.1016/S0021-9258(19)30030-4 | pmid = 2592361 | doi-access = free }} Research has shown that calcium ions activate transcription factors at CYP11B2 through well defined interactions at the 5'-flanking region of CYP11B2.

Aldosterone synthase is a member of the cytochrome P450 superfamily of enzymes.{{cite web| title = CYP11B2| url = http://ghr.nlm.nih.gov/gene/CYP11B2| access-date = 17 September 2013| archive-date = 17 September 2013| archive-url = https://web.archive.org/web/20130917062751/http://ghr.nlm.nih.gov/gene/CYP11B2| url-status = live}} 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.{{cite journal | vauthors = Pascoe L, Curnow KM, Slutsker L, Rösler A, White PC | title = Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 11 | pages = 4996–5000 | date = June 1992 | pmid = 1594605 | pmc = 4921 | doi = 10.1073/pnas.89.11.4996 | bibcode = 1992PNAS...89.4996P | doi-access = free }}

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.{{cite journal | vauthors = Brown RD, Strott CA, Liddle GW | title = Site of stimulation of aldosterone biosynthesis by angiotensin and potassium | journal = The Journal of Clinical Investigation | volume = 51 | issue = 6 | pages = 1413–8 | date = June 1972 | pmid = 4336939 | pmc = 292278 | doi = 10.1172/JCI106937 }}

Image:Renin-angiotensin-aldosterone system.svg

Metabolism

Image:ALDOSTERONESynthesis.svg

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

Image:11-Deoxycorticosterone.svg|11-deoxycorticosterone

Image:Corticosterone-2D-skeletal.svg|Corticosterone

Image:18-hydroxycorticosterone.PNG|18-hydroxycorticosterone

Image:Aldosterone-2D-skeletal.svg|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{{cite journal | vauthors = Williams GH | title = Aldosterone biosynthesis, regulation, and classical mechanism of action | journal = Heart Failure Reviews | volume = 10 | issue = 1 | pages = 7–13 | date = January 2005 | pmid = 15947886 | doi = 10.1007/s10741-005-2343-3 | s2cid = 19588366 }} 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.{{cite web | title = CYP11B1 | url = https://ghr.nlm.nih.gov/gene/CYP11B1 | publisher = U.S. National Library of Medicine | work = Genetics Home Reference | date = Sep 2013 | access-date = 8 September 2020 | archive-date = 23 September 2020 | archive-url = https://web.archive.org/web/20200923011757/https://ghr.nlm.nih.gov/gene/CYP11B1 | url-status = live }}

Substrates

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

strong:
11-deoxycorticosterone to corticosterone{{cite journal | vauthors = Bassett MH, White PC, Rainey WE | title = The regulation of aldosterone synthase expression | journal = Molecular and Cellular Endocrinology | volume = 217 | issue = 1–2 | pages = 67–74 | date = March 2004 | pmid = 15134803 | doi = 10.1016/j.mce.2003.10.011| s2cid = 43133280 }} and aldosterone;
medium:
11-deoxycortisol to 18-hydroxycortisol{{cite journal | vauthors = Lenders JW, Williams TA, Reincke M, Gomez-Sanchez CE | title = DIAGNOSIS OF ENDOCRINE DISEASE: 18-Oxocortisol and 18-hydroxycortisol: is there clinical utility of these steroids? | journal = European Journal of Endocrinology | volume = 178 | issue = 1 | pages = R1–R9 | date = January 2018 | pmid = 28904009 | pmc = 5705277 | doi = 10.1530/EJE-17-0563 }}{{cite journal | vauthors = Freel EM, Shakerdi LA, Friel EC, Wallace AM, Davies E, Fraser R, Connell JM | title = Studies on the origin of circulating 18-hydroxycortisol and 18-oxocortisol in normal human subjects | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 89 | issue = 9 | pages = 4628–33 | date = September 2004 | pmid = 15356073 | pmc = 1283128 | doi = 10.1210/jc.2004-0379 }} and cortisol;
weak:
progesterone to 11β-hydroxyprogesterone,{{cite journal | vauthors = van Rooyen D, Gent R, Barnard L, Swart AC | title = The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 178 | pages = 203–212 | date = April 2018 | pmid = 29277707 | doi = 10.1016/j.jsbmb.2017.12.014 | s2cid = 3700135 }}
testosterone to 18-hydroxytestosterone{{cite journal | vauthors = Lisboa BP, Gustafsson JA | title = Biosynthesis of 18-hydroxytestosterone in the human foetal liver | journal = European Journal of Biochemistry | volume = 9 | issue = 3 | pages = 402–5 | date = June 1969 | pmid = 4307594 | doi = 10.1111/j.1432-1033.1969.tb00622.x | doi-access = free }} and 11β-Hydroxytestosterone,
androstendione (to 11β-Hydroxyandrostendione and 18-hydroxyandrostendione{{check|date=September 2020}});
very weak:
corticosterone,
cortisol to 18-hydroxycortisol,{{cite journal | vauthors = Nakamura Y, Yamazaki Y, Tezuka Y, Satoh F, Sasano H | title = Expression of CYP11B2 in Aldosterone-Producing Adrenocortical Adenoma: Regulatory Mechanisms and Clinical Significance | journal = The Tohoku Journal of Experimental Medicine | volume = 240 | issue = 3 | pages = 183–190 | date = November 2016 | pmid = 27853054 | doi = 10.1620/tjem.240.183 | doi-access = free }}
18-Hydroxy-11-deoxycorticosterone,
21-hydroxypregnenolone.

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.{{cite journal | vauthors = Peter M, Fawaz L, Drop SL, Visser HK, Sippell WG | title = Hereditary defect in biosynthesis of aldosterone: aldosterone synthase deficiency 1964-1997 | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 82 | issue = 11 | pages = 3525–8 | date = November 1997 | doi = 10.1210/jcem.82.11.4399 | pmid = 9360501 | s2cid = 23874859 | doi-access = free }} 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. 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.

Enzymatic inhibition

Inhibition of aldosterone synthase is currently being investigated as a medical treatment for hypertension, heart failure, and renal disorders.{{cite journal | vauthors = Azizi M, Amar L, Menard J | title = Aldosterone synthase inhibition in humans | journal = Nephrology, Dialysis, Transplantation | volume = 28 | issue = 1 | pages = 36–43 | date = January 2013 | pmid = 23045428 | doi = 10.1093/ndt/gfs388 | doi-access = free }} 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. 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. 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.

References

External links

{{MeshName|Aldosterone+synthase}}
{{UCSC gene info|CPN2}}
{{UCSC gene info|CYP11B2}}

Category:Cytochrome P450

Category:Enzymes of known structure