Aldosterone synthase, also calledsteroid 18-hydroxylase,corticosterone 18-monooxygenase orP450C18, is a steroidhydroxylasecytochrome P450 enzyme involved in the biosynthesis of the mineralocorticoidaldosterone 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 theCYP11B2gene in humans.
Aldosterone synthase is encoded onchromosome 8q22[5] by theCYP11B2 gene.[5] The gene contains 9 exons and spans roughly 7000 base pairs of DNA.[5]CYP11B2 is closely related withCYP11B1. The two genes show 93%homology to each other and are both encoded on the same chromosome.[8] Research has shown that calcium ions activatetranscription factors atCYP11B2 through well defined interactions at the 5'-flanking region ofCYP11B2.[5]
Aldosterone synthase is a member of the cytochrome P450 superfamily of enzymes.[9] The cytochrome P450 proteins aremonooxygenases that catalyze many reactions involved in drug metabolism and synthesis ofcholesterol,steroids, and otherlipids.
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.
Whereassteroid 11β-hydroxylase (encoded byCYP11B1 gene) only catalyzes hydroxylation at position 11 beta (mainly of 11-deoxycorticosterone and 11-deoxycortisol), aldosterone synthase (encoded byCYP11B2 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.[10]
Adrenocorticotropic hormone is assumed to play a role in the regulation of aldosterone synthase likely through stimulating the synthesis of11-deoxycorticosterone which is the initial substrate of the enzymatic action in aldosterone synthase.[11]
Renin–angiotensin system schematic showing aldosterone activity on the right
In human metabolism the biosynthesis of aldosterone largely depends on the metabolism ofcholesterol.Cholesterol is metabolized in what is known as the early pathway of aldosterone synthesis[12] and is hydroxylated becoming (20R,22R)-dihydroxycholesterol which is then metabolized as a direct precursor topregnenolone.Pregnenolone can then followed one of two pathways which involve the metabolism ofprogesterone or thetestosterone andestradiol biosynthesis. Aldosterone is synthesized by following the metabolism ofprogesterone.
In the potential case where aldosterone synthase is not metabolically active the body accumulates11-deoxycorticosterone. This increases salt retention leading to increasedhypertension.[13]
Aldosterone synthase shows different catalytic activity during metabolism of its substrates.[7] Here are some of the substrates, grouped by catalytic activity of the enzyme:
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.[20] The in-active proteins are caused by the autosomal recessive inheritance of defectiveCYP11B2 genes in which genetic mutations destroy the enzymatic activity of aldosterone synthase.[20] Deficient aldosterone synthase activity results in impaired biosynthesis ofaldosterone whilecorticosterone in thezona 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.[20]
Inhibition of aldosterone synthase is currently being investigated as a medical treatment forhypertension,heart failure, andrenal disorders.[21] Deactivation of enzymatic activity reduces aldosterone concentrations in plasma and tissues which decreasesmineralocorticoid receptor-dependent and independent effects in cardiac vascular and renal target organs.[21] Inhibition has shown to decrease plasma and urinary aldosterone concentrations by 70 - 80%, rapidhypokalaemia correction, moderate decrease of blood pressure, and an increase plasmarenin activity in patients who are on a low-sodium diet.[21] 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.[21]
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