Aldosterone synthase

Aldosterone synthase is a steroid is_associated_with::hydroxylase is_associated_with::cytochrome P450 enzyme involved in the biosynthesis of the mineralocorticoid is_associated_with::aldosterone. It is a protein which is only expressed in the is_associated_with::zona glomerulosa of the is_associated_with::adrenal cortex and is primarily regulated by the is_associated_with::renin-angiotensin system. It is the sole enzyme capable of synthesizing aldosterone in humans and plays an important role in is_associated_with::electrolyte balance and is_associated_with::blood pressure.

Genetics
Aldosterone synthase is encoded on is_associated_with::chromosome 8q22 by the CYP11B2 gene. The gene contains 9 exons and spans roughly 7000 base pairs of DNA. CYP11B2 is closely related with is_associated_with::CYP11B1. The two genes show 93% homology to each other and are both encodes on the same chromosome. Research has shown that calcium ions act as a is_associated_with::transcription factor for CYP11B2 through well defined interactions at the 5'-flanking region of CYP11B2.

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

Function
Aldosterone, when present, binds to intracellular mineralocorticoid receptors which can then bind to DNA and influence transcription of genes encoding serum and glucocorticoid induced kinase, is_associated_with::SGK. Serum and glucocorticoid induced kinase (SGK) can phosphorylate a uniquitin ligase (is_associated_with::NEDD4) which inactivates its ability to remove and degrade sodium channels from apical membranes. Aldosterone activity is primarily regulated by the is_associated_with::renin-angiotensin system and shows a diurnal rhythm of secretion. is_associated_with::Adrenocorticotropic hormone is also assumed to play a role in the regulation of aldosterone synthase likely through stimulating the synthesis of is_associated_with::11-deoxycorticosterone which is the initial substrate of the enzymatic action in aldosterone synthase.

Aldosterone can be inhibited by antialdosteronic drugs such as is_associated_with::spironolactone and is_associated_with::eplerenone. In the chance that aldosterone activity is too high to be metabolically beneficial salt and fluid build up can occur which may stiffen the heart muscle increasing the risk of cardiovascular malfunction.

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

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

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

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. 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 is_associated_with::aldosterone while is_associated_with::corticosterone in the is_associated_with::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 is_associated_with::hypertension, is_associated_with::heart failure, and is_associated_with::renal disorders. Deactivation of enzymatic activity reduces aldosterone concentrations in plasma and tissues which decreases is_associated_with::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 is_associated_with::hypokalaemia correction, moderate decrease of blood pressure, and an increase plasma is_associated_with::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.