Aldosterone synthase

Aldosterone synthase, also called steroid 18-hydroxylase, corticosterone 18-monooxygenase or P450C18, is a steroid

Aldosterone synthase is a protein which is only expressed in the zona glomerulosa^[5] of the adrenal cortex and is primarily regulated by the renin–angiotensin system.^[6] It is the sole enzyme capable of synthesizing aldosterone in humans and plays an important role in electrolyte balance and blood pressure.^[7]

Genetics

Aldosterone synthase is encoded on

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.^[10]

Metabolism

Aldosterone synthase converts

• 
  11-deoxycorticosterone
• 
  Corticosterone
• 
  18-hydroxycorticosterone
• 
  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^[12] 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

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:

• strong:^[7][14]
  • 11-deoxycorticosterone to corticosterone^[15] and aldosterone;^[14]
• medium:[7]^[14]
  • 11-deoxycortisol to 18-hydroxycortisol^[16][17] and cortisol;^[14]
• weak:[7]^[14]
  • 11β-hydroxyprogesterone,^[14]
  • testosterone to 18-hydroxytestosterone^[18] and 11β-Hydroxytestosterone,^[14]
  • androstendione (to 11β-Hydroxyandrostendione^[14] and 18-hydroxyandrostendione^{[verification needed}
    ]);
• very weak:[7]
  • corticosterone,
  • cortisol to 18-hydroxycortisol,^[19]
  • 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.^[20] 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.^[20] 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.^[20]

Enzymatic inhibition

Inhibition of aldosterone synthase is currently being investigated as a medical treatment for

• Steroidogenic enzyme
• Hypoaldosteronism
• Glucocorticoid remediable aldosteronism

References