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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 ...
These enzymes are nearly identical (they share 11β-hydroxylation and 18-hydroxylation functions), but aldosterone synthase is also able to perform an 18-oxidation. Moreover, aldosterone synthase is found within the zona glomerulosa at the outer edge of the adrenal cortex; 11β-hydroxylase is found in the zona glomerulosa and zona fasciculata.
The genes encoding aldosterone synthase and 11β-hydroxylase are 95% identical and are close together on chromosome 8. In individuals with GRA, there is unequal crossing over so that the 5' regulatory region of the 11-hydroxylase gene is fused to the coding region of the aldosterone synthase. [citation needed]
18-Hydroxylase (aldosterone synthase) – mineralocorticoid synthesis; 21-Hydroxylase – corticosteroid synthesis; Cytochrome P450 (CYP1, 2, 3) – estrogen metabolism; Hydroxysteroid dehydrogenases (and ketosteroid reductases) 3α-Hydroxysteroid dehydrogenase – androgen, progestogen, and neurosteroid synthesis and metabolism
This family contains many enzymes involved in steroidogenesis, such as Cholesterol side-chain cleavage enzyme (CYP11A1), Steroid 11β-hydroxylase (CYP11B1) and Aldosterone synthase (CYP11B2). [3]
Lorundrostat (developmental name MLS 101) is an aldosterone synthase inhibitor developed by Mineralys Therapeutics for high blood pressure. In clinical trials as an add-on medication for people with uncontrolled hypertension, decreased renin and elevated aldosterone it significantly reduced blood pressure. Hyperkalemia occurred in some trial ...
It may be increased in 17α-hydroxylase deficiency, [4] in aldosterone synthase deficiency, [5] in primary aldosteronism, and may also indicate a histologic variant of the aldosteronoma. [4] Excessive secretion of 18-OH-DOC can cause mineralocorticoid excess syndrome, although these cases are very rare.
The inactivating mutation leads to elevated local concentrations of cortisol in the aldosterone sensitive tissues like the kidney. Cortisol at high concentrations can cross-react and activate the mineralocorticoid receptor due to the non-selectivity of the receptor, leading to aldosterone-like effects in the kidney.