Cytochrome P450 family 11 subfamily B member 2 (Aldosterone synthase) (CYP11B2)

Human aldosterone synthase, encoded by the CYP11B2 gene, is a mitochondrial cytochrome P450 enzyme primarily expressed in the zona glomerulosa of the adrenal cortex [3, 19, 21]. It is the sole enzyme responsible for the final three steps of aldosterone biosynthesis, converting 11-deoxycorticosterone into the potent mineralocorticoid aldosterone through sequential 11-beta-hydroxylation, 18-hydroxylation, and 18-oxidation [14, 18, 19]. Aldosterone plays a critical role in maintaining systemic blood pressure and electrolyte homeostasis by promoting sodium reabsorption and potassium excretion in the distal nephron of the kidneys [1, 3, 18]. Pathological overproduction of aldosterone is a major driver of primary aldosteronism and resistant hypertension, leading to increased cardiovascular risk, heart failure, and chronic kidney disease [6, 8, 11]. Therapeutic targeting of CYP11B2 with aldosterone synthase inhibitors (ASIs) aims to reduce circulating aldosterone levels at the source, potentially offering superior efficacy over mineralocorticoid receptor antagonists by also mitigating rapid non-genomic effects [7, 11, 15]. A significant challenge in drug development is achieving high selectivity for CYP11B2 over its close homolog CYP11B1, which is 93-95% identical and essential for cortisol production [11, 15, 18]. Off-target inhibition of CYP11B1 can lead to blunted cortisol responses and clinical adrenal insufficiency, necessitating the development of highly specific next-generation inhibitors like baxdrostat and lorundrostat [11, 13, 15].

Other names

Aldosterone synthaseSteroid 18-hydroxylaseP450C18P450aldoALDOSCPN2CYP11BCYP11BLCYPXIB2Corticosterone methyloxidase

Selective inhibition of the CYP11B2 enzyme, which catalyzes the final three steps of aldosterone biosynthesis: 11-beta-hydroxylation of 11-deoxycorticosterone to corticosterone, 18-hydroxylation to 18-hydroxycorticosterone, and 18-oxidation to aldosterone [11, 14, 18, 19].