Aldosterone synthase

MacKenzie SM, Clark CJ, Fraser R, Gomez-Sanchez CE, Connell JM, et al. 2000. Expression of 1 Ibeta-hydroxylase and aldosterone synthase genes in the rat brain. J Mol Endocrinol 24 321-328. 

B2 family 11, aldosterone synthase cyto- to-rennin CTPllB ... 

Patients with 11/1-hydroxylase deficiency present with features of androgen excess, including masculinization of female newborns and precocious puberty in male children. There are two human isozymes that are responsible for cortisol and aldosterone synthesis, respectively. The CYP11B1 enzyme (p45011B) converts DOC to corticosterone (B) and 11-deoxycortisol (S or 11-dihydrocortisol) to cortisol (F). It is also capable of 18-hydroxylating DOC but cannot convert to aldosterone. The latter transformation is carried out by CYP11B2 (also known as aldosterone synthase), which encompasses activity for 18-hydroxylation and subsequent 18-oxidation. When CAH is associated with hypertension, deficient lljS-hydroxylase (CYP11B1) is suspected at this time more than ten mutations have been defined in affected individuals [103]. 

These conditions are associated with high renin and high aldosterone production. The hybrid corticosteroids 18-OHF, 18-oxo-F and 18-oxo-THF were isolated from the urine of a patient with adrenal adenoma by Ulick and coworkers [11]. These steroids were subsequently also shown to be dominant in GRA. Their formation in the latter condition was explained by Lifton and co-workers [51] with the discovery of a chimeric gene formed crossover of the 1 1//-hydroxylase (CYPllfil) and aldosterone synthase (CYP11B2) genes. 

Table 5.3.11 Steroid excretion and diagnostic ratios in infants with pseudohypoaldosteronism (PHA) and aldosterone synthase deficiency (ASD)...

White PC (2004) Aldosterone synthase deficiency and related disorders. Mol Cell Endocrinol 217 81-87... 

If progesterone is directly acted on by 2l-hydroxylu.se (Cyp21). 11 -deoxycorticosterone is produced, a precursor lo the mineralocorticoid aldosterone. In tissues where aldosterone is synthesized, the multifunctional enzyme aldosterone synthase (Cypl IB2) mediates the hydroxylalion at Cl i as well as the two-step oxidation ofCIS lo an aldehyde, providing aldo.sicronc. which exists predominantly in the cyciic hcmiacclal form. 

Mineralocorticoid refers to those steroids that regulate salt homeostasis (sodium conservation and potassium loss) and extracellular fluid volume.Aldosterone is the most potent naturally occurring mineralocorticoid and is synthesized exclusively in the zona glomerulosa region of the adrenal cortex. This zone uniquely contains the enzyme aldosterone synthase, an obligatory enzyme in the synthetic pathway to aldosterone. Other adrenocortical steroids that have mineralocorticoid properties with varying degrees of potency include DOC, 18-hydroxy-DOC, corticosterone,... 

An aldosterone synthase gene variant is associated with improvement in left ventricular ejection fraction in dilated cardiomyopathy. Cardiovasc Res 54 584-589... 

KurlandL, Melhus H, Karlsson J, et al. Aldosterone synthase (CYPl 1B2) —344 C/T polymorphism is related to antihypertensive response Result from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial. Am J Hypertens 2002 15 389-393. 

Bassett, M. H., White, P C., and Rainey, W. E. (2004a). Regulation of aldosterone synthase expression. Mol Cell Endocrinol 217, 67-74. 

Condon, J. C., Pezzi, V., Drummond, B. M., Yin, S., and Rainey, W. E. (2002). Calmodulin-dependent kinase I regulates adrenal cell expression of aldosterone synthase. Endocrinology 143, 3651-3657. 

Rainey, W. E. (1999). Adrenal zonation clues from 11 beta-hydroxylase and aldosterone synthase. Mol Cell Endocrinol 151, 151-160. 

Freije, W.A., V. Pezzi, A. Ariel, B.R. Carr, and W.E. Rainey (1997). Expression of 11 beta-hydroxylase (CYPlIBl) and aldosterone synthase (CYP11B2) in the human fetal adrenal. J. Soc. Gynecol. Investig. 4, 305-309. 

Bassett, M.H., Y. Zhang, C. Clyne, P.C. White, and WE. Rainey (2002). Differential regulation of aldosterone synthase and 113-hydroxyIase transcription by steroidogenic factor-1. J. Mol. Endocrinol. 28, 125-135. 

S. Cook, S. Ulick et al. (1992). A chimaeric 113-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 355, 262-265. 

R. Bernhardt (2001). Unequal crossing-over between aldosterone synthase and 113-hydroxylase genes causes congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 86,4445-4452. 

Portrat, S., P. Mulatero, K.M. Curnow, J.L. Chaussain, Y. Morel, and L. Pascoe (2001). Deletion hybrid genes, due to unequal crossing over between CYPllBl (113-hydroxylase) and CYP11B2 (aldosterone synthase) cause steroid 113-hydroxylase deficiency and congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 86, 3197-3201. 

Fisher, A., E. Davies, R. Fraser, and J.M. Connell (1998). Structure-function relationships of aldosterone synthase and 113-hydroxylase enzymes Implications for human hypertension. Clin. Exp. Pharmacol. Physiol. Suppl. 25, S42—S46. 

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