LljS-hydroxylase

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]. 

Imrie H, Freel M, Mayosi BM, Davies E, Fraser R, Ingram M, Cordell HJ, Farrall M, Avery PJ, Watkins H, Keavney B, Connell JM (2006) Association between aldosterone production and variation in the lljS-hydroxylase (CYPllBl) gene. J Clin Endocrinol Metab 91 5051-5056 Barr M, MacKenzie SM, Friel EC, Holloway CD, Wilkinson DM, Brain NJ, Ingram MC, Fraser R, Brown M, Samani NJ, Caulfield M, Munroe PB, Farrall M, Webster J, Clayton D, Dominiczak AF, Connell JM, Davies E (2007) Polymorphic variation in the 1 l/ -hydroxylase gene associates with reduced 11-hydroxylase efficiency. Hypertension 49 113-119... 

Peter M, Dubuis JM, Sippell WG (1999) Disorders of the aldosterone synthase and steroid 1 p-hydroxylase deficiencies. Horm Res 51 211-222 Nimkam S, New MI (2008) Steroid 11/ff-hydroxylase deficiency congenital adrenal hyperplasia. Trends Endocrin Metab 19 96-99 White PC (2011) Congenital adrenal hyperplasia owing to lljS-hydroxylase deficiency. Adv Exp Med Biol 707 7-8... 

The cofactor requirement of lljS-hydroxylase was clarified by the discovery that reduced triphosphopyridine nucleotide (TPNH) is essential and specific and that the role of citric acid cycle components and the other cofactors in the system appears to be that of supplying endogenously formed TPNH (288,723) by the sequence of reactions shown in equations (98) to (100). TPNH is oxidized in the absence... 

D. B. Villeeci al. (1961) suggested that the hydroxylation of progesterone by fetal tis.sues is a function of fetal development. These authors established that the 16 - and 17a-hydroxylasc activities appear before that of 21-hydroxylase. The 11/3-hydroxylatioii appears very early in fetal life and the lljS-hydroxylase activity for progesterone w as observed in fetal adrenals in the early weeks of gestation (Longchampt and Axelrod, 1963 E. Bloch ei al., 1965 Pasqualini, 1969a). 

Quantitative differences in corticosterone and cortisol have been noted in various species of animals (Bush, 1953), due perhaps to varying levels of the 17a-hydroxylase. Variations in the ionic milieu surrounding tissue components in in vitro systems have also been noted to alter the ratio of these steroids (Eichhorn and Hechter, 1959). Of incidental interest is the lack of either lljS-hydroxylase or 21-hydroxylase in certain instances of congenital adrenal hyperplasia. 

Fisher A, Fraser R, Me Coimell J, Davies E (2000) Amino acid residue 147 of human aldosterone synthase and 11 -hydroxylase plays a key role in lljS-hydroxylation. J Clin Endoerinol Metab 85 1261-1266... 

In the biosynthetic steps from progesterone to the adrenal cortical hormones are the very important 21-, lljS-, and 18-hydroxylations. The major pathway of synthesis is illustrated in Fig. 18. The properties of the enzyme, 17a-hydroxylase, which catalyzes the initial step in the formation of cortisol, have been described in a previous section, IV.B, of this manuscript. 21-Hydroxylation of progesterone or 17a-hydroxy-progesterone precedes 1 lj8-hydroxylation resulting in the eventual formation of the glucocorticoids, corticosterone, and cortisol respectively. The further conversion of corticosterone by 18-hydroxylation and sub-... 

The participation of several catalytic proteins has been proposed to enter into the lljS-hydroxylation process (Tomkins, 1959). Whether these are directly involved or aid in an accessory capacity is not known. A discussion of 1 lj8-hydroxylase is presented elsewhere in this manuscript (see Section IV. D). 

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