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21-hydroxylase is highly specific for hydroxylation of progesterone and 17-hydroxyprogesterone. No studies have reported sufficient binding of alternate substrates. In this way, it differs from the evolutionarily and functionally related P450 enzyme 17-hydroxylase, which has a large range of substrates.[7][8]
Earlier studies of the human enzyme expressed in yeast classified 17-hydroxyprogesterone as the best substrate for 21-hydroxylase.[8][9][10] However, recent analysis of the purified human enzyme found a lower KM and greater catalytic efficiency for progesterone over 17-hydroxyprogesterone.[3]
The 2015 analysis found the catalytic efficiency of 21-hydroxylase for conversion of progesterone in humans to be approximately 1.3 x 10^7 M-1s-1 at 37 °C. This makes it the most catalytically efficient P450 enzyme of those reported, as of 2015, and more catalytically efficient than the closely related bovine 21-hydroxylase enzyme.[11] C-H bond breaking to create a primary carbon radical is thought to be the rate-limiting step in the hydroxylation.[3]
In humans, 21-Hydroxylase is encoded by the gene CYP21A2.[12] A related pseudogene is located near this gene; gene conversion events involving the functional gene and the pseudogene are thought to account for many cases of steroid 21-hydroxylase deficiency.[6] Both genes are located on chromosome 6, in the major histocompatibility complex, and the pseudogene, CYP21A1, retains 98% exonic sequence identity with the functional gene.[12][13]
Adefect within the CYP21A2 gene causes a disturbance of the development of the enzyme, which leads to congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder, and occurs in approximately 1 in 15000 births globally.[14][15] There are multiple forms of CAH, broken down into classical and nonclassical based on the amount of function retained. The classical forms include salt-wasting (SW), and simple-viralizing (SV). Mutations that interfere with the active site--the heme group or residues involved in substrate binding--result in a complete loss of enzymatic activity, the salt-wasting type.[16] Cortisol and aldosterone deficits are associated with life-threatening salt-loss (hence salt-wasting), as the steroids play roles in regulating sodiumhomeostasis. Retaining minimal enzyme activity, the simple-viralizing type, is associated with mutations in conserved hydrophobic regions or near the transmembrane domain. Simple viralizing CAH patients maintain adequate sodium homeostasis, but exhibit other phenotypical symptoms shared by SW, including accelerated growth in childhood and ambiguous genitalia in female neonates. Nonclassical forms retain 20-60% of hydroxylase function--this form is associated with normal cortisol expression, but an excess of androgens post-puberty.[17][18]
21-Hydroxylase catalyzes the addition of hydroxyl (-OH) to the C21 position of two steroids: progesterone and 17α-hydroxyprogesterone. The overall reactions catalyzed by 21-hydroxylase are below.
^Auchus, R. J., & Miller, W. L. (2015). P450 enzymes in steroid processing. In Cytochrome P450: Structure, Mechanism, and Biochemistry, Fourth Edition (pp. 851-879). Springer International Publishing. DOI: 10.1007/978-3-319-12108-6_12
^White, P. C., Grossberger, D., Onufer, B. J., Chaplin, D. D., New, M. I., Dupont, B., and Strominger, J. L. (1985) Two genes encoding steroid 21- hydroxylase are located near the genes encoding the fourth component of complement in man. Proc. Natl. Acad. Sci. U.S.A. 82, 1089 –1093
^New MI, Wilson RC. Steroid disorders in children: congenital ad- renal hyperplasia and apparent mineralocorticoid excess. Proc Natl
Acad Sci USA. 1999;96:12790 –12797.
^Therrell BL Jr, Berenbaum SA, Manter-Kapanke V, et al. Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics. 1998;101:583–590.
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Helmberg A (Aug 1993). "Twin genes and endocrine disease: CYP21 and CYP11B genes". Acta Endocrinologica. 129 (2): 97–108. doi:10.1530/acta.0.1290097. PMID8372604.
de-Araujo M, et al. (Jan 1996). "Molecular analysis of CYP21 and C4 genes in Brazilian families with the classical form of steroid 21-hydroxylase deficiency". Brazilian Journal of Medical and Biological Research. 29 (1): 1–13. PMID8731325.
Yu CY (1999). "Molecular genetics of the human MHC complement gene cluster". Experimental and Clinical Immunogenetics. 15 (4): 213–30. doi:10.1159/000019075. PMID10072631.
Forest MG, et al. (Jun 2005). "21-Hydroxylase deficiency: an exemplary model of the contribution of molecular biology in the understanding and management of the disease". Annales d'endocrinologie. 66 (3): 225–32. doi:10.1016/s0003-4266(05)81754-8. PMID15988383.