Steroid 11β-hydroxylase explained

steroid 11β-monooxygenase
Ec Number:	1.14.15.4
Cas Number:	9029-66-7
Go Code:	0004507

Steroid 11β-hydroxylase, also known as steroid 11β-monooxygenase, is a steroid hydroxylase found in the zona glomerulosa and zona fasciculata of the adrenal cortex. Named officially the cytochrome P450 11B1, mitochondrial, it is a protein that in humans is encoded by the CYP11B1 gene.^[1] The enzyme is involved in the biosynthesis of adrenal corticosteroids^[2] by catalyzing the addition of hydroxyl groups during oxidation reactions.

Gene

The CYP11B1 gene encodes 11β-hydroxylase, a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. The product of this CYP11B1 gene is the 11β-hydroxylase protein. This protein localizes to the mitochondrial inner membrane and is involved in the conversion of various steroids in the adrenal cortex. Transcript variants encoding different isoforms have been noted for this gene.

The CYP11B1 gene is reversibly inhibited by etomidate^{[3] [4]} and metyrapone.

Function

11β-hydroxylase is a steroidogenic enzyme, i.e. the enzyme involved in the metabolism of steroids. The enzyme is primarily localized in the zona glomerulosa and zona fasciculata of the adrenal cortex. The enzyme functions by introducing a hydroxyl group at carbon position 11β on the steroid nucleus, thereby facilitating the conversion of certain steroids.

Humans have two isozymes with 11β-hydroxylase activity: CYP11B1 and CYP11B2.

CYP11B1 (11β-hydroxylase) is expressed at high levels and is regulated by ACTH, while CYP11B2 (aldosterone synthase) is usually expressed at low levels and is regulated by angiotensin II. In addition to the 11β-hydroxylase activity, both isozymes have 18-hydroxylase activity.^[5] The CYP11B1 isozyme has strong 11β-hydroxylase activity, but the activity of 18-hydroxylase is only one-tenth of CYP11B2.^[6] The weak 18-hydroxylase activity of CYP11B1 explains why an adrenal with suppressed CYP11B2 expression continues to synthesize 18-hydroxycorticosterone.

Here are some of the steroids, grouped by catalytic activity of the CYP11B1 isozyme:

• strong activity:
  • 11-deoxycortisol to cortisol,^[7]
  • 11-deoxycorticosterone to corticosterone;^[8]
• medium activity:
  • progesterone to 11β-hydroxyprogesterone,^{[9] [10] [11]}
  • 17α-hydroxyprogesterone to 21-deoxycortisol,^[10]
  • androstenedione to 11β-hydroxyandrostenedione;^[12]
  • testosterone to 11β-hydroxytestosterone,^{[13] [14] [9]}
• weak activity:^[9]
  • corticosterone to 18-hydroxycorticosterone,^{[15] [16]}
  • cortisol to 18-hydroxycortisol.^{[16] [17] [18]}

Cortisol and corticosterone metabolism

11β-hydroxylase has strong^[19] catalytic activity during conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone, by catalyzing the hydroxylation of carbon hydrogen bond at 11-beta position. Note the extra "–OH" added at the 11 position (near the center, on ring "C"):

Mechanism of action

As a mitochondrial P450 system, P450c11 is dependent on two electron transfer proteins, adrenodoxin reductase and adrenodoxin that transfer 2 electrons from NADPH to the P450 for each monooxygenase reaction catalyzed by the enzyme. In most respects this process of electron transfer appears similar to that of P450scc system that catalyzes cholesterol side chain cleavage.^[20] Similar to P450scc the process of electrons transfer is leaky leading to superoxide production. The rate of electron leakage during metabolism depends on the functional groups of the steroid substrate.^[21]

Regulation

The expression of the enzyme in adrenocortical cells is regulated by the trophic hormone corticotropin (ACTH).^[22]

Clinical significance

A mutation in genes encoding 11β-hydroxylase is associated with congenital adrenal hyperplasia due to 11β-hydroxylase deficiency.

11β-hydroxylase is involved in the metabolism of 17α-hydroxyprogesterone to 21-deoxycortisol,^[10] in cases of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.^{[23] [24]}

See also

• Steroidogenic enzyme

Further reading

• Helmberg A . Twin genes and endocrine disease: CYP21 and CYP11B genes . Acta Endocrinol. . 129 . 2 . 97–108 . August 1993 . 8372604 . 10.1530/acta.0.1290097.
• Stowasser M, Gunasekera TG, Gordon RD . Familial varieties of primary aldosteronism . Clin. Exp. Pharmacol. Physiol. . 28 . 12 . 1087–90 . December 2001 . 11903322 . 10.1046/j.1440-1681.2001.03574.x . 23091842 .
• Helmberg A, Ausserer B, Kofler R . Frame shift by insertion of 2 basepairs in codon 394 of CYP11B1 causes congenital adrenal hyperplasia due to steroid 11 beta-hydroxylase deficiency . J. Clin. Endocrinol. Metab. . 75 . 5 . 1278–81 . November 1992 . 10.1210/jcem.75.5.1430088 . 1430088 .
• Pascoe L, Curnow KM, Slutsker L, Connell JM, Speiser PW, New MI, White PC . Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2 . Proc. Natl. Acad. Sci. U.S.A. . 89 . 17 . 8327–31 . September 1992 . 1518866 . 49911 . 10.1073/pnas.89.17.8327 . 1992PNAS...89.8327P . free .
• Kawamoto T, Mitsuuchi Y, Toda K, Yokoyama Y, Miyahara K, Miura S, Ohnishi T, Ichikawa Y, Nakao K, Imura H . Role of steroid 11 beta-hydroxylase and steroid 18-hydroxylase in the biosynthesis of glucocorticoids and mineralocorticoids in humans . Proc. Natl. Acad. Sci. U.S.A. . 89 . 4 . 1458–62 . February 1992 . 1741400 . 48470 . 10.1073/pnas.89.4.1458 . 1992PNAS...89.1458K . free .
• White PC, Dupont J, New MI, Leiberman E, Hochberg Z, Rösler A . A mutation in CYP11B1 (Arg-448----His) associated with steroid 11 beta-hydroxylase deficiency in Jews of Moroccan origin . J. Clin. Invest. . 87 . 5 . 1664–7 . May 1991 . 2022736 . 295260 . 10.1172/JCI115182 .
• Kawamoto T, Mitsuuchi Y, Toda K, Miyahara K, Yokoyama Y, Nakao K, Hosoda K, Yamamoto Y, Imura H, Shizuta Y . Cloning of cDNA and genomic DNA for human cytochrome P-45011 beta . FEBS Lett. . 269 . 2 . 345–9 . September 1990 . 2401360 . 10.1016/0014-5793(90)81190-Y . 35151332 .
• Mornet E, Dupont J, Vitek A, White PC . Characterization of two genes encoding human steroid 11 beta-hydroxylase (P-450(11) beta) . J. Biol. Chem. . 264 . 35 . 20961–7 . December 1989 . 10.1016/S0021-9258(19)30030-4 . 2592361 . free .
• Chua SC, Szabo P, Vitek A, Grzeschik KH, John M, White PC . Cloning of cDNA encoding steroid 11 beta-hydroxylase (P450c11) . Proc. Natl. Acad. Sci. U.S.A. . 84 . 20 . 7193–7 . October 1987 . 3499608 . 299256 . 10.1073/pnas.84.20.7193 . 1987PNAS...84.7193C . free .
• Naiki Y, Kawamoto T, Mitsuuchi Y, Miyahara K, Toda K, Orii T, Imura H, Shizuta Y . A nonsense mutation (TGG [Trp116]-->TAG [Stop]) in CYP11B1 causes steroid 11 beta-hydroxylase deficiency . J. Clin. Endocrinol. Metab. . 77 . 6 . 1677–82 . December 1993 . 10.1210/jcem.77.6.7903314 . 7903314 .
• Joehrer K, Geley S, Strasser-Wozak EM, Azziz R, Wollmann HA, Schmitt K, Kofler R, White PC . CYP11B1 mutations causing non-classic adrenal hyperplasia due to 11 beta-hydroxylase deficiency . Hum. Mol. Genet. . 6 . 11 . 1829–34 . October 1997 . 9302260 . 10.1093/hmg/6.11.1829 . free .
• Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, Shaw N, Lane CR, Lim EP, Kalyanaraman N, Nemesh J, Ziaugra L, Friedland L, Rolfe A, Warrington J, Lipshutz R, Daley GQ, Lander ES . Characterization of single-nucleotide polymorphisms in coding regions of human genes . Nat. Genet. . 22 . 3 . 231–8 . July 1999 . 10391209 . 10.1038/10290 . 195213008 .
• Halushka MK, Fan JB, Bentley K, Hsie L, Shen N, Weder A, Cooper R, Lipshutz R, Chakravarti A . Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis . Nat. Genet. . 22 . 3 . 239–47 . July 1999 . 10391210 . 10.1038/10297 . 4636523 .
• Cao PR, Bernhardt R . Interaction of CYP11B1 (cytochrome P-45011 beta) with CYP11A1 (cytochrome P-450scc) in COS-1 cells . Eur. J. Biochem. . 262 . 3 . 720–6 . June 1999 . 10411633 . 10.1046/j.1432-1327.1999.00414.x . free .
• Loidi L, Quinteiro C, Barros F, Domínguez F, Barreiro J, Pombo M . The C494F variant in the CYP11B1 gene is a sequence polymorphism in the Spanish population . J. Clin. Endocrinol. Metab. . 84 . 12 . 4749 . December 1999 . 10599751 . 10.1210/jcem.84.12.6272-6 . free .
• Chabre O, Portrat-Doyen S, Chaffanjon P, Vivier J, Liakos P, Labat-Moleur F, Chambaz E, Morel Y, Defaye G . Bilateral laparoscopic adrenalectomy for congenital adrenal hyperplasia with severe hypertension, resulting from two novel mutations in splice donor sites of CYP11B1 . J. Clin. Endocrinol. Metab. . 85 . 11 . 4060–8 . November 2000 . 11095433 . 10.1210/jcem.85.11.6897 . free .
• Fisher A, Friel EC, Bernhardt R, Gomez-Sanchez C, Connell JM, Fraser R, Davies E . Effects of 18-hydroxylated steroids on corticosteroid production by human aldosterone synthase and 11beta-hydroxylase . J. Clin. Endocrinol. Metab. . 86 . 9 . 4326–9 . September 2001 . 10.1210/jcem.86.9.7797 . 11549669 . free .
• Hampf M, Dao NT, Hoan NT, Bernhardt R . Unequal crossing-over between aldosterone synthase and 11beta-hydroxylase genes causes congenital adrenal hyperplasia . J. Clin. Endocrinol. Metab. . 86 . 9 . 4445–52 . September 2001 . 10.1210/jcem.86.9.7820 . 11549691 . free .

Notes and References

1. Lifton RP, Dluhy RG, Powers M, Rich GM, Gutkin M, Fallo F, Gill JR, Feld L, Ganguly A, Laidlaw JC . 6 . Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase . Nature Genetics . 2 . 1 . 66–74 . September 1992 . 1303253 . 10.1038/ng0992-66 . 11577/133580 . 975796 . free .
2. Zöllner A, Kagawa N, Waterman MR, Nonaka Y, Takio K, Shiro Y, Hannemann F, Bernhardt R . 6 . Purification and functional characterization of human 11beta hydroxylase expressed in Escherichia coli . The FEBS Journal . 275 . 4 . 799–810 . February 2008 . 18215163 . 10.1111/j.1742-4658.2008.06253.x . 45997341 .
3. Dörr HG, Kuhnle U, Holthausen H, Bidlingmaier F, Knorr D . Etomidate: a selective adrenocortical 11 beta-hydroxylase inhibitor . Klinische Wochenschrift . 62 . 21 . 1011–3 . November 1984 . 6096625 . 10.1007/bf01711722. 20077711 .
4. Book: Lake CL . Pediatric Cardiac Anesthesia . 30 April 2012 . 7 December 2004 . Lippincott Williams & Wilkins . 978-0-7817-5175-9 . 68.
5. White PC, Curnow KM, Pascoe L . Disorders of steroid 11 beta-hydroxylase isozymes . Endocrine Reviews . 15 . 4 . 421–38 . August 1994 . 7988480 . 10.1210/edrv-15-4-421 .
6. Book: 10.1007/978-3-642-77763-9_41 . Steroid 11β-Hydroxylase Isozymes (CYP11B1 and CYP11B2) . 81304246 . White PC, Curnow KM, Pascoe L. Cytochrome P450 . Handbook of Experimental Pharmacology. 1993 . 105. 641–650. Springer . 978-3-642-77765-3 .
7. Mello, Penachioni, Amaral, Castro . 11beta-hydroxylase deficiency . pt . Arquivos Brasileiros de Endocrinologia e Metabologia . 48 . 5 . 713–23 . October 2004 . 15761543 . 10.1590/s0004-27302004000500018. free .
8. Bulsari K, Falhammar H . Clinical perspectives in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency . Endocrine . 55 . 1 . 19–36 . January 2017 . 27928728 . 10.1007/s12020-016-1189-x . 11153844 .
9. van Rooyen D, Gent R, Barnard L, Swart AC . The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway . The Journal of Steroid Biochemistry and Molecular Biology . 178 . 203–212 . April 2018 . 29277707 . 10.1016/j.jsbmb.2017.12.014 . 3700135 .
10. Turcu AF, Rege J, Chomic R, Liu J, Nishimoto HK, Else T, Moraitis AG, Palapattu GS, Rainey WE, Auchus RJ . 6 . Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency . The Journal of Clinical Endocrinology and Metabolism . 100 . 6 . 2283–90 . June 2015 . 25850025 . 4454804 . 10.1210/jc.2015-1023 .
11. 10.15347/WJM/2023.003 . free . Alternative androgen pathways . 3 April 2023 . Masiutin MM, Yadav MK . WikiJournal of Medicine . 10 . 29 . 257943362 .
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13. Book: Storbeck KH, Mostaghel EA . Prostate Cancer . Canonical and Noncanonical Androgen Metabolism and Activity . Advances in Experimental Medicine and Biology . 1210 . 239–277 . 2019 . Springer . 31900912 . 10.1007/978-3-030-32656-2_11 . 978-3-030-32655-5 . 209748543 . CYP11B1 and 2 have also been shown to 11β-hydroxylate T, yielding 11β-hydroxytestosterone (11OHT), though the levels produced by the adrenal are low due to the limited availability of adrenal derived T.
14. Stárka L, Dušková M, Vítků J . 11-Keto-testosterone and other androgens of adrenal origin . Physiological Research . 69 . Suppl 2 . S187–S192 . September 2020 . 33094617 . 10.33549/physiolres.934516. 8603739 . free .
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18. Lenders JW, Williams TA, Reincke M, Gomez-Sanchez CE . DIAGNOSIS OF ENDOCRINE DISEASE: 18-Oxocortisol and 18-hydroxycortisol: is there clinical utility of these steroids? . European Journal of Endocrinology . 178 . 1 . R1–R9 . January 2018 . 28904009 . 5705277 . 10.1530/EJE-17-0563 .
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