(肝チトクロムP450ステロイド代謝酵素の一種)11β水酸化酵素、11βヒドロキシラーゼ

関: 11-beta-hydroxylase

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/04/27 11:23:05」(JST)

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Steroid 11β-hydroxylase is a steroid hydroxylase found in the zona glomerulosa and zona fasciculata. Named officially the cytochrome P450 11B1, mitochondrial, it is a protein that in humans is encoded by the CYP11B1 gene.^[1]^[2]

This gene encodes 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. This protein localizes to the mitochondrial inner membrane and is involved in the conversion of 11-deoxycortisol to cortisol in the adrenal cortex. Transcript variants encoding different isoforms have been noted for this gene.^[2]

It is reversibly inhibited by etomidate ^[3]^[4] and metyrapone.

Function

It generates cortisol from 11-deoxycortisol and corticosterone from 11-deoxycorticosterone. Note the extra "–OH" added at the 11 position (near the center, on ring "C"):

11-Deoxycortisol
Cortisol
11-deoxycorticosterone
Corticosterone

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.^[5] 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.^[6]

Regulation

The expression of the enzyme in adrenocortical cells is regulated by the trophic hormone corticotropin (ACTH.^[7]

Clinical significance

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

Additional images

Steroidogenesis, showing steroid 11-beta-hydroxylase vertically at right.

Corticosteroid biosynthetic pathway in rat
Steroid numbering

References

^ Lifton RP, Dluhy RG, Powers M, Rich GM, Gutkin M, Fallo F, Gill JR Jr, Feld L, Ganguly A (Jun 1993). "Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase". Nat Genet 2 (1): 66–74. doi:10.1038/ng0992-66. PMID 1303253.
^ ^a ^b "Entrez Gene: CYP11B1 cytochrome P450, family 11, subfamily B, polypeptide 1".
^ Dörr HG, Kuhnle U, Holthausen H, Bidlingmaier F, Knorr D (November 1984). "Etomidate: a selective adrenocortical 11 beta-hydroxylase inhibitor". Klinische Wochenschrift 62 (21): 1011–3. doi:10.1007/bf01711722. PMID 6096625.
^ Carol L. Lake (7 December 2004). Pediatric Cardiac Anesthesia. Lippincott Williams & Wilkins. p. 68. ISBN 978-0-7817-5175-9. Retrieved 30 April 2012.
^ Hanukoglu I, Privalle CT, Jefcoate CR (May 1981). "Mechanisms of ionic activation of adrenal mitochondrial cytochromes P-450scc and P-45011 beta" (PDF). J. Biol. Chem. 256 (9): 4329–35. PMID 6783659.
^ Rapoport R, Sklan D, Hanukoglu I (March 1995). "Electron leakage from the adrenal cortex mitochondrial P450scc and P450c11 systems: NADPH and steroid dependence". Arch. Biochem. Biophys. 317 (2): 412–6. doi:10.1006/abbi.1995.1182. PMID 7893157.
^ Hanukoglu I, Feuchtwanger R, Hanukoglu A (November 1990). "Mechanism of corticotropin and cAMP induction of mitochondrial cytochrome P450 system enzymes in adrenal cortex cells" (PDF). J. Biol. Chem. 265 (33): 20602–8. PMID 2173715.

External links

Steroid 11-beta-hydroxylase at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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1. Uncommon congenital adrenal hyperplasias
2. 副腎ステロイド生合成 adrenal steroid biosynthesis
3. 副腎アンドロゲン過剰症 adrenal hyperandrogenism
4. 思春期における多嚢胞性卵巣症候群の診断的評価 diagnostic evaluation of polycystic ovary syndrome in adolescents
5. Genetic factors in the pathogenesis of hypertension

English Journal

Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency: functional consequences of four CYP11B1 mutations.

Menabò S1, Polat S2, Baldazzi L1, Kulle AE3, Holterhus PM3, Grötzinger J4, Fanelli F5, Balsamo A1, Riepe FG3.Author information 1Program of Pediatric Endocrinology, Pediatric Unit, Department of Medical and Surgical Sciences; Azienda Policlinico S. Orsola Malpighi, University of Bologna, Bologna, Italy.2Erciyes University, Medical Faculty, Medical Genetics Department, Kayseri, Turkey.3Division of Pediatric Endocrinology, Department of Pediatrics, University Hospital, Schleswig-Holstein, Campus Kiel, Kiel, Germany.4Biochemical Institute, Christian-Albrecht-University of Kiel, Kiel, Germany.5Endocrinology Unit - Department of Medical and Surgical Sciences; Center for Applied Biomedical Research (CRBA), Bologna, Italy.AbstractCongenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive inherited endocrine disease. Steroid 11β-hydroxylase deficiency (11β-OHD) is the second most common form of CAH. The aim of the study was to study the functional consequences of three novel and one previously described CYP11B1 gene mutations (p.(Arg143Trp), p.(Ala306Val), p.(Glu310Lys) and p.(Arg332Gln)) detected in patients suffering from classical and non-classical 11β-OHD. Functional analyses were performed by using a HEK293 cell in vitro expression system comparing wild type (WT) with mutant 11β-hydroxylase activity. Mutant proteins were examined in silico to study their effect on the three-dimensional structure of the protein. Two mutations (p.(Ala306Val) and p.(Glu310Lys)) detected in patients with classical 11β-OHD showed a nearly complete loss of 11β-hydroxylase activity. The mutations p.(Arg143Trp) and p.(Arg332Gln) detected in patients with non-classical 11β-OHD showed a partial functional impairment with approximately 8% and 6% of WT activity, respectively. Functional mutation analysis allows the classification of novel CYP11B1 mutations as causes of classical and non-classical 11β-OHD. The detection of patients with non-classical phenotypes underscores the importance to screen patients with a phenotype comparable to non-classical 21-hydroxylase deficiency for mutations in the CYP11B1 gene in case of a negative analysis of the CYP21A2 gene. As CYP11B1 mutations are most often individual for a family, the in vitro analysis of novel mutations is essential for clinical and genetic counselling.
European journal of human genetics : EJHG.Eur J Hum Genet.2014 May;22(5):610-6. doi: 10.1038/ejhg.2013.197. Epub 2013 Sep 11.
Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive inherited endocrine disease. Steroid 11β-hydroxylase deficiency (11β-OHD) is the second most common form of CAH. The aim of the study was to study the functional consequences of three novel and one previously descri
PMID 24022297

Estrogen-related Receptor γ (ERRγ) Serves a Role in Blood Pressure Homeostasis during Pregnancy.

Luo Y1, Kumar P, Chen CC, Latham J, Wang L, Tudela C, Alexander JM, Shelton JM, McKown L, Mendelson CR.Author information 1Department of Biochemistry, N Texas March of Dimes Birth Defects Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390-9038, U.S.A;AbstractPersistent hypoxia caused by shallow invasion and poor placental perfusion may underlie the pathophysiology of preeclampsia, a leading cause of maternal and neonatal morbidity and mortality. Previously, we found that estrogen-related receptor γ (ERRγ) serves a critical and O2-dependent role in differentiation of human trophoblasts in culture and expression of tissue kallikrein and voltage-gated K+ channels. In this study, we surprisingly observed that ERRγ expression was significantly increased in placentas from preeclamptic, compared to gestation-matched normotensive women. To further investigate a functional role for ERRγ during pregnancy, we analyzed ERRγ-deficient mice. Maternal systolic blood pressure was significantly reduced in pregnant ERRγ+/- females bred to ERRγ+/- males, compared to wild-type (WT), and was markedly upregulated by treatment of WT pregnant mice with the ERRγ agonist DY131. Placentas of ERRγ+/- mice manifested increased vascular endothelial growth factor A (VEGFA) expression, compared to WT. Notably, circulating levels of the anti-angiogenic factor, soluble fms-like tyrosine kinase-1 (sFlt-1), were significantly reduced in ERRγ+/- pregnant mice, as was serum aldosterone. This was associated with a decrease in maternal adrenal Cyp11b1 (steroid 11β-hydroxylase) and Cyp11b2 (aldosterone synthase) expression. By contrast, adrenal Cyp11b1 and Cyp11b2 mRNA was increased in pregnant WT mice treated with DY131. Moreover, chromatin immunoprecipitation and luciferase reporter assays identified Cyp11b2 as a transcriptional target of ERRγ. Collectively, these findings reveal a potential role of ERRγ in maternal blood pressure homeostasis during pregnancy and suggest that aberrant ERRγ expression may contribute to pathogenesis of preeclampsia.
Molecular endocrinology (Baltimore, Md.).Mol Endocrinol.2014 Apr 11:me20141003. [Epub ahead of print]
Persistent hypoxia caused by shallow invasion and poor placental perfusion may underlie the pathophysiology of preeclampsia, a leading cause of maternal and neonatal morbidity and mortality. Previously, we found that estrogen-related receptor γ (ERRγ) serves a critical and O2-dependent role in dif
PMID 24725083

Characterisation of three novel CYP11B1 mutations in classic and non-classic 11β-hydroxylase deficiency.

Polat S1, Kulle A, Karaca Z, Akkurt I, Kurtoglu S, Kelestimur F, Grötzinger J, Holterhus PM, Riepe FG.Author information 1Department of Medical Genetics, Erciyes University, Kayseri, Turkey.AbstractBACKGROUND: Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive inherited endocrine diseases. Steroid 11β-hydroxylase (P450c11) deficiency (11OHD) is the second most common form of CAH.
European journal of endocrinology / European Federation of Endocrine Societies.Eur J Endocrinol.2014 Apr 10;170(5):697-706. doi: 10.1530/EJE-13-0737. Print 2014.
BACKGROUND: Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive inherited endocrine diseases. Steroid 11β-hydroxylase (P450c11) deficiency (11OHD) is the second most common form of CAH.AIM: The aim of the study was to study the functional consequences of three novel C
PMID 24536089

Related Pictures

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リンク元	「11β-水酸化酵素」
拡張検索	「steroid 11beta-hydroxylase」「11beta-hydroxylase deficiency」

「11β-水酸化酵素」

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steroid 11β-monooxygenase
Identifiers
EC number	1.14.15.4
CAS number	9029-66-7
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
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NCBI	proteins

Cytochrome P450, family 11, subfamily B, polypeptide 1
Identifiers
Symbols	CYP11B1 ; CPN1; CYP11B; FHI; P450C11
External IDs	OMIM: 610613 MGI: 88584 HomoloGene: 128035 ChEMBL: 1908 GeneCards: CYP11B1 Gene
EC number	1.14.15.4
Gene ontology
Molecular function	• steroid 11-beta-monooxygenase activity; • iron ion binding; • heme binding;
Cellular component	• mitochondrion; • mitochondrial inner membrane;
Biological process	• C21-steroid hormone biosynthetic process; • glucocorticoid biosynthetic process; • xenobiotic metabolic process; • immune response; • steroid metabolic process; • regulation of blood pressure; • sterol metabolic process; • aldosterone biosynthetic process; • cellular response to hormone stimulus; • cortisol biosynthetic process; • cellular response to potassium ion; • glucose homeostasis; • small molecule metabolic process; • oxidation-reduction process;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	v; t; e;

　　[★]

英: 11β-hydroxylase, 11beta-hydroxylase
同: 11β水酸化酵素、11βヒドロキシラーゼ、11β-ヒドロキシラーゼ; ステロイド11β-水酸化酵素 steroid 11β-hydroxylase、ステロイド11β-モノオキシゲナーゼ steroid 11β-monooxygenase、P-450C11、P-45011β
関: 副腎皮質ホルモン

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11β-水酸化酵素 : 約 16,300 件
11β-ヒドロキシラーゼ : 約 3,460 件
ステロイド11β-水酸化酵素 : 25 件
ステロイド11β-モノオキシゲナーゼ : 16 件

蓄積

デオキシコルチコステロン DOC

症状

デオキシコルチコステロン：高血圧
過剰のアンドロゲン：男性：性早熟、女性：外陰部の男性化

臨床関連

11β-水酸化酵素欠損症

同: P450Cll欠損症

「steroid 11beta-hydroxylase」

　　[★]

ステロイド11β水酸化酵素、ステロイド11βヒドロキシラーゼ

関: steroid 11-beta-hydroxylase

「11beta-hydroxylase deficiency」

　　[★]

11β水酸化酵素欠損症、11βヒドロキシラーゼ欠損症

関: 11-beta-hydroxylase deficiency

[pmid1303253-1] Lifton RP, Dluhy RG, Powers M, Rich GM, Gutkin M, Fallo F, Gill JR Jr, Feld L, Ganguly A (Jun 1993). "Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase". Nat Genet 2 (1): 66–74. doi:10.1038/ng0992-66. PMID 1303253.

[entrez-2] "Entrez Gene: CYP11B1 cytochrome P450, family 11, subfamily B, polypeptide 1".

[pmid6096625-3] Dörr HG, Kuhnle U, Holthausen H, Bidlingmaier F, Knorr D (November 1984). "Etomidate: a selective adrenocortical 11 beta-hydroxylase inhibitor". Klinische Wochenschrift 62 (21): 1011–3. doi:10.1007/bf01711722. PMID 6096625.

[Lake2004-4] Carol L. Lake (7 December 2004). Pediatric Cardiac Anesthesia. Lippincott Williams & Wilkins. p. 68. ISBN 978-0-7817-5175-9. Retrieved 30 April 2012.

[pmid6783659-5] Hanukoglu I, Privalle CT, Jefcoate CR (May 1981). "Mechanisms of ionic activation of adrenal mitochondrial cytochromes P-450scc and P-45011 beta" (PDF). J. Biol. Chem. 256 (9): 4329–35. PMID 6783659.

[pmid7893157-6] Rapoport R, Sklan D, Hanukoglu I (March 1995). "Electron leakage from the adrenal cortex mitochondrial P450scc and P450c11 systems: NADPH and steroid dependence". Arch. Biochem. Biophys. 317 (2): 412–6. doi:10.1006/abbi.1995.1182. PMID 7893157.

[pmid2173715-7] Hanukoglu I, Feuchtwanger R, Hanukoglu A (November 1990). "Mechanism of corticotropin and cAMP induction of mitochondrial cytochrome P450 system enzymes in adrenal cortex cells" (PDF). J. Biol. Chem. 265 (33): 20602–8. PMID 2173715.

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案内

案内

11beta-hydroxylase