同: 18-hydroxylase

WordNet

a corticosteroid hormone that is secreted by the cortex of the adrenal gland; regulates salt (sodium and potassium) and water balance

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/02/28 00:12:30」(JST)

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Aldosterone synthase is a steroid hydroxylase cytochrome P450 enzyme involved in the biosynthesis of the mineralocorticoid aldosterone. It is a protein which is only expressed in the zona glomerulosa^[1] of the adrenal cortex and is primarily regulated by the renin-angiotensin system.^[2] It is the sole enzyme capable of synthesizing aldosterone in humans and plays an important role in electrolyte balance and blood pressure. ^[3]

Genetics[edit]

Aldosterone synthase is encoded on chromosome 8q22^[1] by the CYP11B2 gene.^[1] The gene contains 9 exons and spans roughly 7000 base pairs of DNA.^[1] CYP11B2 is closely related with CYP11B1. The two genes show 93 % homology to each other and are both encodes on the same chromosome. ^[4] Research has shown that calcium ions act as a transcription factor for CYP11B2 through well defined interactions at the 5'-flanking region of CYP11B2.^[1]

Aldosterone synthase is a member of the cytochrome P450 superfamily of enzymes.^[5] The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids.

Function[edit]

Aldosterone, when present, binds to intracellular mineralocorticoid receptors which can then bind to DNA and influence transcription of genes encoding serum and glucocorticoid induced kinase, SGK. Serum and glucocorticoid induced kinase (SGK) can phosphorylate a uniquitin ligase (NEDD4) which inactivates its ability to remove and degrade sodium channels from apical membranes.^[6] Aldosterone activity is primarily regulated by the renin-angiotensin system and shows a diurnal rhythm of secretion.^[2] Adrenocorticotropic hormone is also assumed to play a role in the regulation of aldosterone synthase likely through stimulating the synthesis of 11-deoxycorticosterone which is the initial substrate of the enzymatic action in aldosterone synthase.^[7]

Renin-angiotensin system schematic showing aldosterone activity on the right

Aldosterone can be inhibited by antialdosteronic drugs such as spironolactone and eplerenone. In the chance that aldosterone activity is too high to be metabolically beneficial salt and fluid build up can occur which may stiffen the heart muscle increasing the risk of cardiovascular malfunction.^[8]

Metabolism[edit]

Biosynthetic pathway of aldosterone starting with progesterone

Aldosterone synthase converts 11-deoxycorticosterone to corticosterone, to 18-hydroxycorticosterone, and finally to aldosterone:

11-Deoxycorticosterone
Corticosterone
18-hydroxycorticosterone
Aldosterone

In human metabolism the biosynthesis of aldosterone largely depends on the metabolism of cholesterol. Cholesterol is metabolized in what is known as the early pathway of aldosterone synthesis^[9] and is hydroxylated becoming (20R,22R)-dihydroxycholesterol which is then metabolized as a direct precursor to pregnenolone. Pregnenolone can then followed one of two pathways which involve the metabolism of progesterone or the testosterone and estradiol biosynthesis. Aldosterone is synthesized by following the metabolism of progesterone.

In the potential case where aldosterone synthase is not metabolically active the body accumulates 11-deoxycorticosterone. This increases salt retention leading to increased hypertension.^[10]

Methyl oxidase deficiency[edit]

Lack of metabolically active aldosterone synthase leads to corticosterone methyl oxidase deficiency type I and II. The deficiency is characterized clinically by salt-wasting, failure to thrive, and growth retardation.^[11] The in-active proteins are caused by the autosomal recessive inheritance of defective CYP11B2 genes in which genetic mutations destroy the enzymatic activity of aldosterone synthase.^[11] Deficient aldosterone synthase activity results in impaired biosynthesis of aldosterone while corticosterone in the zona glomerulosa is excessively produced in both corticosterone methyl oxidase deficiency type I and II. The corticosterone methyl oxidase deficiencies both share this effect however type I causes an overall deficiency of 18-hydroxycorticosterone while type II overproduces it.^[11]

Enzymatic inhibition[edit]

Inhibition of aldosterone synthase is currently being investigated as a medical treatment for hypertension, heart failure, and renal disorders. ^[12] Deactivation of enzymatic activity reduces aldosterone concentrations in plasma and tissues which decreases mineralocorticoid receptor-dependent and independent effects in cardiac vascular and renal target organs. ^[12] Inhibition has shown to decrease plasma and urinary aldosterone concentrations by 70 - 80%, rapid hypokalaemia correction, moderate decrease of blood pressure, and an increase plasma renin activity in patients who are on a low-sodium diet.^[12] Ongoing medical research is focusing on the synthesis of second-generation aldosterone synthase inhibitors to create an ideally selective inhibitor as the current, orally delivered, LCl699 has shown to be non-specific to aldosterone synthase.^[12]

Additional images[edit]

Steroidogenesis, showing aldosterone synthase at right.

References[edit]

^ ^a ^b ^c ^d ^e Bassett MH, White PC, Rainey WE (March 2004). "The regulation of aldosterone synthase expression". Mol. Cell. Endocrinol. 217 (1–2): 67–74. doi:10.1016/j.mce.2003.10.011. PMID 15134803.
^ ^a ^b Peter M, Dubuis JM, Sippell WG (1999). "Disorders of the aldosterone synthase and steroid 11β-hydroxylase deficiencies". Horm. Res. 51 (5): 211–22. doi:10.1159/000023374. PMID 10559665.
^ Strushkevich N, Gilep AA, Shen Limin, Arrowsmith CH, Edwards AM, Usanov SA, Park HW (February 2013). "Structural insights into aldosterone synthase substrate specificity and targeted inhibition". Molecular Endocrinology 27 (2): 315–324. doi:10.1210/me.2012-1287. PMID 23322723.
^ Mornet E, Dupont J, Vitek A, White PC (June 1989). "Characterization of two genes encoding human steroid 11-beta-hydroxylase (P-45011-beta)". J Biol Chem 264 (15): 20961–20967. PMID 2592361.
^ "CYP11B2". Retrieved 17 September 2013.
^ White PC (March 2004). "Aldosterone synthase deficiency and related disorders". Mol. Cell. Endocrinol. 217 (1–2): 81–7. doi:10.1016/j.mce.2003.10.013. PMID 15134805.
^ Brown RD, Strott CA, Liddle GW (June 1972). "Site of stimulation of aldosterone biosynthesis by angiotensin and potassium". J Clin Invest. 51 (6): 1413–8. doi:10.1172/JCI106937. PMC 292278. PMID 4336939.
^ Martinez FA (Aug 2010). "Aldosterone inhibition and cardiovascular protection: more important than it once appeared". Cardiovascular drugs and therapy 24 (4): 345–350. doi:10.1007/s10557-010-6256-6. PMID 20676926.
^ Williams GH (January 2005). "Aldosterone Biosynthesis, Regulation, and Classical Mechanism of Action". Heart failure reviews 10 (1): 7–13. doi:10.1007/s10741-005-2343-3.
^ National Library of Medicine (US) (Sep 2013). "CYP11B1". Genetics Home Reference.
^ ^a ^b ^c Peter M, Fawaz L, Drop SL, Visser HK, Sippell WG (November 1997). "Hereditary defect in biosynthesis of aldosterone: aldosterone synthase deficiency 1964-1997". J. Clin. Endocrinol. Metab. 82 (11): 3525–8. doi:10.1210/jc.82.11.3525. PMID 9360501.
^ ^a ^b ^c ^d Azizi M, Amar L, Menard J (October 2013). "Aldosterone synthase inhibition in humans". Nephrol. Dial. Transplant 28 (1): 36–43. doi:10.1093/ndt/gfs388. PMID 23045428.

External links[edit]

Aldosterone synthase at the US National Library of Medicine Medical Subject Headings (MeSH)

Category:Cytochrome P450

UpToDate Contents

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1. 副腎ステロイド生合成 adrenal steroid biosynthesis
2. 11βヒドロキシラーゼ欠損症による先天性副腎過形成 congenital adrenal hyperplasia due to 11 beta hydroxylase deficiency
3. 小児における原発性副腎不全の原因および臨床症状 causes and clinical manifestations of primary adrenal insufficiency in children
4. 低アルドステロン症（4型RTA）の病因、診断、および治療 etiology diagnosis and treatment of hypoaldosteronism type 4 rta
5. 原発性（本態性）の病因における遺伝的要因 genetic factors in the pathogenesis of primary essential hypertension

English Journal

Therapeutic targeting of aldosterone: a novel approach to the treatment of glomerular disease.

Brem AS1, Gong R1.
Clinical science (London, England : 1979).Clin Sci (Lond).2015 May 1;128(9):527-35. doi: 10.1042/CS20140432.
Numerous studies have established a role for mineralocorticoids in the development of renal fibrosis. Originally, the research focus for mineralocorticoid-induced fibrosis was on the collecting duct, where 'classical' mineralocorticoid receptors (MRs) involved with electrolyte transport are present.
PMID 25671776

New approaches in the treatment of hypertension.

Oparil S1, Schmieder RE2.
Circulation research.Circ Res.2015 Mar 13;116(6):1074-95. doi: 10.1161/CIRCRESAHA.116.303603.
Hypertension is the most common modifiable risk factor for cardiovascular disease and death, and lowering blood pressure with antihypertensive drugs reduces target organ damage and prevents cardiovascular disease outcomes. Despite a plethora of available treatment options, a substantial portion of t
PMID 25767291

Novel Pyridyl Substituted 4,5-Dihydro-[1,2,4]triazolo[4,3-a]quinolines as Potent and Selective Aldosterone Synthase Inhibitors with Improved in Vitro Metabolic Stability.

Hu Q1, Yin L, Ali A, Cooke AJ, Bennett J, Ratcliffe P, Lo MM, Metzger E, Hoyt S, Hartmann RW.
Journal of medicinal chemistry.J Med Chem.2015 Mar 12;58(5):2530-7. doi: 10.1021/acs.jmedchem.5b00079. Epub 2015 Mar 3.
CYP11B2 inhibition is a promising treatment for diseases caused by excessive aldosterone. To improve the metabolic stability in human liver miscrosomes of previously reported CYP11B2 inhibitors, modifications were performed via a combination of ligand- and structure-based drug design approaches, lea
PMID 25711516

Japanese Journal

Multiple noncoding exons 1 of nuclear receptors NR4A family (nerve growth factor-induced clone B, Nur-related factor 1 and neuron-derived orphan receptor 1) and NR5A1 (steroidogenic factor 1) in human cardiovascular and adrenal tissues

Demura Masashi,Wang Fen,Yoneda Takashi,Karashima Shigehiro,Mori Shunsuke,Oe Masashi,Kometani Mitsuhiro,Sawamura Toshitaka,Cheng Yuan,Maeda Yuji,Namiki Mikio,Ino Hidekazu,Fujino Noboru,Uchiyama Katsuharu,Tsubokawa Toshinari,Yamagishi Masakazu,Nakamura Yasuhiro,Ono Katsuhiko,Sasano Hironobu,Demura Yoshiki,Takeda Yoshiyu　　
Journal of Hypertension 29(6), 1185-1195, 2011-06
… Nuclear receptor families NR4A [nerve growth factor-induced clone B (NGFIB), Nur-related factor 1 (NURR1) and neuron-derived orphan receptor 1 (NOR1)] and NR2F [chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TFI), COUP-TFII and NR2F6) activate, whereas NR5A1 [steroidogenic factor 1 (SF1)] represses CYP11B2 (aldosterone synthase) gene transcription. …
NAID 120003141563

Aldosterone synthase (CYP11B2) C-344T polymorphism affects the association of age-related changes of the serum C-reactive protein

OKI Kenji,YAMANE Kiminori,SATOH Kenichi,NAKANISHI Shuhei,YAMAMOTO Hideya,KOHNO Nobuoki
Hypertension research : clinical and experimental : official journal of the Japanese Society of Hypertension 33(4), 326-330, 2010-04-01
NAID 10026127640

Related Pictures

★リンクテーブル★

リンク元	「アルドステロン」「アルドステロンシンターゼ」「アルドステロン合成酵素」「CYP11B2」
関連記事	「synthase」

「アルドステロン」

Cytochrome P450, family 11, subfamily B, polypeptide 2
	; PDB rendering completed using PISA software. Human aldosterone synthase in complex with 11-deoxycorticosterone
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	4DVQ, 4FDH
Identifiers
Symbols	CYP11B2; ALDOS; CPN2; CYP11B; CYP11BL; CYPXIB2; P-450C18; P450C18; P450aldo
External IDs	OMIM: 124080 MGI: 88583 HomoloGene: 106948 ChEMBL: 2722 GeneCards: CYP11B2 Gene
EC number	1.14.15.4, 1.14.15.5
Gene Ontology
Molecular function	• steroid 11-beta-monooxygenase activity; • iron ion binding; • electron carrier activity; • heme binding; • corticosterone 18-monooxygenase activity;
Cellular component	• mitochondrion; • mitochondrial inner membrane;
Biological process	• regulation of blood volume by renal aldosterone; • renal water homeostasis; • C21-steroid hormone biosynthetic process; • mineralocorticoid biosynthetic process; • xenobiotic metabolic process; • steroid metabolic process; • aldosterone biosynthetic process; • cellular response to hormone stimulus; • cortisol biosynthetic process; • cellular response to potassium ion; • small molecule metabolic process; • potassium ion homeostasis; • sodium ion homeostasis;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	This box: view; talk; edit;

　　[★]

英: aldosterone
関: 尿細管

基準値

血漿濃度は35-240 pg/ml, EDTA加血漿安静臥位　30-160 pg/ml
30-160 pg/ml (LAB.715)
35.7-240 pg/ml (随時), 29.9-159pg/ml (臥位), 38.9-307pg/ml (立位) (SRL)

分類

副腎皮質ホルモン

電解質コルチコイド

性状

ステロイド

産生組織

副腎皮質球状層

標的組織

主に集合管(SP.792)

生理作用

1. 腎の接合尿細管と集合管、唾液腺、乳腺、汗腺等に働いてNa⁺の再吸収を促進し、K⁺の排出(分泌)を促進する (SP.791,792 によれば、腎接合尿細管を含む)
2. 腎集合管でH⁺の排出(分泌)を促進する。

Na+/K+-ATPase活性↑＠遠位尿細管・皮質集合管　→　管腔側K↑　→　K再吸収/H+分泌 (QB CBT vol2 p.360)　←　成書での裏付けがないが、確かにアルドステロン↑によりK+分泌が↑となれば、管腔側にK+があふれるのでα間在細胞上の管腔側にあるK+/H+交換輸送体担体によりH+管腔側にくみ出されるな。