CYP17タンパク質

関: steroid 17-alpha-hydroxylase

steroid 17alpha-hydroxylase

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/05/12 18:31:55」(JST)

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Cytochrome P450 17A1, or steroid 17-alpha-monooxygenase, or 17α-hydroxylase/17,20 lyase/17,20 desmolase is an enzyme that in humans is encoded by the CYP17A1 gene. It is found in the zona reticularis of the adrenal cortex. 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 endoplasmic reticulum. It has both 17alpha-hydroxylase and 17,20-lyase activities, and is a key enzyme in the steroidogenic pathway that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens.

More specifically, CYP17A1 acts upon pregnenolone and progesterone to add a hydroxyl (-OH) group at carbon 17 of the steroid D ring (the hydroxylase activity), or acts upon 17-hydroxyprogesterone and 17-hydroxypregnenolone to split the side-chain off the steroid nucleus (the lyase activity).^[1]

Clinical significance

Mutations in this gene are associated with 17 alpha-hydroxylase deficiency, 17 alpha-hydroxylase/17,20-lyase deficiency, pseudohermaphroditism, and adrenal hyperplasia.^[2]

The drug abiraterone which is used to treat castration-resistant prostate cancer blocks the biosynthesis of androgens by inhibiting the CYP17A1 enzyme. Abiterone binds in the active site of the enzyme and coordinates the heme iron through its pyridine nitrogen, mimicking the subtrate.^[3]

Steroidogenesis

17α-hydroxylase converts pregnenolone and progesterone to their 17-hydroxy forms, and converts 17-hydroxypregnenolone and 17-hydroxyprogesterone to DHEA and androstenedione, respectively. It corresponds to the downward arrows in this reaction scheme.

Steroidogenesis, showing, at left side, both reactions of 17-alpha hydroxylase, and both actions of 17, 20 lyase.

Additional images

Pregnenolone
17-Hydroxypregnenolone
Progesterone
17-Hydroxyprogesterone
Steroid numbering

References

^ Boulpaep EL, Boron, WF (2005). Medical physiology: a cellular and molecular approach. St. Louis, Mo: Elsevier Saunders. p. 1180. ISBN 1-4160-2328-3.
^ "Entrez Gene: CYP17A1 cytochrome P450, family 17, subfamily A, polypeptide 1".
^ PDB 3ruk; DeVore NM, Scott EE (February 2012). "Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001". Nature 482 (7383): 116–9. doi:10.1038/nature10743. PMC 3271139. PMID 22266943.

External links

CYP17A1 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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1. Overview of pharmacogenomics
2. 副腎ステロイド生合成 adrenal steroid biosynthesis
3. まれな先天性副腎過形成 uncommon congenital adrenal hyperplasias
4. アゾールの薬理学 pharmacology of azoles
5. 去勢抵抗性前立腺癌：アンドロゲンのシグナル経路を標的にする療法 castration resistant prostate cancer treatments targeting the androgen pathway

English Journal

Ecotoxicological assessment of cimetidine and determination of its potential for endocrine disruption using three test organisms: Daphnia magna, Moina macrocopa, and Danio rerio.

Lee S1, Jung D2, Kho Y3, Ji K4, Kim P5, Ahn B6, Choi K7.
Chemosphere.Chemosphere.2015 Sep;135:208-16. doi: 10.1016/j.chemosphere.2015.04.033. Epub 2015 May 15.
Cimetidine is a histamine H2-receptor antagonist used for treatment of gastrointestinal disorders. It is often detected in aquatic environments, but its ecotoxicological effects have not been well studied. Thus, ecotoxicity of cimetidine was evaluated using Daphnia magna and Moina macrocopa, and zeb
PMID 25957140

The impact of long term exposure to phthalic acid esters on reproduction in Chinese rare minnow (Gobiocypris rarus).

Guo Y1, Yang Y2, Gao Y2, Wang X1, Zhou B3.
Environmental pollution (Barking, Essex : 1987).Environ Pollut.2015 Aug;203:130-6. doi: 10.1016/j.envpol.2015.04.005. Epub 2015 Apr 14.
The environmental risk of phthalic acid esters (PAEs) is of great concern. We investigated the reproductive impairment of di-(2-ethylhexyl)-phthalate (DEHP) on Chinese rare minnow, an endemic fish inhabiting the upper streams of the Yangtze River. Chinese rare minnow larvae were exposed to environme
PMID 25880617

A new pregnenolone analogues as privileged scaffolds in inhibition of CYP17 hydroxylase enzyme. Synthesis and in silico molecular docking study.

Al-Masoudi NA1, Mahdi KM2, Abdul-Rida NA2, Saeed BA3, Engel M4.
Steroids.Steroids.2015 Aug;100:52-9. doi: 10.1016/j.steroids.2015.05.002. Epub 2015 May 16.
A new series of 17-(N-(arylimino)-5-pregnen-3β-ol derivatives 19-32 as well as carboxylate and acrylate analogues of pregnenolone 37-40 were synthesized and evaluated for their inhibitory activity against human CYP17 hydroxylase expressed in Escherichia coli. Compounds 32 and 37 were the most poten
PMID 25988615

Japanese Journal

転移性去勢抵抗性前立腺がんに対する早期開発段階の化学療法 (特集婦人科がん・泌尿器がんに対する新治療)

腫瘍内科 = Clinical oncology 18(2), 140-144, 2016-08
NAID 40020943725

Identification of candidate target Cyp genes for microRNAs whose expression is altered by PCN and TCPOBOP, representative ligands of PXR and CAR

Biological and Pharmaceutical Bulletin advpub(0), 1381-1386, 2016
NAID 130005153293

CYP17A阻害薬 : アビラテロン酢酸エステル (特集前立腺癌の内分泌療法 : 気になる最新の動向)

臨床泌尿器科 = Japanese journal of clinical urology 69(5), 378-384, 2015-04
NAID 40020400470

Related Pictures

★リンクテーブル★

リンク元	「副腎皮質ホルモン」
拡張検索	「CYP17B1タンパク質」「CYP17タンパク質」

「副腎皮質ホルモン」

Cytochrome P450, family 17, subfamily A, polypeptide 1
	; Human Cytochrome P450 CYP17A1 PDB. 3ruk
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	3RUK, 3SWZ
Identifiers
Symbols	CYP17A1 ; CPT7; CYP17; P450C17; S17AH
External IDs	OMIM: 609300 MGI: 88586 HomoloGene: 73875 ChEMBL: 3522 GeneCards: CYP17A1 Gene
EC number	1.14.99.9
Gene ontology
Molecular function	• steroid 17-alpha-monooxygenase activity; • iron ion binding; • electron carrier activity; • oxygen binding; • heme binding; • 17-alpha-hydroxyprogesterone aldolase activity;
Cellular component	• mitochondrion; • endoplasmic reticulum; • endoplasmic reticulum membrane; • axon; • neuronal cell body;
Biological process	• steroid biosynthetic process; • androgen biosynthetic process; • glucocorticoid biosynthetic process; • xenobiotic metabolic process; • sex differentiation; • steroid metabolic process; • response to herbicide; • response to acetate; • response to ionizing radiation; • response to insecticide; • biphenyl metabolic process; • dibenzo-p-dioxin metabolic process; • phenol-containing compound metabolic process; • phthalate metabolic process; • hippocampus development; • adrenal gland development; • ovulation; • response to nutrient levels; • response to retinoic acid; • Leydig cell differentiation; • response to cytokine stimulus; • hormone biosynthetic process; • progesterone metabolic process; • response to drug; • small molecule metabolic process; • response to steroid hormone stimulus; • response to cAMP; • response to methylmercury; • response to fungicide; • cellular response to lipopolysaccharide; • cellular response to antibiotic; • cellular response to gonadotropin stimulus; • positive regulation of steroid hormone biosynthetic process;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	This box: view; talk; edit;

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英: adrenocortical hormone
同: 副腎皮質ステロイド adrenocorticoids
関: 副腎皮質刺激ホルモン放出ホルモン、副腎皮質刺激ホルモン; ステロイド
関: 副腎、副腎皮質、ステロイド、コルチコステロイド、ステロイドホルモン、コルチコイド。副腎皮質ホルモン剤

図：SP.891(組織),892(構造式)
副腎皮質の球状層、索状層、網状層で合成される

種類(主要なもののみ)

電解質コルチコイド

球状層から分泌される。アルドステロン

糖質コルチコイド

索状層から分泌される。コルチゾール

副腎アンドロジェン

網状層から分泌される。アンドロステンジオン

コレステロール cholesterol
↓CYP11A1
プレグネノロン pregnenolone	－－→ CYP17 17α-hydroxylase	17α-ヒドロキシプレグネノロン 17α-hydroxypregnenolone	－－→ CYP17 17α-hydroxylase	デヒドロエピアンドロステロン dehydroepiandrosterone DHEA
↓3β-HSD 3β-hydroxysteroid dehydrogenase		↓3β-HSD		↓3β-HSD
プロゲステロン progesterone	－－→ CYP17 17α-hydroxylase	17α-ヒドロキシプロゲステロン 17α-hydroxyprogesterone	－－→ CYP17 17α-hydroxylase	アンドロステンジオン androstenedione Δ⁴androstene-3,17-dion
↓CYP21 21-hydroxylase		↓CYP21 21-hydroxylase
デオキシコルチコステロン deoxycorticosterone		11-デオキシコルチゾール 11-deoxycortisol
↓CYP11B2　11β-hydroxylase		↓CYP11B1　11β-hydroxylase
コルチコステロン corticosterone		コルチゾール cortisol
↓CYP11B2 18-hydroxylase
18-ヒドロキシコルチコステロン 18-hydroxycorticosterone
↓CYP11B2 18-hydroxydehydrogenase
アルドステロン aldosterone

球状増 zona glomerulosa		索状層 zona fasciculata		網状層 zona reticularis

臨床関連

21-hydroxylaseが正常に機能しないことにより生じる (L.320)

薬理学

副腎皮質ホルモン製剤

副腎皮質から分泌されるホルモン (SP.895)

名称		血漿濃度 (ng/ml)	1日分泌量 (mg/day)
糖質コルチコイド	コルチゾール	40～180	15～20
糖質コルチコイド	コルチコステロン	2～6	2～5
鉱質コルチコイド	アルドステロン	0.05～0.20	0.05～0.15
鉱質コルチコイド	11-DOC	0.05～0.30	0.10～0.20
副腎アンドロジェン	DHEA	2～8	7～15
	DHEA-S	1～4
	アンドロステンジオン	1～2	2～3