Overview of dehydroepiandrosterone biosynthesis

被引:69
作者
Auchus, RJ [1 ]
机构
[1] Univ Texas, SW Med Ctr, Dept Internal Med, Div Endocrinol & Metab, Dallas, TX USA
关键词
adrenal gland; dehydroepiandrosterone sulfate; CYP17; 3 beta-hydroxysteroid dehydrogenase/Delta(5/4)-isomerases; cytochrome b(5);
D O I
10.1055/s-2004-861545
中图分类号
R71 [妇产科学];
学科分类号
100211 ;
摘要
The biosynthesis of dehydroepiandrosterone (DHEA) from cholesterol involves only two enzymes, both cytochrome P450s. The conversion of cholesterol to pregnenolone is mediated by cholesterol side-chain cleavage enzyme (CYP11A1), which is found in the mitochondria. The cleavage of pregnenolone to DHEA requires both the 17alpha-hydroxylase and 17,20-lyase activities of CYP17, which is found in the endoplasmic reticulum. These conversions require pairs of electron transfer proteins or redox partners, which are adrenodoxin and adrenodoxin reductase for CYP11A1 and cytochrome P450-oxidoreductase and cytochrome b(5) for CYP17. In addition, the steroidogenic acute regulatory (StAR) protein regulates the flux of cholesterol into the biosynthetic pathway and represents the mechanism of acute regulation. Finally, in addition to possessing CYP11A1 and CYP17, it is equally important that a steroidogenic cell not contain other enzymes that drain the flux of pregnenolone to DHEA. These characteristics are illustrated by the fetal adrenal cortex and the zona reticularis, which are dedicated to the synthesis of DHEA and DHEA-sulfate.
引用
收藏
页码:281 / 288
页数:8
相关论文
共 70 条
[1]   Thiazolidinediones but not metformin directly inhibit the steroidogenic enzymes P450c17 and 3β-hydroxysteroid dehydrogenase [J].
Arlt, W ;
Auchus, RJ ;
Miller, WL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (20) :16767-16771
[2]   Molecular modeling of human P450c17 (17α-hydroxylase/17,20-lyase):: Insights into reaction mechanisms and effects of mutations [J].
Auchus, RJ ;
Miller, WL .
MOLECULAR ENDOCRINOLOGY, 1999, 13 (07) :1169-1182
[3]   Adrenarche - physiology, biochemistry and human disease [J].
Auchus, RJ ;
Rainey, WE .
CLINICAL ENDOCRINOLOGY, 2004, 60 (03) :288-296
[4]   The enantiomer of progesterone (ent-progesterone) is a competitive inhibitor of human cytochromes P450c17 and P450c21 [J].
Auchus, RJ ;
Kumar, AS ;
Boswell, CA ;
Gupta, MK ;
Bruce, K ;
Rath, NP ;
Covey, DF .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 2003, 409 (01) :134-144
[5]   Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer [J].
Auchus, RJ ;
Lee, TC ;
Miller, WL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (06) :3158-3165
[6]   The genetics, pathophysiology, and management of human deficiencies of P450c17 [J].
Auchus, RJ .
ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA, 2001, 30 (01) :101-+
[7]   ROLE OF CALCIUM IN ANGIOTENSIN II-MEDIATED ALDOSTERONE SECRETION [J].
BARRETT, PQ ;
BOLLAG, WB ;
ISALES, CM ;
MCCARTHY, RT ;
RASMUSSEN, H .
ENDOCRINE REVIEWS, 1989, 10 (04) :496-518
[8]  
BAXTER JD, 1987, T ASSOC AM PHYSICIAN, V100, pR167
[9]   17-HYDROXYLATION DEFICIENCY IN MAN [J].
BIGLIERI, EG ;
HERRON, MA ;
BRUST, N .
JOURNAL OF CLINICAL INVESTIGATION, 1966, 45 (12) :1946-&
[10]   THE MITOCHONDRIAL ENVIRONMENT IS REQUIRED FOR ACTIVITY OF THE CHOLESTEROL SIDE-CHAIN CLEAVAGE ENZYME, CYTOCHROME P450SCC [J].
BLACK, SM ;
HARIKRISHNA, JA ;
SZKLARZ, GD ;
MILLER, WL .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (15) :7247-7251