3beta-Hydroxysteroid dehydrogenase

hydroxy-Δ-5-steroid dehydrogenase, 3β- and steroid Δ-isomerase 1
Identifiers
Symbol	HSD3B1
Alt. symbols	HSDB3, HSD3B
Entrez	3283
HUGO	5217
OMIM	109715
RefSeq	NM_000862
UniProt	P14060
Other data
EC number	1.1.1.145
Locus	Chr. 1 p13-p11

hydroxy-Δ-5-steroid dehydrogenase, 3β- and steroid Δ-isomerase 2
Identifiers
Symbol	HSD3B2
Entrez	3284
HUGO	5218
OMIM	613890
RefSeq	NM_000198
UniProt	P26439
Other data
EC number	1.1.1.145
Locus	Chr. 1 p13.1

3β-Hydroxysteroid dehydrogenase/Δ^5-4 isomerase (3β-HSD) (EC 1.1.1.145) is an enzyme that catalyzes the biosynthesis of progesterone from pregnenolone, 17α-hydroxyprogesterone from 17α-hydroxypregnenolone, and androstenedione from dehydroepiandrosterone (DHEA) in the adrenal gland. It is the only enzyme in the adrenal pathway of corticosteroid synthesis that is not a member of the cytochrome P450 family.^[1] In humans, there are two 3β-HSD isozymes encoded by the HSD3B1 and HSD3B2 genes.

3β-HSD is also known as delta Δ^5-4-isomerase, which catalyzes the oxidative conversion of Δ^5-3-β-hydroxysteroids to the Δ^4-3-keto configuration and is, therefore, essential for the biosynthesis of all classes of hormonal steroids, namely progesterone, glucocorticoids, mineralocorticoids, androgens, and estrogens.^[2]

The 3β-HSD complex is responsible for the conversion of:

Pregnenolone to progesterone
17α-Hydroxypregnenolone to 17α-hydroxyprogesterone
DHEA to androstenedione
Androstenediol to testosterone
Androstadienol to androstadienone

Reaction

3β-HSD belongs to the family of oxidoreductases, to be specific, those acting on the CH-OH group of donor with NAD⁺ or NADP⁺ as acceptor. This enzyme participates in C21-steroid hormone metabolism and androgen and estrogen metabolism.

3β-HSD catalysis|catalyzes the chemical reaction:

a 3β-hydroxy-Δ⁵-steroid + NAD⁺

\rightleftharpoons

a 3-oxo-Δ⁵-steroid + NADH + H⁺

Thus, the two substrates of this enzyme are 3β-hydroxy-Δ⁵-steroid and NAD⁺, whereas its three products are 3-oxo-Δ⁵-steroid, NADH, and H⁺.

Isozymes

Humans express two 3β-HSD isozymes, HSD3B1 (type I) and HSD3B2 (type II).^[3] The type I isoenzyme is expressed in placenta and peripheral tissues, whereas the type II 3β-HSD isoenzyme is expressed in the adrenal gland, ovary, and testis.

Nomenclature

The systematic name of this enzyme class is 3β-hydroxy-Δ⁵-steroid:NAD⁺ 3-oxidoreductase. Other names in common use include:

progesterone reductase
Δ⁵-3β-hydroxysteroid dehydrogenase
3β-hydroxy-5-ene steroid dehydrogenase
3β-hydroxy steroid dehydrogenase/isomerase
3β-hydroxy-Δ⁵-C27-steroid dehydrogenase/isomerase
3β-hydroxy-Δ⁵-C27-steroid oxidoreductase
3β-hydroxy-5-ene-steroid oxidoreductase
steroid-Δ⁵-3β-ol dehydrogenase
3β-HSDH
5-ene-3β-hydroxysteroid dehydrogenase
3β-hydroxy-5-ene-steroid dehydrogenase

Inhibitors

3β-HSD is inhibited by trilostane.^[4]

Biosynthetic pathway

Human steroidogenesis, showing reactions of 3β-HSD near-left in green box.

Corticosteroid biosynthetic pathway in the rat, showing reaction catalyzed by 3β-HSD (second arrow from the top).

Clinical significance

A deficiency in the type II form through mutations in HSD3B2 is responsible for a rare form of congenital adrenal hyperplasia.^[5] No human condition has yet been linked to a deficiency in the type I enzyme. Its importance in placental progesterone production expression suggests that such a mutation would be embryonically lethal.

The fetal adrenal cortex lacks expression of the enzyme early on, thus mineralocorticoids (i.e. aldosterone) and glucocorticoids (i.e. cortisol) cannot be synthesized. This is significant because cortisol induces type II pneumocytes of the lungs to synthesize and secrete pulmonary surfactant; without pulmonary surfactant to reduce the alveolar surface tension, premature neonates may die of neonatal respiratory distress syndrome. If delivery is unavoidable (i.e. because of placental abruption, or pre-eclampsia/HELLP syndrome), then glucocorticoids (i.e. cortisol) can be administered to induce type II pneumocytes to synthesize and secrete pulmonary surfactant, improving the chances of newborn survival (by preventing neonatal respiratory distress syndrome).

References

↑ Cravioto MD, Ulloa-Aguirre A, Bermudez JA, Herrera J, Lisker R, Mendez JP, Perez-Palacios G (August 1986). "A new inherited variant of the 3 beta-hydroxysteroid dehydrogenase-isomerase deficiency syndrome: evidence for the existence of two isoenzymes". J. Clin. Endocrinol. Metab. 63 (2): 360–7. doi:10.1210/jcem-63-2-360. PMID 3088022.
↑ Lachance Y, Luu-The V, Labrie C, Simard J, Dumont M, de Launoit Y, Guérin S, Leblanc G, Labrie F (February 1992). "Characterization of human 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase gene and its expression in mammalian cells". J. Biol. Chem. 267 (5): 3551. PMID 1737804.
↑ Simard J, Ricketts ML, Gingras S, Soucy P, Feltus FA, Melner MH (June 2005). "Molecular biology of the 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase gene family". Endocr. Rev. 26 (4): 525–82. doi:10.1210/er.2002-0050. PMID 15632317.
↑ Cooke GM (April 1996). "Differential effects of trilostane and cyanoketone on the 3 beta-hydroxysteroid dehydrogenase-isomerase reactions in androgen and 16-androstene biosynthetic pathways in the pig testis". J. Steroid Biochem. Mol. Biol. 58 (1): 95–101. doi:10.1016/0960-0760(96)00002-7. PMID 8809191.
↑ Rhéaume E, Simard J, Morel Y, Mebarki F, Zachmann M, Forest MG, New MI, Labrie F (July 1992). "Congenital adrenal hyperplasia due to point mutations in the type II 3 beta-hydroxysteroid dehydrogenase gene". Nat. Genet. 1 (4): 239–45. doi:10.1038/ng0792-239. PMID 1363812.

Cheatum SG, Watten JC (1966). "Purification and properties of 3-beta-hydroxysteroid dehydrogenase and delta-5-3-ketosteroid isomerase from bovine corpora lutea". Biochim. Biophys. Acta 122 (1): 1–13. doi:10.1016/0926-6593(66)90086-5. PMID 4226148.
Koritz SB (1964). "The conversion of prepnenolone to progesterone by small particle from rat adrenal". Biochemistry 3 (8): 1098–1102. doi:10.1021/bi00896a015. PMID 14220672.
Neville AM, Orr, JC and Engel LL (1968). "Delta5-3beta-Hydroxy steroid dehydrogenase activities of bovine adrenal cortex". Biochem. J. 107: 20.

Oxidoreductases: alcohol oxidoreductases (EC 1.1)

1.1.1: NAD/NADP acceptor	3-hydroxyacyl-CoA dehydrogenase 3-hydroxybutyryl-CoA dehydrogenase Alcohol dehydrogenase Aldo-keto reductase 1A1 1B1 1B10 1C1 1C3 1C4 7A2 Aldose reductase Beta-Ketoacyl ACP reductase Carbohydrate dehydrogenases Carnitine dehydrogenase D-malate dehydrogenase (decarboxylating) DXP reductoisomerase Glucose-6-phosphate dehydrogenase Glycerol-3-phosphate dehydrogenase HMG-CoA reductase IMP dehydrogenase Isocitrate dehydrogenase Lactate dehydrogenase L-threonine dehydrogenase L-xylulose reductase Malate dehydrogenase Malate dehydrogenase (decarboxylating) Malate dehydrogenase (NADP+) Malate dehydrogenase (oxaloacetate-decarboxylating) Malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+) Phosphogluconate dehydrogenase Sorbitol dehydrogenase Hydroxysteroid dehydrogenase: 3 Beta 3-beta-HSD NSDHL 11 Beta HSD11B1 HSD11B2 17 Beta

1.1.2: cytochrome acceptor	D-lactate dehydrogenase (cytochrome) D-lactate dehydrogenase (cytochrome c-553) Mannitol dehydrogenase (cytochrome)

1.1.3: oxygen acceptor	Glucose oxidase L-gulonolactone oxidase Xanthine oxidase

1.1.4: disulfide as acceptor	Vitamin K epoxide reductase Vitamin-K-epoxide reductase (warfarin-insensitive)

1.1.5: quinone/similar acceptor	Malate dehydrogenase (quinone) Quinoprotein glucose dehydrogenase

1.1.99: other acceptors	Choline dehydrogenase L2HGDH

Metabolism: lipid metabolism – ketones/cholesterol synthesis enzymes/steroid metabolism

Mevalonate pathway

To HMG-CoA	Acetyl-Coenzyme A acetyltransferase HMG-CoA synthase (regulated step)

Ketogenesis	HMG-CoA lyase 3-hydroxybutyrate dehydrogenase Thiophorase

To Mevalonic acid	HMG-CoA reductase

To DMAPP	Mevalonate kinase Phosphomevalonate kinase Pyrophosphomevalonate decarboxylase Isopentenyl-diphosphate delta isomerase

Geranyl-	Dimethylallyltranstransferase Geranyl pyrophosphate

To cholesterol

To lanosterol	Farnesyl-diphosphate farnesyltransferase Squalene monooxygenase Lanosterol synthase

7-Dehydrocholesterol path	Lanosterol 14α-demethylase Sterol-C5-desaturase-like 7-Dehydrocholesterol reductase

Desmosterol path	24-dehydrocholesterol reductase

To Bile acids

Steroidogenesis

To pregnenolone

Side-chain cleavage

To corticosteroids

aldosterone: 18-hydroxylase

To sex hormones

To androgens	17α-hydroxylase/17,20 lyase 3β dehydrogenase 17β dehydrogenase 5α reductase 1 2

To estrogens	Aromatase

Other/ungrouped

Steroid hormone metabolism modulators

20,22-Desmolase	Inhibitors: 22-ABC 3,3′-Dimethoxybenzidine 3-Methoxybenzidine Aminoglutethimide Canrenone Cyanoketone Danazol Etomidate Ketoconazole Mitotane Spironolactone Trilostane

17α-Hydroxylase, 17,20-Lyase	Inhibitors: 22-ABC 22-Oxime Abiraterone Abiraterone acetate Bifonazole Canrenone CFG-920 Clotrimazole Cyanoketone Cyproterone acetate Danazol Econazole Galeterone Gestrinone Isoconazole Ketoconazole L-39 Liarozole LY-207,320 MDL-27,302 Miconazole Mifepristone Orteronel Pioglitazone Prochloraz Rosiglitazone Spironolactone Stanozolol SU-10,603 TGF-β Tioconazole Troglitazone VN/87-1 VT-464 YM116

3α-HSD	Inhibitors: Coumestrol Daidzein Genistein Indomethacin Medroxyprogesterone acetate Inducers: Fluoxetine Fluvoxamine Mirtazapine Paroxetine Sertraline Venlafaxine

3β-HSD	Inhibitors: 4-MA Abiraterone Abiraterone acetate Azastene Cyanoketone Cyproterone acetate Danazol Epostane Genistein Gestrinone Metyrapone Norethisterone Oxymetholone Pioglitazone Rosiglitazone Trilostane Troglitazone

11β-HSD	Inhibitors: 18α-Glycyrrhizic acid ABT-384 Acetoxolone Carbenoxolone Enoxolone (glycyrrhetinic acid) Epigallocatechin gallate Glycyrrhizin (glycyrrhizic acid)

21-Hydroxylase	Inhibitors: Aminoglutethimide Amphenone B Bifonazole Canrenone Clotrimazole Diazepam Econazole Genistein Isoconazole Ketoconazole Metyrapone Miconazole Midazolam Spironolactone Tioconazole

11β-Hydroxylase	Inhibitors: Abiraterone Abiraterone acetate Aminoglutethimide Canrenone Etomidate Fadrozole FETO Ketoconazole Metomidate Metyrapone Mitotane Potassium canrenoate Spironolactone Trilostane

18-Hydroxylase	Inhibitors: Aminoglutethimide Canrenone FAD286 Fadrozole Ketoconazole LCI699 Metyrapone Mespirenone Potassium canrenoate Spironolactone

17β-HSD	Inhibitors: Danazol Simvastatin

5α-Reductase	Inhibitors: 22-Oxime Alfatradiol Azelaic acid β-Sitosterol Bexlosteride Chlormadinone acetate Cl-4AS-1 Dutasteride Epitestosterone Epristeride Fatty acids (α-linolenic acid, linoleic acid, γ-linolenic acid, monolinolein, oleic acid) Finasteride Ganoderic acid Izonsteride L-39 Lapisteride Saw palmetto TFM-4AS-1 Turosteride Vitamin B6 Zinc

Aromatase	Inhibitors: 4-AT 4-Cyclohexylaniline 4-Hydroxytestosterone 5α-DHNET Abyssinone II Aminoglutethimide Anastrozole Ascorbic acid (vitamin C) Atamestane ATD Bifonazole CGP-45,688 CGS-47,645 Chalconoids (e.g., isoliquiritigenin) Corynesidone A Clotrimazole DHT Difeconazole Econazole Ellagitannins Endosulfan Exemestane Fadrozole Fatty acids (e.g., conjugated linoleic acid, linoleic acid, linolenic acid, palmitic acid) Fenarimol Finrozole Flavonoids (e.g., 7-hydroxyflavone, 7-hydroxyflavanone, 7,8-DHF, acacetin, apigenin, baicalein, biochanin A, chrysin, EGCG, gossypetin, hesperetin, liquiritigenin, myricetin, naringenin, pinocembrin, rotenone, quercetin, sakuranetin, tectochrysin) Formestane Imazalil Isoconazole Ketoconazole Letrozole Liarozole Melatonin MEN-11066 Miconazole Minamestane Nimorazole NKS01 Norendoxifen ORG-33,201 Penconazole Phenytoin Prochloraz PGE2 (dinoprostone) Plomestane Prochloraz Propioconazole Pyridoglutethimide Quinolinoids (e.g., berberine, casimiroin, triptoquinone A, XHN22, XHN26, XHN27) Resorcylic acid lactones (e.g., zearalenone) Rogletimide Stilbenoids (e.g., resveratrol) Talarozole Terpenoids (e.g., dehydroabietic acid, (–)-dehydrololiolide, retinol (vitamin A), Δ⁹-THC, tretinoin) Testolactone Tioconazole Triadimefon Triadimenol Troglitazone Valproic acid Vorozole Xanthones (e.g., garcinone D, garcinone E, α-mangostin, γ-mangostin, monodictyochrome A, monodictyochrome B) YM-511 Zinc Inducers: Atrazine Flavonoids (e.g., genistein, quercetin)

27-Hydroxylase	Inhibitors: Anastrozole Bicalutamide Dexmedetomidine Fadrozole Posaconazole Ravuconazole

See also: Androgenics • Estrogenics • Glucocorticoidics • Mineralocorticoidics • Progestogenics

Enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases(list) EC2 Transferases(list) EC3 Hydrolases(list) EC4 Lyases(list) EC5 Isomerases(list) EC6 Ligases(list)

This article is issued from Wikipedia - version of the Wednesday, March 30, 2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.