3-beta-HSD

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3-beta-HSD

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3β-hydroxysteroid dehydrogenase/Δ-5-4 isomerase

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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

3-β-HSD (or 3-β-hydroxysteroid dehydrogenase/Δ-5-4 isomerase) is an enzyme that catalyses the synthesis of progesterone from pregnenolone, 17-hydroxyprogesterone from 17-hydroxypregnenolone, and androstenedione from dehydroepiandrosterone 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 3-β-HSD isozymes encoded by the HSD3B1 and HSD3B2 genes, respectively.

It is also known as delta 5-delta 4-isomerase, which catalyzes the oxidative conversion of delta 5-3 beta- hydroxysteroids to the delta 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 3-beta HSD complex is responsible for the conversion of:

pregnenolone to progesterone
17-alpha-pregnenolone to 17-alpha-progesterone
dehydroepiandrosterone (DHEA) to androstenedione
androstenediol to testosterone

Contents

1 Reaction
2 Isozymes
3 Nomenclature
4 Inhibitors
5 Biosynthetic pathway
6 Clinical significance
7 See also
8 References
9 Further reading

Reaction

3-β-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.

3-β-HSD 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 3 products are 3-oxo-Δ5-steroid, NADH, and H⁺.

Isozymes

Humans express two 3-β-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

3-β-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.

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. 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

Hydroxysteroid dehydrogenase: 3 Beta (3-beta-HSD
NSDHL)
11 Beta (HSD11B1
HSD11B2)
17 Beta

1.1.2: cytochrome acceptor

1.1.3: oxygen acceptor

1.1.4: disulfide as acceptor

1.1.5: quinone/similar acceptor

1.1.99: other acceptors

B
enzm
- 1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
2.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
2.7.10
2.7.11-12
3.1
- 2
- 3
- 4
- 5
- 6
- 7
3.1.3.48
3.4.21
- 22
- 23
- 24
4.1
- 2
- 3
- 4
- 5
- 6
5.1
- 2
- 3
- 4
- 99
6.1-3
- 4
- 5-6

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

Cholesterol 7α-hydroxylase · Sterol 27-hydroxylase

aldosterone: 18-hydroxylase

cortisol/cortisone: 17α-hydroxylase · 11β dehydrogenase (HSD11B1, HSD11B2)

both: 3β dehydrogenase · 21α-hydroxylase · 11β-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 metabolism: sulfatase (Steroid sulfatase) · sulfotransferase (SULT1A1, SULT2A1)

Steroidogenic acute regulatory protein

M: MET

mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m

k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon

m(A16/C10),i(k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)

M: END

anat/phys/devp/horm

noco(d)/cong/tumr, sysi/epon

proc, drug (A10/H1/H2/H3/H5)

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