3β-Hydroxysteroid dehydrogenase

3β-Hydroxysteroid dehydrogenase
3β-Hydroxysteroid dehydrogenase
Identifiers
Symbol	HSD3B
Pfam	PF01073
InterPro	IPR002225
Membranome	245
Pfam
Available protein structures:
Pfam	structures / ECOD
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

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3β-hydroxysteroid dehydrogenase/Δ-5-4 isomerase
3β-hydroxysteroid dehydrogenase/Δ-5-4 isomerase
Identifiers
EC no.	1.1.1.145
CAS no.	9044-85-3
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
PMC
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3β-Hydroxysteroid dehydrogenase/Δ^5-4 isomerase (3β-HSD) (EC 1.1.1.145) is an enzyme that catalyzes the biosynthesis of the steroid 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] It is also present in other steroid-producing tissues, including the ovary, testis and placenta. In humans, there are two 3β-HSD isozymes encoded by the HSD3B1 and HSD3B2 genes.

hydroxy-Δ-5-steroid dehydrogenase,
3β- and steroid Δ-isomerase 1

Identifiers

Symbol

HSD3B1

Alt. symbols

HSDB3, HSD3B

Other data

Chr. 1 p13-p11

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Structures	Swiss-model
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hydroxy-Δ-5-steroid dehydrogenase,
3β- and steroid Δ-isomerase 2

Identifiers

Symbol

Other data

Chr. 1 p13.1

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Structures	Swiss-model
Domains	InterPro

3β-HSD is also known as delta Δ^5-4-isomerase, which catalyzes the oxidative conversion of Δ⁵-3β-hydroxysteroids to the Δ⁴-3-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 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⁺ ⇌ 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 potently inhibited by azastene, cyanoketone, epostane, and trilostane.^[4] Medroxyprogesterone acetate and medrogestone are weak inhibitors of 3β-HSD which may substantially inhibit it at high dosages.

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 (e.g. aldosterone) and glucocorticoids (e.g. 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 (e.g. because of placental abruption, or pre-eclampsia/HELLP syndrome), then glucocorticoids (e.g. cortisol) can be administered.

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. doi:10.1016/S0021-9258(19)50764-5. 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. S2CID 23048546.
^ 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. S2CID 26468595.