View source for 3β-Hydroxysteroid dehydrogenase

{{Short description|Class of enzymes}}
{{infobox enzyme
| EC_number  = 1.1.1.145
| CAS_number = 9044-85-3
| Name       = 3β-hydroxysteroid dehydrogenase/Δ-5-4 isomerase
| GO_code    = 0003854
| image      =
| width      = 
| caption    =  
}}
{{Pfam_box
| Symbol = HSD3B
| Name = 3β-Hydroxysteroid dehydrogenase
| image = 
| width =
| caption = 
| InterPro= IPR002225
| SMART=
| PROSITE = 
| SCOP = 
| TCDB =
| OPM family=
| OPM protein=
| Pfam= PF01073
| PDB=
| Membranome superfamily= 245
}}
{{infobox protein
| Name = [[HSD3B1|hydroxy-Δ-5-steroid dehydrogenase,<br/>3β- and steroid Δ-isomerase 1]]
| caption = 
| image = 
| width = 
| HGNCid = 5217
| Symbol = [[HSD3B1]]
| AltSymbols = HSDB3, HSD3B
| EntrezGene = 3283
| OMIM = 109715
| RefSeq = NM_000862
| UniProt = P14060
| PDB = 
| ECnumber = 1.1.1.145
| Chromosome = 1
| Arm = p
| Band = 13
| LocusSupplementaryData = -p11
}}
{{infobox protein
| Name = [[HSD3B2|hydroxy-Δ-5-steroid dehydrogenase,<br/>3β- and steroid Δ-isomerase 2]]
| caption = 
| image = 
| width = 
| HGNCid = 5218
| Symbol = [[HSD3B2]]
| AltSymbols = 
| EntrezGene = 3284
| OMIM = 613890
| RefSeq = NM_000198
| UniProt = P26439
| PDB = 
| ECnumber = 1.1.1.145
| Chromosome = 1
| Arm = p
| Band = 13.1
| LocusSupplementaryData = 
}}

'''3β-Hydroxysteroid dehydrogenase/Δ<sup>5-4</sup> isomerase''' ('''3β-HSD''') ({{EC number|1.1.1.145}}) is an [[enzyme]] that [[catalysis|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.<ref name="pmid3088022" /> It is also present in other steroid-producing tissues, including the [[ovary]], [[testis]] and [[placenta]].  In humans, there are two 3β-HSD [[isozyme]]s encoded by the [[HSD3B1]] and [[HSD3B2]] [[gene]]s.

3β-HSD is also known as delta Δ<sup>5-4</sup>-isomerase, which catalyzes the oxidative conversion of Δ<sup>5</sup>-3β-[[hydroxysteroid]]s to the Δ<sup>4</sup>-3-keto configuration and is, therefore, essential for the [[biosynthesis]] of all classes of [[hormonal]] [[steroid]]s, namely [[progesterone]], [[glucocorticoid]]s, [[mineralocorticoid]]s, [[androgen]]s, and [[estrogen]]s.<ref name="pmid1737804" />

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

* [[Pregnenolone]] to [[progesterone]]
* [[17α-Hydroxypregnenolone]] to [[17α-hydroxyprogesterone]]
* [[Dehydroepiandrosterone|DHEA]] to [[androstenedione]]
* [[Androstenediol]] to [[testosterone]]
* [[Androstadienol]] to [[androstadienone]]

==Reaction==
3β-HSD belongs to the family of [[oxidoreductase]]s, to be specific, those acting on the CH-OH group with NAD<sup>+</sup> or NADP<sup>+</sup> 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-Δ<sup>5</sup>-steroid + NAD<sup>+</sup> {{eqm}} a 3-oxo-Δ<sup>5</sup>-steroid + NADH + H<sup>+</sup>

Thus, the two [[substrate (chemistry)|substrates]] of this enzyme are 3β-hydroxy-Δ<sup>5</sup>-steroid and [[nicotinamide adenine dinucleotide|NAD<sup>+</sup>]], whereas its three [[product (chemistry)|products]] are 3-oxo-Δ<sup>5</sup>-steroid, [[nicotinamide adenine dinucleotide|NADH]], and [[hydrogen ion|H<sup>+</sup>]].

==Isozymes==
Humans express two 3β-HSD isozymes, [[HSD3B1]] (type I) and [[HSD3B2]] (type II).<ref name="pmid15632317" /> 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 [[List of enzymes|systematic name]] of this enzyme class is '''3β-hydroxy-Δ<sup>5</sup>-steroid:NAD<sup>+</sup> 3-oxidoreductase'''. Other names in common use include:

* progesterone reductase
* Δ<sup>5</sup>-3β-hydroxysteroid dehydrogenase
* 3β-hydroxy-5-ene steroid dehydrogenase
* 3β-hydroxy steroid dehydrogenase/isomerase
* 3β-hydroxy-Δ<sup>5</sup>-C27-steroid dehydrogenase/isomerase
* 3β-hydroxy-Δ<sup>5</sup>-C27-steroid oxidoreductase
* 3β-hydroxy-5-ene-steroid oxidoreductase
* steroid-Δ<sup>5</sup>-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]].<ref name="pmid8809191" /> [[Medroxyprogesterone acetate]] and [[medrogestone]] are weak inhibitors of 3β-HSD which may substantially inhibit it at high dosages.

==Biosynthetic pathway==
{{Gallery 
|title=
|footer=
|width=300
|File:Steroidogenesis.svg|Human [[steroidogenesis]], showing reactions of 3β-HSD near-left in green box.
|Image:Corticosteroid-biosynthetic-pathway-rat.png| 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 [[congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency|rare form of congenital adrenal hyperplasia]].<ref name="pmid1363812" /> 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 [[Pulmonary alveolus|alveolar]] [[surface tension]], [[premature birth|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.

==See also==
* [[Steroidogenic enzyme]]
* [[3α-Hydroxysteroid dehydrogenase]]

==References==
{{Reflist|30em|refs=
<ref name="pmid3088022">{{cite journal | vauthors = Cravioto MD, Ulloa-Aguirre A, Bermudez JA, Herrera J, Lisker R, Mendez JP, Perez-Palacios G | title = A new inherited variant of the 3 beta-hydroxysteroid dehydrogenase-isomerase deficiency syndrome: evidence for the existence of two isoenzymes | journal = J. Clin. Endocrinol. Metab. | volume = 63 | issue = 2 | pages = 360–7 |date=August 1986 | pmid = 3088022 | doi = 10.1210/jcem-63-2-360}}</ref>
<ref name="pmid1737804">{{cite journal | vauthors = Lachance Y, Luu-The V, Labrie C, Simard J, Dumont M, de Launoit Y, Guérin S, Leblanc G, Labrie F | title = Characterization of human 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase gene and its expression in mammalian cells | journal = J. Biol. Chem. | volume = 267 | issue = 5 | pages = 3551 |date=February 1992 | doi = 10.1016/S0021-9258(19)50764-5 | pmid = 1737804 | doi-access = free }}</ref>
<ref name="pmid15632317">{{cite journal | vauthors = Simard J, Ricketts ML, Gingras S, Soucy P, Feltus FA, Melner MH | title = Molecular biology of the 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase gene family | journal = Endocr. Rev. | volume = 26 | issue = 4 | pages = 525–82 |date=June 2005 | pmid = 15632317 | doi = 10.1210/er.2002-0050 | doi-access = free }}</ref>
<ref name="pmid8809191">{{cite journal | author = Cooke GM | title = 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 | journal = J. Steroid Biochem. Mol. Biol. | volume = 58 | issue = 1 | pages = 95–101 |date=April 1996 | pmid = 8809191 |doi = 10.1016/0960-0760(96)00002-7| s2cid = 23048546 }}</ref>
<ref name="pmid1363812">{{cite journal | vauthors = Rhéaume E, Simard J, Morel Y, Mebarki F, Zachmann M, Forest MG, New MI, Labrie F | title = Congenital adrenal hyperplasia due to point mutations in the type II 3 beta-hydroxysteroid dehydrogenase gene | journal = Nat. Genet. | volume = 1 | issue = 4 | pages = 239–45 |date=July 1992 | pmid = 1363812 | doi = 10.1038/ng0792-239 | s2cid = 26468595 }}</ref>
}}

==Further reading==
{{refbegin|30em}}

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

{{Alcohol oxidoreductases}}
{{Steroid metabolism enymes}}
{{Enzymes}}
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[[Category:EC 1.1.1]]
[[Category:NADH-dependent enzymes]]
[[Category:Enzymes of unknown structure]]
[[Category:Steroid hormone biosynthesis]]