3-beta-HSD

3β-hydroxysteroid dehydrogenase/Δ-5-4 isomerase
Identifiers
EC number 1.1.1.145
CAS number 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 / EGO
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:

Contents

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:

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.

See also

References

  1. ^ 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. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ 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. 
  5. ^ 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. 

Further reading

  • 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. 
1.1.1: NAD/NADP acceptor
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
Mevalonate pathway
Geranyl-
To cholesterol
To Bile acids
Steroidogenesis
Other/ungrouped

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)