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MetaCyc Enzyme: 3α hydroxysteroid dehydrogenase III

Gene: AKR1C2 Accession Number: HS07754 (MetaCyc)

Synonyms: DDH2, 3-α-hydroxysteroid dehydrogenase type 3, bile acid-binding protein, 3α-HSD

Species: Homo sapiens

Summary:
The different isozymes of 3α-hydroxysteroid dehydrogenases work in concert with the 5-α/5-β-steroid reductases to convert steroid hormones into the 3-α/5-α and 3-α/5-β-tetrahydrosteroids. These enzymes catalyze the inactivation of androgens, estrogens, progestins, and glucocorticoids [Nahoum01]. The enzyme is a member of the aldo-keto reductase (AKR) superfamily [Nishizawa00].

The best known reaction catalyzed by this enzyme is the inactivation of the most potent androgen, 5-α-dihydrotestosterone, to 5-α-androstan-3α,17β-diol. In addition to its 3α-HSD activity, the enzyme also possesses some 17β-HSD activity, but the latter activity is much weaker than in the case of the type 2 3α-HSD.

The enzyme has a high bile-binding ability [Hara96]. It was also shown to have a trans-1,2-dihydrobenzene-1,2-diol dehydrogenase (EC 1.3.1.20) activity [Hara96].

The structure of the enzyme, which is a monomer in solution, has been determined at a resolution of 1.25 Å [Nahoum01].

cDNA clones have been isolated and sequenced multiple times. Expression was detected in liver and 10 other tissue samples [Winters90, Stolz93, Qin93, Ciaccio94, Dufort96, Shiraishi98]. The structure and sequence of the gene encoding the enzyme has been reported [Qin94]. The gene is located on chromosome 10p14-p15 [Khanna95a].

Map Position: [4,991,700 <- 5,005,759]

Molecular Weight of Polypeptide: 36.735 kD (from nucleotide sequence)

Unification Links: ArrayExpress:P52895 , Entrez-gene:1646 , MOPED:P52895 , UniProt:P52895

Gene-Reaction Schematic: ?

Instance reactions of [allopregnanolone + NAD(P)+ ↔ 5-α-pregnane-3,20-dione + NAD(P)H + H+] (1.1.1.213):
i1: allopregnanolone + NAD+ → 5-α-pregnane-3,20-dione + NADH + H+ (1.1.-.-)

i2: allopregnanolone + NADP+ ← 5-α-pregnane-3,20-dione + NADPH + H+ (1.1.1.278)

GO Terms:

Biological Process: GO:0006629 - lipid metabolic process
GO:0007586 - digestion
GO:0015721 - bile acid and bile salt transport
GO:0015722 - canalicular bile acid transport
Molecular Function: GO:0005488 - binding
GO:0015125 - bile acid transmembrane transporter activity
GO:0016491 - oxidoreductase activity

Credits:
Created 22-Mar-2011 by Caspi R , SRI International


Enzymatic reaction of: 3α hydroxysteroid dehydrogenase III

EC Number: 1.1.1.-

cholate + NAD+ <=> 3-dehydrocholate + NADH + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the direction in which it was curated.

This reaction is reversible.

Credits:
Imported from HumanCyc 13-May-2014 by Montanucci L , Universitat Pompeu Fabra Barcelona


Enzymatic reaction of: 3α hydroxysteroid dehydrogenase III

EC Number: 1.1.1.-

choloyl-CoA + NAD(P)+ <=> 3-oxo-cholyl-CoA + NAD(P)H + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the direction in which it was curated.

This reaction is reversible.

Credits:
Imported from HumanCyc 13-May-2014 by Montanucci L , Universitat Pompeu Fabra Barcelona


Enzymatic reaction of: 3α-hydroxysteroid dehydrogenase (3α hydroxysteroid dehydrogenase III)

allopregnanolone + NAD(P)+ <=> 5-α-pregnane-3,20-dione + NAD(P)H + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the direction in which it was curated.

The reaction is physiologically favored in the opposite direction. [Trauger02]

In Pathways: allopregnanolone biosynthesis

Credits:
Imported from HumanCyc 13-May-2014 by Montanucci L , Universitat Pompeu Fabra Barcelona


Enzymatic reaction of: trans-1,2-dihydrobenzene-1,2-diol dehydrogenase (3α hydroxysteroid dehydrogenase III)

EC Number: 1.3.1.20

trans-1,2-dihydrobenzene-1,2-diol + NADP+ <=> catechol + NADPH + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

Reversibility of this reaction is unspecified.

Credits:
Imported from HumanCyc 04-Nov-2011 by Caspi R , SRI International


Enzymatic reaction of: 5-α-dihydrotestosterone dehydrogenase (3α hydroxysteroid dehydrogenase III)

5-α-androstan-3α,17β-diol + NAD(P)+ <=> 5-α-dihydrotestosterone + NAD(P)H + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

Reversibility of this reaction is unspecified.


Enzymatic reaction of: androsterone dehydrogenase (3α hydroxysteroid dehydrogenase III)

EC Number: 1.1.1.209

androsterone + NAD(P)+ <=> 5α-androstane-3,17-dione + NAD(P)H + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the direction shown.

Exons/Introns:


References

Ciaccio94: Ciaccio PJ, Tew KD (1994). "cDNA and deduced amino acid sequences of a human colon dihydrodiol dehydrogenase." Biochim Biophys Acta 1186(1-2);129-32. PMID: 8011662

Dufort96: Dufort I, Soucy P, Labrie F, Luu-The V (1996). "Molecular cloning of human type 3 3 alpha-hydroxysteroid dehydrogenase that differs from 20 alpha-hydroxysteroid dehydrogenase by seven amino acids." Biochem Biophys Res Commun 228(2);474-9. PMID: 8920937

Hara96: Hara A, Matsuura K, Tamada Y, Sato K, Miyabe Y, Deyashiki Y, Ishida N (1996). "Relationship of human liver dihydrodiol dehydrogenases to hepatic bile-acid-binding protein and an oxidoreductase of human colon cells." Biochem J 313 ( Pt 2);373-6. PMID: 8573067

Khanna95a: Khanna M, Qin KN, Klisak I, Belkin S, Sparkes RS, Cheng KC (1995). "Localization of multiple human dihydrodiol dehydrogenase (DDH1 and DDH2) and chlordecone reductase (CHDR) genes in chromosome 10 by the polymerase chain reaction and fluorescence in situ hybridization." Genomics 25(2);588-90. PMID: 7789999

Nahoum01: Nahoum V, Gangloff A, Legrand P, Zhu DW, Cantin L, Zhorov BS, Luu-The V, Labrie F, Breton R, Lin SX (2001). "Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution." J Biol Chem 276(45);42091-8. PMID: 11514561

Nishizawa00: Nishizawa M, Nakajima T, Yasuda K, Kanzaki H, Sasaguri Y, Watanabe K, Ito S (2000). "Close kinship of human 20alpha-hydroxysteroid dehydrogenase gene with three aldo-keto reductase genes." Genes Cells 5(2);111-25. PMID: 10672042

Penning03: Penning TM, Jin Y, Heredia VV, Lewis M (2003). "Structure-function relationships in 3alpha-hydroxysteroid dehydrogenases: a comparison of the rat and human isoforms." J Steroid Biochem Mol Biol 85(2-5);247-55. PMID: 12943710

Qin93: Qin KN, New MI, Cheng KC (1993). "Molecular cloning of multiple cDNAs encoding human enzymes structurally related to 3 alpha-hydroxysteroid dehydrogenase." J Steroid Biochem Mol Biol 46(6);673-9. PMID: 8274401

Qin94: Qin KN, Khanna M, Cheng KC (1994). "Structure of a gene coding for human dihydrodiol dehydrogenase/bile acid-binding protein." Gene 149(2);357-61. PMID: 7959017

Shiraishi98: Shiraishi H, Ishikura S, Matsuura K, Deyashiki Y, Ninomiya M, Sakai S, Hara A (1998). "Sequence of the cDNA of a human dihydrodiol dehydrogenase isoform (AKR1C2) and tissue distribution of its mRNA." Biochem J 334 ( Pt 2);399-405. PMID: 9716498

Stolz93: Stolz A, Hammond L, Lou H, Takikawa H, Ronk M, Shively JE (1993). "cDNA cloning and expression of the human hepatic bile acid-binding protein. A member of the monomeric reductase gene family." J Biol Chem 268(14);10448-57. PMID: 8486699

Trauger02: Trauger JW, Jiang A, Stearns BA, LoGrasso PV (2002). "Kinetics of allopregnanolone formation catalyzed by human 3 alpha-hydroxysteroid dehydrogenase type III (AKR1C2)." Biochemistry 41(45);13451-9. PMID: 12416991

Winters90: Winters CJ, Molowa DT, Guzelian PS (1990). "Isolation and characterization of cloned cDNAs encoding human liver chlordecone reductase." Biochemistry 29(4);1080-7. PMID: 2187532


Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 18.5 on Fri Nov 28, 2014, BIOCYC14B.