3-alpha-HSD

Aldo-keto reductase family 1, member C4

PDB rendering based on 2fvl.

Available structures

Ortholog search: PDBe, RCSB

List of PDB id codes
2FVL

Identifiers

Symbols

AKR1C4 ; 3-alpha-HSD; C11; CDR; CHDR; DD-4; DD4; HAKRA

External IDs

OMIM: 600451 MGI: 2653678 HomoloGene: 84695 ChEMBL: 4999 GeneCards: AKR1C4 Gene

EC number

1.1.1.225, 1.1.1.357

Gene ontology
Molecular function	• retinal dehydrogenase activity • aldo-keto reductase (NADP) activity • electron carrier activity • bile acid transmembrane transporter activity • oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor • androsterone dehydrogenase activity • chlordecone reductase activity
Cellular component	• cytoplasm • cytosol • extracellular exosome
Biological process	• retinoid metabolic process • bile acid biosynthetic process • phototransduction, visible light • steroid metabolic process • bile acid metabolic process • androgen metabolic process • bile acid and bile salt transport • small molecule metabolic process • daunorubicin metabolic process • doxorubicin metabolic process • oxidation-reduction process • cellular response to jasmonic acid stimulus
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 10:
5.2 – 5.22 Mb

Chr 13:
4.43 – 4.46 Mb

PubMed search

3α-hydroxysteroid dehydrogenase (3α-HSD), also known as aldo-keto reductase family 1 member C4, is an enzyme that in humans is encoded by the AKR1C4 gene.^[1]^[2] It is known to be necessary for the synthesis of the endogenous neurosteroids allopregnanolone, THDOC, and 3α-androstanediol. It is also known to catalyze the reversible conversion of 3α-androstanediol (5α-androstane-3α,17β-diol) to dihydrotestosterone (DHT) (5α-androstan-17β-ol-3-one) and vice versa.^[3]

Function

This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme catalyzes the bioreduction of chlordecone, a toxic organochlorine pesticide, to chlordecone alcohol in liver. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14.^[2]

Clinical significance

Various antidepressants, including the SSRIs fluoxetine, fluvoxamine, sertraline, and paroxetine, the SNRI venlafaxine, and mirtazapine, have been found to activate certain 3α-HSD enzymes, resulting in a selective facilitation of 5α-dihydroprogesterone conversion into allopregnanolone. This action has been implicated in their effectiveness in affective disorders, and has resulted in them being described as selective brain steroidogenic stimulants (SBSSs).^[4]^[5]^[6]

References

↑ Khanna M, Qin KN, Klisak I, Belkin S, Sparkes RS, Cheng KC (Jul 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. doi:10.1016/0888-7543(95)80066-U. PMID 7789999.
1 2 "Entrez Gene: AKR1C4 aldo-keto reductase family 1, member C4 (chlordecone reductase; 3-alpha hydroxysteroid dehydrogenase, type I; dihydrodiol dehydrogenase 4)".
↑ Rizner TL, Lin HK, Peehl DM, Steckelbroeck S, Bauman DR, Penning TM (July 2003). "Human type 3 3alpha-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) and androgen metabolism in prostate cells". Endocrinology 144 (7): 2922–32. doi:10.1210/en.2002-0032. PMID 12810547.
↑ Griffin LD, Mellon SH (November 1999). "Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes". Proc. Natl. Acad. Sci. U.S.A. 96 (23): 13512–7. doi:10.1073/pnas.96.23.13512. PMC 23979. PMID 10557352.
↑ Pinna G (September 2010). "In a mouse model relevant for post-traumatic stress disorder, selective brain steroidogenic stimulants (SBSS) improve behavioral deficits by normalizing allopregnanolone biosynthesis". Behav Pharmacol 21 (5-6): 438–50. doi:10.1097/FBP.0b013e32833d8ba0. PMC 2942072. PMID 20716970.
↑ Schüle C, Romeo E, Uzunov DP, Eser D, di Michele F, Baghai TC, Pasini A, Schwarz M, Kempter H, Rupprecht R (March 2006). "Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3alpha-hydroxysteroid dehydrogenase activity". Mol. Psychiatry 11 (3): 261–72. doi:10.1038/sj.mp.4001782. PMID 16344854.

Binstock JM, Iyer RB, Hamby CV, Fried VA, Schwartz IS, Weinstein BI, Southren AL (1992). "Human hepatic 3 alpha-hydroxysteroid dehydrogenase: possible identity with human hepatic chlordecone reductase.". Biochem. Biophys. Res. Commun. 187 (2): 760–6. doi:10.1016/0006-291X(92)91260-W. PMID 1530633.
Winters CJ, Molowa DT, Guzelian PS (1990). "Isolation and characterization of cloned cDNAs encoding human liver chlordecone reductase.". Biochemistry 29 (4): 1080–7. doi:10.1021/bi00456a034. PMID 2187532.
Khanna M, Qin KN, Cheng KC (1995). "Distribution of 3 alpha-hydroxysteroid dehydrogenase in rat brain and molecular cloning of multiple cDNAs encoding structurally related proteins in humans.". J. Steroid Biochem. Mol. Biol. 53 (1–6): 41–6. doi:10.1016/0960-0760(95)00019-V. PMID 7626489.
Khanna M, Qin KN, Wang RW, Cheng KC (1995). "Substrate specificity, gene structure, and tissue-specific distribution of multiple human 3 alpha-hydroxysteroid dehydrogenases". J. Biol. Chem. 270 (34): 20162–8. doi:10.1074/jbc.270.34.20162. PMID 7650035.
Deyashiki Y, Ogasawara A, Nakayama T, Nakanishi M, Miyabe Y, Sato K, Hara A (1994). "Molecular cloning of two human liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase isoenzymes that are identical with chlordecone reductase and bile-acid binder". Biochem. J. 299 (2): 545–52. PMC 1138306. PMID 8172617.
Qin KN, New MI, Cheng KC (1994). "Molecular cloning of multiple cDNAs encoding human enzymes structurally related to 3 alpha-hydroxysteroid dehydrogenase". J. Steroid Biochem. Mol. Biol. 46 (6): 673–9. doi:10.1016/0960-0760(93)90308-J. PMID 8274401.
Kume T, Iwasa H, Shiraishi H, Yokoi T, Nagashima K, Otsuka M, Terada T, Takagi T, Hara A, Kamataki T (2000). "Characterization of a novel variant (S145C/L311V) of 3alpha-hydroxysteroid/dihydrodiol dehydrogenase in human liver". Pharmacogenetics 9 (6): 763–71. doi:10.1097/00008571-199912000-00011. PMID 10634139.
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. doi:10.1046/j.1365-2443.2000.00310.x. PMID 10672042.
Dufort I, Labrie F, Luu-The V (2001). "Human types 1 and 3 3 alpha-hydroxysteroid dehydrogenases: differential lability and tissue distribution". J. Clin. Endocrinol. Metab. 86 (2): 841–6. doi:10.1210/jc.86.2.841. PMID 11158055.
Ozeki T, Takahashi Y, Kume T, Nakayama K, Yokoi T, Nunoya K, Hara A, Kamataki T (2001). "Co-operative regulation of the transcription of human dihydrodiol dehydrogenase (DD)4/aldo-keto reductase (AKR)1C4 gene by hepatocyte nuclear factor (HNF)-4alpha/gamma and HNF-1alpha". Biochem. J. 355 (Pt 2): 537–44. doi:10.1042/0264-6021:3550537. PMC 1221767. PMID 11284743.
Ozeki T, Takahashi Y, Nakayama K, Kamataki T (2002). "Hepatocyte nuclear factor (HNF)-4 alpha/gamma, HNF-1 alpha, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene". Arch. Biochem. Biophys. 405 (2): 185–90. doi:10.1016/S0003-9861(02)00384-3. PMID 12220531.
Ozeki T, Takahashi Y, Nakayama K, Funayama M, Nagashima K, Kodama T, Kamataki T (2003). "Hepatocyte nuclear factor-4 alpha/gamma and hepatocyte nuclear factor-1 alpha as causal factors of interindividual difference in the expression of human dihydrodiol dehydrogenase 4 mRNA in human livers". Pharmacogenetics 13 (1): 49–53. doi:10.1097/00008571-200301000-00007. PMID 12544512.
Schüle C, Romeo E, Uzunov DP, Eser D, di Michele F, Baghai TC, Pasini A, Schwarz M, Kempter H, Rupprecht R (2006). "Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3alpha-hydroxysteroid dehydrogenase activity". Mol. Psychiatry 11 (3): 261–72. doi:10.1038/sj.mp.4001782. PMID 16344854.

PDB gallery

2fvl: Crystal structure of human 3-alpha hydroxysteroid/dihydrodiol dehydrogenase (AKR1C4) complexed with NADP+

Oxidoreductases: alcohol oxidoreductases (EC 1.1)

1.1.1: NAD/NADP acceptor	3-hydroxyacyl-CoA dehydrogenase 3-hydroxybutyryl-CoA dehydrogenase Alcohol dehydrogenase Aldo-keto reductase 1A1 1B1 1B10 1C1 1C3 1C4 7A2 Aldose reductase Beta-Ketoacyl ACP reductase Carbohydrate dehydrogenases Carnitine dehydrogenase D-malate dehydrogenase (decarboxylating) DXP reductoisomerase Glucose-6-phosphate dehydrogenase Glycerol-3-phosphate dehydrogenase HMG-CoA reductase IMP dehydrogenase Isocitrate dehydrogenase Lactate dehydrogenase L-threonine dehydrogenase L-xylulose reductase Malate dehydrogenase Malate dehydrogenase (decarboxylating) Malate dehydrogenase (NADP+) Malate dehydrogenase (oxaloacetate-decarboxylating) Malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+) Phosphogluconate dehydrogenase Sorbitol dehydrogenase Hydroxysteroid dehydrogenase: 3 Beta 3-beta-HSD NSDHL 11 Beta HSD11B1 HSD11B2 17 Beta

1.1.2: cytochrome acceptor	D-lactate dehydrogenase (cytochrome) D-lactate dehydrogenase (cytochrome c-553) Mannitol dehydrogenase (cytochrome)

1.1.3: oxygen acceptor	Glucose oxidase L-gulonolactone oxidase Xanthine oxidase

1.1.4: disulfide as acceptor	Vitamin K epoxide reductase Vitamin-K-epoxide reductase (warfarin-insensitive)

1.1.5: quinone/similar acceptor	Malate dehydrogenase (quinone) Quinoprotein glucose dehydrogenase

1.1.99: other acceptors	Choline dehydrogenase L2HGDH

Proteins: enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases(list) EC2 Transferases(list) EC3 Hydrolases(list) EC4 Lyases(list) EC5 Isomerases(list) EC6 Ligases(list)

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3-alpha-HSD

Function

Clinical significance

See also

References

Further reading