AKR1C4

Protein-coding gene in the species Homo sapiens

AKR1C4

Available structures

PDB

Ortholog search: PDBe RCSB

List of PDB id codes
2FVL

Identifiers

Aliases

AKR1C4, 3-alpha-HSD, C11, CDR, CHDR, DD-4, DD4, HAKRA, aldo-keto reductase family 1, member C4, aldo-keto reductase family 1 member C4

External IDs

OMIM: 600451; MGI: 1933427; HomoloGene: 84695; GeneCards: AKR1C4; OMA:AKR1C4 - orthologs

EC number

1.1.1.225

Gene location (Human)

Chr.	Chromosome 10 (human)^[1]

Band	10p15.1	Start	5,195,462 bp^[1]
Band	10p15.1	End	5,218,949 bp^[1]

Gene location (Mouse)

Chr.	Chromosome 13 (mouse)^[2]

Band	13 A1\|13 2.48 cM	Start	4,484,305 bp^[2]
Band	13 A1\|13 2.48 cM	End	4,507,876 bp^[2]

RNA expression pattern

Bgee

Human

Mouse (ortholog)

Top expressed in

right lobe of liver

gallbladder

testicle

islet of Langerhans

duodenum

jejunal mucosa

gonad

granulocyte

Achilles tendon

muscle of thigh

Top expressed in

left lobe of liver

gallbladder

bronchus

urethra

lobar bronchus

Lumen of fundus of stomach

abdominal aorta

vasculature of trunk

proximal convoluted tubule

sexually immature organism

More reference expression data

BioGPS


More reference expression data

Gene ontology
Molecular function	retinal dehydrogenase activity aldo-keto reductase (NADP) activity bile acid transmembrane transporter activity oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor chlordecone reductase activity electron transfer activity oxidoreductase activity androsterone dehydrogenase activity alditol:NADP+ 1-oxidoreductase activity alcohol dehydrogenase (NADP+) activity steroid dehydrogenase activity ketosteroid monooxygenase activity
Cellular component	cytoplasm cytosol extracellular exosome
Biological process	cellular response to jasmonic acid stimulus steroid metabolic process daunorubicin metabolic process doxorubicin metabolic process androgen metabolic process retinoid metabolic process bile acid and bile salt transport bile acid biosynthetic process electron transport chain prostaglandin metabolic process progesterone metabolic process
Sources:Amigo / QuickGO

Orthologs

Species

Human

Mouse

Entrez


1109


83702

Ensembl


ENSG00000198610


ENSMUSG00000021210

UniProt


P17516


P70694

RefSeq (mRNA)


NM_001818


NM_030611

RefSeq (protein)


NP_001809


NP_085114

Location (UCSC)

Chr 10: 5.2 – 5.22 Mb

Chr 13: 4.48 – 4.51 Mb

PubMed search

^[3]

^[4]

Wikidata

View/Edit Human

View/Edit Mouse

Aldo-keto reductase family 1 member C4, also known as 3α-Hydroxysteroid dehydrogenase type 1 (3α-HSD1),^[5]^[6]^[7] is an enzyme that in humans is encoded by the AKR1C4 gene.^[8]^[9]^[10] It is known to be necessary for the synthesis of the endogenous neurosteroids allopregnanolone, tetrahydrodeoxycorticosterone, 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.^[11]

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 10p15-p14 on chromosome 10.^[10]

Clinical significance

Various antidepressants, including the SSRIs fluoxetine, fluvoxamine, sertraline, and paroxetine, the SNRI venlafaxine, and mirtazapine, have been found to activate certain isoforms of the 3α-hydroxysteroid dehydrogenase, 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).^[12]^[13]^[14]

Isozymes of aldo-keto reductase family 1 member C


HGNC Gene Symbol	Enzyme Name Aliases^[15]
AKR1C1	aldo-keto reductase family 1 member C1; 20α-hydroxysteroid dehydrogenase
AKR1C2	aldo-keto reductase family 1 member C2; 3α-hydroxysteroid dehydrogenase type 3
AKR1C3	aldo-keto reductase family 1 member C3; 3α-hydroxysteroid dehydrogenase type 2; 17β-hydroxysteroid dehydrogenase type 5; HSD17B5
AKR1C4	aldo-keto reductase family 1 member C4; 3α-hydroxysteroid dehydrogenase type 1

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000198610 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000021210 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Li, Tang; Zhang, Wenfa; Lin, Sheng-Xiang (February 2020). "Steroid enzyme and receptor expression and regulations in breast tumor samples – A statistical evaluation of public data". The Journal of Steroid Biochemistry and Molecular Biology. 196: 105494. doi:10.1016/j.jsbmb.2019.105494. PMID 31610224.
^ Longone, Patrizia; Rupprecht, Rainer; Manieri, Gaia A.; Bernardi, Giorgio; Romeo, Elena; Pasini, Augusto (March 2008). "The complex roles of neurosteroids in depression and anxiety disorders". Neurochemistry International. 52 (4–5): 596–601. doi:10.1016/j.neuint.2007.10.001. PMID 17996986.
^ Savchuk, I.; Morvan, M.L.; Antignac, J.P.; Gemzell-Danielsson, K.; Le Bizec, B.; Söder, O.; Svechnikov, K. (December 2018). "The human genital tubercle is steroidogenic organ at early pregnancy". Molecular and Cellular Endocrinology. 477: 148–155. doi:10.1016/j.mce.2018.06.012. PMID 29928928.
^ Masiutin MM, Yadav MK (3 April 2023). "Alternative androgen pathways" (PDF). WikiJournal of Medicine. 10: 29. doi:10.15347/WJM/2023.003. S2CID 257943362. This article incorporates text from this source, which is available under the CC BY 4.0 license.
^ Khanna M, Qin KN, Klisak I, Belkin S, Sparkes RS, Cheng KC (January 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.
^ ^a ^b EntrezGene 1109 AKR1C4 aldo-keto reductase family 1 member C4 [ Homo sapiens (human) ]
^ 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". Proceedings of the National Academy of Sciences of the United States of America. 96 (23): 13512–7. Bibcode:1999PNAS...9613512G. 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". Behavioural Pharmacology. 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". Molecular Psychiatry. 11 (3): 261–72. doi:10.1038/sj.mp.4001782. PMID 16344854. S2CID 21473462.
^ Dufort I, Labrie F, Luu-The V (February 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/jcem.86.2.7216. PMID 11158055. human types 1 and 3 3α-HSD, 20α-HSD, and type 5 17β-HSD were named AKR1C4, AKR1C2, AKR1C1, and AKR1C3, respectively

External links

Human AKR1C4 genome location and AKR1C4 gene details page in the UCSC Genome Browser.

Binstock JM, Iyer RB, Hamby CV, Fried VA, Schwartz IS, Weinstein BI, Southren AL (September 1992). "Human hepatic 3 alpha-hydroxysteroid dehydrogenase: possible identity with human hepatic chlordecone reductase". Biochemical and Biophysical Research Communications. 187 (2): 760–6. doi:10.1016/0006-291X(92)91260-W. PMID 1530633.
Winters CJ, Molowa DT, Guzelian PS (January 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 (June 1995). "Distribution of 3 alpha-hydroxysteroid dehydrogenase in rat brain and molecular cloning of multiple cDNAs encoding structurally related proteins in humans". The Journal of Steroid Biochemistry and Molecular Biology. 53 (1–6): 41–6. doi:10.1016/0960-0760(95)00019-V. PMID 7626489. S2CID 11316547.
Khanna M, Qin KN, Wang RW, Cheng KC (August 1995). "Substrate specificity, gene structure, and tissue-specific distribution of multiple human 3 alpha-hydroxysteroid dehydrogenases". The Journal of Biological Chemistry. 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 (April 1994). "Molecular cloning of two human liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase isoenzymes that are identical with chlordecone reductase and bile-acid binder". The Biochemical Journal. 299 ( Pt 2) (2): 545–52. doi:10.1042/bj2990545. PMC 1138306. PMID 8172617.
Qin KN, New MI, Cheng KC (December 1993). "Molecular cloning of multiple cDNAs encoding human enzymes structurally related to 3 alpha-hydroxysteroid dehydrogenase". The Journal of Steroid Biochemistry and Molecular Biology. 46 (6): 673–9. doi:10.1016/0960-0760(93)90308-J. PMID 8274401. S2CID 36210133.
Kume T, Iwasa H, Shiraishi H, Yokoi T, Nagashima K, Otsuka M, Terada T, Takagi T, Hara A, Kamataki T (December 1999). "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 (February 2000). "Close kinship of human 20alpha-hydroxysteroid dehydrogenase gene with three aldo-keto reductase genes". Genes to Cells. 5 (2): 111–25. doi:10.1046/j.1365-2443.2000.00310.x. PMID 10672042. S2CID 25136637.
Dufort I, Labrie F, Luu-The V (February 2001). "Human types 1 and 3 3 alpha-hydroxysteroid dehydrogenases: differential lability and tissue distribution". The Journal of Clinical Endocrinology and Metabolism. 86 (2): 841–6. doi:10.1210/jcem.86.2.7216. PMID 11158055.
Ozeki T, Takahashi Y, Kume T, Nakayama K, Yokoi T, Nunoya K, Hara A, Kamataki T (April 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". The Biochemical Journal. 355 (Pt 2): 537–44. doi:10.1042/0264-6021:3550537. PMC 1221767. PMID 11284743.
Ozeki T, Takahashi Y, Nakayama K, Kamataki T (September 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". Archives of Biochemistry and Biophysics. 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 (January 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 (March 2006). "Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3alpha-hydroxysteroid dehydrogenase activity". Molecular Psychiatry. 11 (3): 261–72. doi:10.1038/sj.mp.4001782. PMID 16344854. S2CID 21473462.

PDB gallery

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

v t e 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: 3β 3β-HSD NSDHL 11β 11β-HSD1 11β-HSD2 17β
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 Alcohol 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

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)