AKR1C4

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)
End	5,218,949 bp
Gene location (Mouse)
Chr.	Chromosome 13 (mouse)
End	4,507,876 bp
RNA expression pattern
	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
	; ;
	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
	1109
	83702
	ENSG00000198610
	ENSMUSG00000021210
	P17516
	P70694
	NM_001818
	NM_030611
	NP_001809
	NP_085114
	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


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 T, Zhang W, Lin SX (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 P, Rupprecht R, Manieri GA, Bernardi G, Romeo E, Pasini A (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 ML, Antignac JP, Gemzell-Danielsson K, Le Bizec B, Söder O, et al. (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): 588–590. 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): 2922–2932. 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): 13512–13517. 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): 438–450. doi:10.1097/FBP.0b013e32833d8ba0. PMC 2942072. PMID 20716970.
^ Schüle C, Romeo E, Uzunov DP, Eser D, di Michele F, Baghai TC, et al. (March 2006). "Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3alpha-hydroxysteroid dehydrogenase activity". Molecular Psychiatry. 11 (3): 261–272. 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.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000198610 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000021210 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[5] Li T, Zhang W, Lin SX (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.

[6] Longone P, Rupprecht R, Manieri GA, Bernardi G, Romeo E, Pasini A (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.

[7] Savchuk I, Morvan ML, Antignac JP, Gemzell-Danielsson K, Le Bizec B, Söder O, et al. (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.

[wj-8] 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.

[pmid7789999-9] 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): 588–590. doi:10.1016/0888-7543(95)80066-U. PMID 7789999.

[entrez-10] EntrezGene 1109 AKR1C4 aldo-keto reductase family 1 member C4 [ Homo sapiens (human) ]

[pmid12810547-11] 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): 2922–2932. doi:10.1210/en.2002-0032. PMID 12810547.

[pmid10557352-12] 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): 13512–13517. Bibcode:1999PNAS...9613512G. doi:10.1073/pnas.96.23.13512. PMC 23979. PMID 10557352.

[pmid20716970-13] 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): 438–450. doi:10.1097/FBP.0b013e32833d8ba0. PMC 2942072. PMID 20716970.

[pmid16344854-14] Schüle C, Romeo E, Uzunov DP, Eser D, di Michele F, Baghai TC, et al. (March 2006). "Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3alpha-hydroxysteroid dehydrogenase activity". Molecular Psychiatry. 11 (3): 261–272. doi:10.1038/sj.mp.4001782. PMID 16344854. S2CID 21473462.

[pmid11158055-15] 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

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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)