Cytosolic aldo-keto reductase that catalyzes the NADH and NADPH-dependent reduction of ketosteroids to hydroxysteroids. Acts as a NAD(P)(H)-dependent 3-, 17- and 20-ketosteroid reductase on the steroid nucleus and side chain and regulates the metabolism of androgens, estrogens and progesterone (PubMed:10622721, PubMed:11165022, PubMed:7650035, PubMed:9415401, PubMed:9927279). Displays the ability to catalyze both oxidation and reduction in vitro, but most probably acts as a reductase in vivo since the oxidase activity measured in vitro is inhibited by physiological concentration of NADPH (PubMed:14672942, PubMed:11165022). Acts preferentially as a 17-ketosteroid reductase and has the highest catalytic efficiency of the AKR1C enzyme for the reduction of delta4-androstenedione to form testosterone (PubMed:20036328). Reduces prostaglandin (PG) D2 to 11beta-prostaglandin F2, progesterone to 20alpha-hydroxyprogesterone and estrone to 17beta-estradiol (PubMed:15047184, PubMed:20036328, PubMed:10622721, PubMed:11165022, PubMed:10998348, PubMed:19010934). Catalyzes the transformation of the potent androgen dihydrotestosterone (DHT) into the less active form, 5-alpha-androstan-3-alpha,17-beta-diol (3-alpha-diol) (PubMed:10998348, PubMed:14672942, PubMed:11165022, PubMed:7650035, PubMed:9415401, PubMed:10557352). Displays also retinaldehyde reductase activity toward 9-cis-retinal (PubMed:21851338). (updated: Feb. 10, 2021)

Protein identification was indicated in the following studies:

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

Publication	Identification ¹	Uniprot mapping ²	Not mapped / Obsolete	TrEMBL	Swiss-Prot
Goodman (2013)	2289 (gene list)	2278	53	20599	2269
Lange (2014)	1234	1234	7	28	1224
Hegedus (2015)	2638	2622	0	235	2387
Wilson (2016)	1658	1528	170	291	1068
d'Alessandro (2017)	1826	1817	2	0	1815
Bryk (2017)	2090	2060	10	108	1942
Chu (2018)	1853	1804	55	362	1387

¹ as available in the article and/or in supplementary material
² uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

Protein sequence (FASTA)

Protein coevolution profile (FreeContact)

Multiple Sequence Alignment (Muscle)

Total structural coverage: 100%

Model score: 100

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Variant	Description
	dbSNP:rs12529
	dbSNP:rs35961894
	dbSNP:rs11551177
	dbSNP:rs35575889
	No effect on 17beta-HSD activity
	dbSNP:rs34186955

No binding partner found

Biological Process

Arachidonic acid metabolic process

C21-steroid hormone metabolic process

Cellular response to cadmium ion

Cellular response to calcium ion

Cellular response to corticosteroid stimulus

Cellular response to jasmonic acid stimulus

Cellular response to prostaglandin D stimulus

Cellular response to prostaglandin stimulus

Cellular response to reactive oxygen species

Cellular response to starvation

Cyclooxygenase pathway

Daunorubicin metabolic process

Doxorubicin metabolic process

Farnesol catabolic process

G protein-coupled receptor signaling pathway

Keratinocyte differentiation

Macromolecule metabolic process

Male gonad development

Multicellular organismal macromolecule metabolic process

Negative regulation of retinoic acid biosynthetic process

Obsolete protein import into nucleus, translocation

Oxidation-reduction process

Phototransduction, visible light

Positive regulation of cell death

Positive regulation of cell population proliferation

Positive regulation of endothelial cell apoptotic process

Positive regulation of protein kinase B signaling

Positive regulation of reactive oxygen species metabolic process

Progesterone metabolic process

Prostaglandin metabolic process

Regulation of retinoic acid receptor signaling pathway

Regulation of testosterone biosynthetic process

Renal absorption

Response to nutrient

Retinal metabolic process

Retinoid metabolic process

Retinol metabolic process

Small molecule metabolic process

Steroid metabolic process

Testosterone biosynthetic process

Cellular Component

Cytoplasm

Cytosol

Extracellular exosome

Intracellular anatomical structure

Nucleus

Molecular Function

15-hydroxyprostaglandin-D dehydrogenase (NADP+) activity

17-beta-hydroxysteroid dehydrogenase (NAD+) activity

17-beta-hydroxysteroid dehydrogenase (NADP+) activity

5alpha-androstane-3beta,17beta-diol dehydrogenase activity

Alcohol dehydrogenase (NADP+) activity

Alditol:NADP+ 1-oxidoreductase activity

Aldo-keto reductase (NADP) activity

Androstan-3-alpha,17-beta-diol dehydrogenase activity

Androsterone dehydrogenase activity

Bile acid binding

D-threo-aldose 1-dehydrogenase activity

Delta4-3-oxosteroid 5beta-reductase activity

Dihydrotestosterone 17-beta-dehydrogenase activity

Geranylgeranyl reductase activity

Indanol dehydrogenase activity

Ketoreductase activity

Ketosteroid monooxygenase activity

NAD-retinol dehydrogenase activity

NADP-retinol dehydrogenase activity

Oxidoreductase activity

Oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor

Phenanthrene 9,10-monooxygenase activity

Prostaglandin D2 11-ketoreductase activity

Prostaglandin H2 endoperoxidase reductase activity

Prostaglandin-F synthase activity

Retinal dehydrogenase activity

Steroid binding

Steroid dehydrogenase activity

Testosterone 17-beta-dehydrogenase (NADP+) activity

Testosterone dehydrogenase (NAD+) activity

Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase activity

The reference OMIM entry for this protein is 603966

Aldo-keto reductase family 1, member c3; akr1c3
Aldo-keto reductase b; hakrb
Dihydrodiol dehydrogenase 3; dd3
3-@alpha-hydroxysteroid dehydrogenase, type ii
17-@beta-hydroxysteroid dehydrogenase v; hsd17b5

CLONING

The aldo-keto reductase family includes 3-alpha-hydroxysteroid dehydrogenase (3-alpha-HSD) as well as dihydrodiol dehydrogenase (AKR1C3) and human chlordecone reductase (CHDR, or AKR1C4; 600451). Aldo-keto reductases catalyze the conversion of aldehydes and ketones to alcohols by utilizing NADH and/or NADPH as a cofactor. 3-Alpha-HSD is a versatile aldo-keto reductase, able to utilize a large array of substrates. By screening a human liver expression library with an antibody against rat 3-alpha-HSD, Qin et al. (1993) isolated cDNAs encoding 4 distinct human aldo-keto reductases: HAKRa (AKR1C4), HAKRb, HAKRc (AKR1C1; 600449), and HAKRd (AKR1C2; 600450). The predicted 323-amino acid HAKR proteins share more than 85% identity. Northern blot analysis revealed that HAKRb is expressed as 1.4- and 1.2-kb mRNAs in several human tissues. Nagase et al. (1995) isolated KIAA0119, an HAKRb cDNA, from a human immature myeloid cell line. Mills et al. (1998) isolated an identical cDNA, which they designated HAKRe.

GENE FUNCTION

Khanna et al. (1995) reported that recombinant type I (AKR1C4) and type II (AKR1C3) human 3-alpha-HSD proteins exhibited both reductase and dehydrogenase activities.

GENE STRUCTURE

By sequence analysis, Khanna et al. (1995) demonstrated that the AKR1C3 and AKR1C4 genes contain 9 exons and span 15 to 20 kb. The sizes and boundaries of the exons are identical in both genes.

MAPPING

By analysis of somatic cell hybrids, Nagase et al. (1995) mapped the KIAA0119 gene to chromosome 10. Khanna et al. (1995) isolated 2 genes encoding dihydrodiol dehydrogenase, referred to as type I or DDH1, and type II or DDH2, as well as 1 gene for chlordecone reductase. However, sequence analysis revealed that the type I gene of Khanna et al. (1995) corresponded to either AKR1C1 or AKR1C2, the type II gene corresponded to AKR1C3, and the CHDR gene corresponded to AKR1C4 (White, 1999). By a combination of somatic cell hybrid analysis and fluorescence in situ hybridization, Khanna et al. (1995) mapped all 3 genes to 10p15-p14.

MOLECULAR GENETICS

Qin et al. (2006) identified a functional polymorphism in the promoter region of the HSD17B5 gene (-71G) that may contribute to testosterone excess in a subset of patients with polycystic ovary syndrome (see 184700). ... More on the omim web site

Subscribe to this protein entry history

Feb. 16, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

March 25, 2017: Additional information
No protein expression data in P. Mayeux work for AKR1C3

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 603966 was added.

Jan. 27, 2016: Protein entry updated
Automatic update: model status changed

Jan. 24, 2016: Protein entry updated
Automatic update: model status changed

Aldo-keto reductase family 1 member C3 (AKR1C3)