AKR1C2

Aldo-keto reductase family 1 member C2, also known as bile acid binding protein, 3α-hydroxysteroid dehydrogenase type 3 (3α-HSD3),^[5][6] and dihydrodiol dehydrogenase type 2, is an enzyme that in humans is encoded by the AKR1C2 gene.^[7]

AKR1C2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1IHI, 1J96, 1XJB, 2HDJ, 2IPJ, 4JQ1, 4JQ2, 4JQ3, 4JQ4, 4JQA, 4JTQ, 4JTR, 4L1W, 4L1X, 4XO6, 4XO7
Identifiers
Aliases	AKR1C2, AKR1C-pseudo, BABP, DD, DD2, DDH2, HAKRD, HBAB, MCDR2, SRXY8, TDD, DD-2, DD/BABP, aldo-keto reductase family 1, member C2, aldo-keto reductase family 1 member C2
External IDs	OMIM: 600450; MGI: 1924587; HomoloGene: 134114; GeneCards: AKR1C2; OMA:AKR1C2 - orthologs
EC number	1.1.1.357
Gene location (Human) Chr. Chromosome 10 (human)[1] Band 10p15.1 Start 4,987,775 bp[1] End 5,018,031 bp[1]
Gene location (Mouse) Chr. Chromosome 13 (mouse)[2] Band 13|13 A1 Start 4,624,074 bp[2] End 4,636,540 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in islet of Langerhans right lobe of liver olfactory zone of nasal mucosa gallbladder gastrocnemius muscle Descending thoracic aorta ascending aorta muscle of thigh left coronary artery minor salivary glands Top expressed in right kidney human kidney proximal tubule morula embryo primary oocyte primary visual cortex secondary oocyte blastocyst muscle of thigh More reference expression data BioGPS n/a
Gene ontology Molecular function trans-1,2-dihydrobenzene-1,2-diol dehydrogenase activity alditol:NADP+ 1-oxidoreductase activity phenanthrene 9,10-monooxygenase activity oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor bile acid binding carboxylic acid binding oxidoreductase activity ketosteroid monooxygenase activity alcohol dehydrogenase (NADP+) activity steroid dehydrogenase activity Cellular component cytoplasm cytosol Biological process prostaglandin metabolic process G protein-coupled receptor signaling pathway cellular response to jasmonic acid stimulus steroid metabolic process positive regulation of protein kinase B signaling epithelial cell differentiation daunorubicin metabolic process doxorubicin metabolic process lipid metabolism progesterone metabolic process digestion cellular response to prostaglandin D stimulus positive regulation of cell population proliferation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1646 77337 Ensembl ENSG00000151632 ENSMUSG00000021207 UniProt P52895 Q91WR5 RefSeq (mRNA) NM_001135241 NM_001354 NM_205845 NM_001321027 NM_001393392 NM_029901 RefSeq (protein) NP_001128713 NP_001307956 NP_001345 NP_995317 NP_084177 Location (UCSC) Chr 10: 4.99 – 5.02 Mb Chr 13: 4.62 – 4.64 Mb PubMed search [3] [4]
Wikidata
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Superfamily of enzymes

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 using NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This particular enzyme, AKR1C2, binds bile acid with high affinity, and shows minimal 3α-hydroxysteroid dehydrogenase activity. The AKR1C2 gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14. Three transcript variants encoding two different isoforms have been found for this gene.^[7] The AKR1C2 enzyme catalyzes reactions at specific positions on the steroid nucleus. Specifically, AKR enzymes, including AKR1C2, act as 3α/β-HSDs, 17β-HSDs, and 20α-HSDs, catalyzing NAD(P)(H)-dependent oxidoreduction of substituents at the C3, C17, and C20 positions of the steroid nucleus.^[8][9][10]

Aldo-keto reductase activity

AKR1C2 binds bile acid with high affinity catalyzing aldo-keto reduction reaction.^[7]

Aldo-keto reductases, including AKR1C2, are NAD(P)H-linked oxidoreductases that primarily catalyze the reduction of aldehydes and ketones to primary and secondary alcohols. This reduction is dependent on NADPH.^[11][12]

In the context of bile acids, the AKR1C2 enzyme would bind to the bile acid (a type of steroid molecule) and catalyze the reduction of a carbonyl group (C=O) present in the bile acid to a hydroxy group (-OH), using NADPH as a cofactor.^[11][12] This reaction is part of the broader metabolic processes that these enzymes are involved in, which include biosynthesis, intermediary metabolism, and detoxification.^[11][12]

3α-hydroxysteroid dehydrogenase activity

The AKR1C2 enzyme is also known as 3α-hydroxysteroid dehydrogenase type 3 (3α-HSD3), meaning that the enzyme possesses 3α-hydroxysteroid dehydrogenase activity, i.e. it can hydroxylate steroids at a carbon position 3α of the steroid nucleus, attaching the hydroxy group (-OH) to carbon 3 in α stereiodirection. 3α-hydroxysteroid dehydrogenases, including AKR1C2, are NAD(P)H-linked oxidoreductases that primarily catalyze the oxidation of 3α-hydroxysteroids to their corresponding 3-ketosteroids. This oxidation is dependent on NAD+. The substrates for the 3α-HSD3 enzyme are steroids such as androgens, estrogens, and progestins, which regulate various sex functions. For example, 3α-HSD3 can catalyze the conversion of the potent androgen 5α-dihydrotestosterone (DHT) into its much less active form, 5α-androstan-3α,17β-diol (3α-diol), effectively deactivating biological action of DHT.^{[13][14][15][16]}

Isozymes of aldo-keto reductase family 1 member C

HGNC Gene Symbol	Enzyme Name Aliases[17]
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