AKR1C2

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. 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.{{cite book|doi=10.1007/978-1-4684-3875-8_3|isbn=978-1-4684-3875-8|year=1981 |chapter=Essentials of Steroid Structure, Nomenclature, Reactions, Biosynthesis, and Measurements |title=Neuroendocrinology of Reproduction |pages=19–63 | vauthors = Feder HH }}{{cite journal|doi=10.1210/er.2018-00089|date = 20 August 2018 | title=Structural and Functional Biology of Aldo-Keto Reductase Steroid-Transforming Enzymes | journal=Endocrine Reviews | volume=40 | issue=2 | pages=447–475 | pmid=30137266 | pmc=6405412 | vauthors = Penning TM, Wangtrakuldee P, Auchus RJ }}{{cite journal |vauthors=Zhou Y, Lin Y, Li W, Liu Q, Gong H, Li Y, Luo D |title=Expression of AKRs superfamily and prognostic in human gastric cancer |journal=Medicine (Baltimore) |volume=102 |issue=8 |pages=e33041 |date=February 2023 |pmid=36827074 |doi=10.1097/MD.0000000000033041 |doi-access=free |pmc=11309706 }}

AKR1C2 binds bile acid with high affinity catalyzing aldo-keto reduction reaction.

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.{{cite journal |vauthors=Zeng CM, Chang LL, Ying MD, Cao J, He QJ, Zhu H, Yang B |title=Aldo-Keto Reductase AKR1C1-AKR1C4: Functions, Regulation, and Intervention for Anti-cancer Therapy |journal=Front Pharmacol |volume=8 |pages=119 |date=14 March 2017 |pmid=28352233 |pmc=5349110 |doi=10.3389/fphar.2017.00119 |doi-access=free }}{{cite journal |vauthors=Chen WD, Zhang Y |title=Regulation of aldo-keto reductases in human diseases |journal=Front Pharmacol |volume=3 |pages=35 |date=9 March 2012 |pmid=22408622 |pmc=3297832 |doi=10.3389/fphar.2012.00035|doi-access=free }}

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. This reaction is part of the broader metabolic processes that these enzymes are involved in, which include biosynthesis, intermediary metabolism, and detoxification.

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.{{cite journal|doi=10.1210/en.2002-0032|doi-access=free|date=1 July 2003|title=Human Type 3 3α-Hydroxysteroid Dehydrogenase (Aldo-Keto Reductase 1C2) and Androgen Metabolism in Prostate Cells|journal=Endocrinology |volume=144 |issue=7 |pages=2922–2932 | vauthors = Rižner TL, Lin HK, Peehl DM, Steckelbroeck S, Bauman DR, Penning TM |pmid=12810547 }}{{cite journal | doi=10.1186/1471-2407-4-27 | doi-access=free | title=Expression of progesterone metabolizing enzyme genes (AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2) is altered in human breast carcinoma | date=2004 | journal=BMC Cancer | volume=4 | page=27 | pmid=15212687 | pmc=459223 | vauthors = Lewis MJ, Wiebe JP, Heathcote JG }}{{cite web | url=https://go.drugbank.com/articles/A10070 | title=Human type 3 3alpha-hydroxysteroid dehydrogenase (Aldo-keto reductase 1C2) and androgen metabolism in prostate cells. | DrugBank Online | access-date=2024-04-17 | archive-date=2024-04-17 | archive-url=https://web.archive.org/web/20240417075132/https://go.drugbank.com/articles/A10070 | url-status=live }}{{cite journal|doi=10.1210/jcem.86.2.7216|doi-access=free|date=1 February 2001|title=Human Types 1 and 3 3α-Hydroxysteroid Dehydrogenases: Differential Lability and Tissue Distribution1|journal=The Journal of Clinical Endocrinology & Metabolism |volume=86 |issue=2 |pages=841–846 | vauthors = Dufort I, Labrie F, Luu-The V |pmid=11158055 }}

{{AKR1CN}}

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Category:EC 1.1.1

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