AKR1C2 explained

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

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.[3] 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.[4] [5] [6]

Aldo-keto reductase activity

AKR1C2 binds bile acid with high affinity catalyzing aldo-keto reduction reaction.[3]

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.[7] [8]

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.[7] [8] This reaction is part of the broader metabolic processes that these enzymes are involved in, which include biosynthesis, intermediary metabolism, and detoxification.[7] [8]

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.[9] [10] [11] [12]

Notes and References

  1. Human 3-alpha hydroxysteroid dehydrogenase type 3 (3α-HSD3): The V54L mutation restricting the steroid alternative binding and enhancing the 20α-HSD activity . 10.1016/j.jsbmb.2014.01.003 . 2014 . Zhang . Bo . Zhu . Dao-Wei . Hu . Xiao-Jian . Zhou . Ming . Shang . Peng . Lin . Sheng-Xiang . The Journal of Steroid Biochemistry and Molecular Biology . 141 . 135–143 . 24434280 . subscription .
  2. Steroid enzyme and receptor expression and regulations in breast tumor samples – A statistical evaluation of public data . 10.1016/j.jsbmb.2019.105494 . 2020 . Li . Tang . Zhang . Wenfa . Lin . Sheng-Xiang . The Journal of Steroid Biochemistry and Molecular Biology . 196 . 31610224 . subscription . 2024-04-08 . 2024-04-17 . https://web.archive.org/web/20240417075146/https://www.sciencedirect.com/science/article/abs/pii/S0960076019302699 . live .
  3. Web site: Entrez Gene: AKR1C2 aldo-keto reductase family 1, member C2 (dihydrodiol dehydrogenase 1; 20-alpha (3-alpha)-hydroxysteroid dehydrogenase) . National Center for Biotechnology Information, U.S. National Library of Medicine . 2019-03-29 . https://web.archive.org/web/20190329132306/https://www.ncbi.nlm.nih.gov/gene/1646 . live .
  4. Book: 10.1007/978-1-4684-3875-8_3. 978-1-4684-3875-8. 1981 . Essentials of Steroid Structure, Nomenclature, Reactions, Biosynthesis, and Measurements . Neuroendocrinology of Reproduction . 19–63 . Feder HH .
  5. 10.1210/er.2018-00089. 20 August 2018 . Structural and Functional Biology of Aldo-Keto Reductase Steroid-Transforming Enzymes . Endocrine Reviews . 40 . 2 . 447–475 . 30137266 . 6405412 . Penning TM, Wangtrakuldee P, Auchus RJ .
  6. Zhou Y, Lin Y, Li W, Liu Q, Gong H, Li Y, Luo D . Expression of AKRs superfamily and prognostic in human gastric cancer . Medicine (Baltimore) . 102 . 8 . e33041 . February 2023 . 36827074 . 10.1097/MD.0000000000033041 . free . 11309706 .
  7. Zeng CM, Chang LL, Ying MD, Cao J, He QJ, Zhu H, Yang B . Aldo-Keto Reductase AKR1C1-AKR1C4: Functions, Regulation, and Intervention for Anti-cancer Therapy . Front Pharmacol . 8 . 119 . 14 March 2017 . 28352233 . 5349110 . 10.3389/fphar.2017.00119 . free .
  8. Chen WD, Zhang Y . Regulation of aldo-keto reductases in human diseases . Front Pharmacol . 3 . 35 . 9 March 2012 . 22408622 . 3297832 . 10.3389/fphar.2012.00035. free .
  9. 10.1210/en.2002-0032. free. 1 July 2003. Human Type 3 3α-Hydroxysteroid Dehydrogenase (Aldo-Keto Reductase 1C2) and Androgen Metabolism in Prostate Cells. Endocrinology . 144 . 7 . 2922–2932 . Rižner TL, Lin HK, Peehl DM, Steckelbroeck S, Bauman DR, Penning TM . 12810547 .
  10. 10.1186/1471-2407-4-27 . free . Expression of progesterone metabolizing enzyme genes (AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2) is altered in human breast carcinoma . 2004 . BMC Cancer . 4 . 27 . 15212687 . 459223 . Lewis MJ, Wiebe JP, Heathcote JG .
  11. Web site: Human type 3 3alpha-hydroxysteroid dehydrogenase (Aldo-keto reductase 1C2) and androgen metabolism in prostate cells. | DrugBank Online . 2024-04-17 . 2024-04-17 . https://web.archive.org/web/20240417075132/https://go.drugbank.com/articles/A10070 . live .
  12. 10.1210/jcem.86.2.7216. free. 1 February 2001. Human Types 1 and 3 3α-Hydroxysteroid Dehydrogenases: Differential Lability and Tissue Distribution1. The Journal of Clinical Endocrinology & Metabolism . 86 . 2 . 841–846 . Dufort I, Labrie F, Luu-The V . 11158055 .

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