Biology:AKR1C2
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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]
Isozymes of aldo-keto reductase family 1 member C
References
- ↑ Zhang, Bo; Zhu, Dao-Wei; Hu, Xiao-Jian; Zhou, Ming; Shang, Peng; Lin, Sheng-Xiang (2014). "Human 3-alpha hydroxysteroid dehydrogenase type 3 (3α-HSD3): The V54L mutation restricting the steroid alternative binding and enhancing the 20α-HSD activity". The Journal of Steroid Biochemistry and Molecular Biology 141: 135–143. doi:10.1016/j.jsbmb.2014.01.003. PMID 24434280. https://www.sciencedirect.com/science/article/pii/S0960076014000065.
- ↑ Li, Tang; Zhang, Wenfa; Lin, Sheng-Xiang (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. doi:10.1016/j.jsbmb.2019.105494. PMID 31610224. https://www.sciencedirect.com/science/article/pii/S0960076019302699. Retrieved 2024-04-08.
- ↑ 3.0 3.1 3.2 "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. https://www.ncbi.nlm.nih.gov/gene/1646.
This article incorporates text from this source, which is in the public domain.
- ↑ "Essentials of Steroid Structure, Nomenclature, Reactions, Biosynthesis, and Measurements". Neuroendocrinology of Reproduction. 1981. pp. 19–63. doi:10.1007/978-1-4684-3875-8_3. ISBN 978-1-4684-3875-8.
- ↑ "Structural and Functional Biology of Aldo-Keto Reductase Steroid-Transforming Enzymes". Endocrine Reviews 40 (2): 447–475. 20 August 2018. doi:10.1210/er.2018-00089. PMID 30137266.
- ↑ "Expression of AKRs superfamily and prognostic in human gastric cancer". Medicine (Baltimore) 102 (8). February 2023. doi:10.1097/MD.0000000000033041. PMID 36827074.
- ↑ 7.0 7.1 7.2 "Aldo-Keto Reductase AKR1C1-AKR1C4: Functions, Regulation, and Intervention for Anti-cancer Therapy". Front Pharmacol 8: 119. 14 March 2017. doi:10.3389/fphar.2017.00119. PMID 28352233.
- ↑ 8.0 8.1 8.2 "Regulation of aldo-keto reductases in human diseases". Front Pharmacol 3: 35. 9 March 2012. doi:10.3389/fphar.2012.00035. PMID 22408622.
- ↑ "Human Type 3 3α-Hydroxysteroid Dehydrogenase (Aldo-Keto Reductase 1C2) and Androgen Metabolism in Prostate Cells". Endocrinology 144 (7): 2922–2932. 1 July 2003. doi:10.1210/en.2002-0032. PMID 12810547.
- ↑ "Expression of progesterone metabolizing enzyme genes (AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2) is altered in human breast carcinoma". BMC Cancer 4. 2004. doi:10.1186/1471-2407-4-27. PMID 15212687.
- ↑ "Human type 3 3alpha-hydroxysteroid dehydrogenase (Aldo-keto reductase 1C2) and androgen metabolism in prostate cells. | DrugBank Online". https://go.drugbank.com/articles/A10070.
- ↑ "Human Types 1 and 3 3α-Hydroxysteroid Dehydrogenases: Differential Lability and Tissue Distribution1". The Journal of Clinical Endocrinology & Metabolism 86 (2): 841–846. 1 February 2001. doi:10.1210/jcem.86.2.7216. PMID 11158055.
External links
- Human AKR1C2 genome location and AKR1C2 gene details page in the UCSC Genome Browser.
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