Aldo-keto reductase family 1 member C2, also known as bile acid binding protein, 3α-hydroxysteroid dehydrogenase type 3 (3α-HSD3), and dihydrodiol dehydrogenase type 2, is an enzyme that in humans is encoded by the AKR1C2 gene.
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. 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.
Aldo-keto reductase activity
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.
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.
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.
Isozymes of aldo-keto reductase family 1 member C
HGNC Gene Symbol | Enzyme Name Aliases |
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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 |
References
- ^ GRCh38: Ensembl release 89: ENSG00000151632 – Ensembl, May 2017
- ^ GRCm38: Ensembl release 89: ENSMUSG00000021207 – Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- Zhang B, Zhu DW, Hu XJ, Zhou M, Shang P, Lin SX (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.
- Li T, Zhang W, Lin SX (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. Archived from the original on 2024-04-17. Retrieved 2024-04-08.
- ^ "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. Archived from the original on 2019-03-29. This article incorporates text from this source, which is in the public domain.
- Feder HH (1981). "Essentials of Steroid Structure, Nomenclature, Reactions, Biosynthesis, and Measurements". Neuroendocrinology of Reproduction. pp. 19–63. doi:10.1007/978-1-4684-3875-8_3. ISBN 978-1-4684-3875-8.
- Penning TM, Wangtrakuldee P, Auchus RJ (20 August 2018). "Structural and Functional Biology of Aldo-Keto Reductase Steroid-Transforming Enzymes". Endocrine Reviews. 40 (2): 447–475. doi:10.1210/er.2018-00089. PMC 6405412. PMID 30137266.
- Zhou Y, Lin Y, Li W, Liu Q, Gong H, Li Y, Luo D (February 2023). "Expression of AKRs superfamily and prognostic in human gastric cancer". Medicine (Baltimore). 102 (8): e33041. doi:10.1097/MD.0000000000033041. PMC 11309706. PMID 36827074.
- ^ Zeng CM, Chang LL, Ying MD, Cao J, He QJ, Zhu H, Yang B (14 March 2017). "Aldo-Keto Reductase AKR1C1-AKR1C4: Functions, Regulation, and Intervention for Anti-cancer Therapy". Front Pharmacol. 8: 119. doi:10.3389/fphar.2017.00119. PMC 5349110. PMID 28352233.
- ^ Chen WD, Zhang Y (9 March 2012). "Regulation of aldo-keto reductases in human diseases". Front Pharmacol. 3: 35. doi:10.3389/fphar.2012.00035. PMC 3297832. PMID 22408622.
- Rižner TL, Lin HK, Peehl DM, Steckelbroeck S, Bauman DR, Penning TM (1 July 2003). "Human Type 3 3α-Hydroxysteroid Dehydrogenase (Aldo-Keto Reductase 1C2) and Androgen Metabolism in Prostate Cells". Endocrinology. 144 (7): 2922–2932. doi:10.1210/en.2002-0032. PMID 12810547.
- Lewis MJ, Wiebe JP, Heathcote JG (2004). "Expression of progesterone metabolizing enzyme genes (AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2) is altered in human breast carcinoma". BMC Cancer. 4: 27. doi:10.1186/1471-2407-4-27. PMC 459223. PMID 15212687.
- "Human type 3 3alpha-hydroxysteroid dehydrogenase (Aldo-keto reductase 1C2) and androgen metabolism in prostate cells. | DrugBank Online". Archived from the original on 2024-04-17. Retrieved 2024-04-17.
- Dufort I, Labrie F, Luu-The V (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. doi:10.1210/jcem.86.2.7216. PMID 11158055.
- Dufort I, Labrie F, Luu-The V (February 2001). "Human types 1 and 3 3 alpha-hydroxysteroid dehydrogenases: differential lability and tissue distribution". J Clin Endocrinol Metab. 86 (2): 841–6. doi:10.1210/jcem.86.2.7216. PMID 11158055.
human types 1 and 3 3α-HSD, 20α-HSD, and type 5 17β-HSD were named AKR1C4, AKR1C2, AKR1C1, and AKR1C3, respectively
External links
- Human AKR1C2 genome location and AKR1C2 gene details page in the UCSC Genome Browser.
Oxidoreductases: alcohol oxidoreductases (EC 1.1) | |
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1.1.1: NAD/NADP acceptor |
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1.1.2: cytochrome acceptor | |
1.1.3: oxygen acceptor | |
1.1.4: disulfide as acceptor | |
1.1.5: quinone/similar acceptor | |
1.1.99: other acceptors |
Enzymes | |
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Activity | |
Regulation | |
Classification | |
Kinetics | |
Types |
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