| Title: | "Porcine aldo-keto reductase 1C subfamily members AKR1C1 and AKR1C4: Substrate specificity, inhibitor sensitivity and activators" |
| Author(s): | Endo S; Morikawa Y; Matsunaga T; Hara A; Nishinaka T; |
| Address: | "Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan. Electronic address: sendo@gifu-pu.ac.jp. Forensic Science Laboratory, Gifu Prefectural Police Headquarters, Gifu 500-8501, Japan. Laboratory of Bioinformatics, Gifu Pharmaceutical University, Gifu 502-8585, Japan. Faculty of Engineering, Gifu University, Gifu 501-1193, Japan. Faculty of Pharmacy, Osaka-Ohtani University, Osaka 584-8540, Japan" |
| Journal Title: | J Steroid Biochem Mol Biol |
| DOI: | 10.1016/j.jsbmb.2022.106113 |
| ISSN/ISBN: | 1879-1220 (Electronic) 0960-0760 (Linking) |
| Abstract: | "Most members of the aldo-keto reductase (AKR) 1 C subfamily are hydroxysteroid dehydrogenases (HSDs). Similarly to humans, four genes for AKR1C proteins (AKR1C1-AKR1C4) have been identified in the pig, which is a suitable species for biomedical research model of human diseases and optimal organ donor for xenotransplantation. Previous study suggested that, among the porcine AKR1Cs, AKR1C1 and AKR1C4 play important roles in steroid hormone metabolism in the reproductive tissues; however, their biological functions are still unknown. Herein, we report the biochemical properties of the two recombinant enzymes. Kinetic and product analyses of steroid specificity indicated that AKR1C1 is a multi-specific reductase, which acts as 3alpha-HSD for 3-keto-5beta-dihydro-C(19)/C(21)-steroids, 3beta-HSD for 3-keto-5alpha-dihydro-C(19)-steroids including androstenone, 17beta-HSD for 17-keto-C(19)-steroids including estrone, and 20alpha-HSD for progesterone, showing K(m) values of 0.5-11 microM. By contrast, AKR1C4 exhibited only 3alpha-HSD activity for 3-keto groups of 5alpha/beta-dihydro-C(19)-steroids, 5beta-dihydro-C(21)-steroids and bile acids (K(m): 1.0-1.9 microM). AKR1C1 and AKR1C4 also showed broad substrate specificity for nonsteroidal carbonyl compounds including endogenous 4-oxo-2-nonenal, 4-hydroxy-nonenal, acrolein, isocaproaldehyde, farnesal, isatin and methylglyoxal, of which 4-oxo-2-nonenal was reduced with the lowest K(m) value of 0.9 microM. Moreover, AKR1C1 had the characteristic of reducing aliphatic ketones and all-trans-retinal. The enzymes were inhibited by flavonoids, synthetic estrogens, nonsteroidal anti-inflammatory drugs, triterpenoids and phenolphthalein, whereas only AKR1C4 was activated by bromosulfophthalein. These results suggest that AKR1C1 and AKR1C4 function as 3alpha/3beta/17beta/20alpha-HSD and 3alpha-HSD, respectively, in metabolism of steroid hormones and a sex pheromone androstenone, both of which also play roles in metabolism of nonsteroidal carbonyl compounds" |
| Keywords: | *20-Hydroxysteroid Dehydrogenases/metabolism 3-Hydroxysteroid Dehydrogenases/metabolism Aldo-Keto Reductases/genetics/metabolism Animals Estrone *Hydroxysteroid Dehydrogenases/metabolism Progesterone/metabolism Substrate Specificity Swine Aldo-keto reduct; |
| Notes: | "MedlineEndo, Satoshi Morikawa, Yoshifumi Matsunaga, Toshiyuki Hara, Akira Nishinaka, Toru eng England 2022/04/11 J Steroid Biochem Mol Biol. 2022 Jul; 221:106113. doi: 10.1016/j.jsbmb.2022.106113. Epub 2022 Apr 6" |
