Abstract
Four soluble human 3α-hydroxysteroid dehydrogenase (HSD) isoforms exist which are aldo–keto reductase (AKR) superfamily members. They share 86% sequence identity and correspond to: AKR1C1 (20α(3α)-HSD); AKR1C2 (type 3 3α-HSD and bile-acid binding protein); AKR1C3 (type 2 3α-HSD and type 5 17β-HSD); and AKR1C4 (type 1 3α-HSD). Each of the homogeneous recombinant enzymes are plastic and display 3-, 17- and 20-ketosteroid reductase and 3α- 17β- and 20α-hydroxysteroid oxidase activities with different k cat/ K m ratios in vitro. The crystal structure of the AKR1C2·NADP +·ursodeoxycholate complex provides an explanation for this functional plasticity. Ursodeoxycholate is bound backwards (D-ring in the A-ring position) and upside down (β-face of steroid inverted) relative to the position of 3-ketosteroids in the related rat liver 3α-HSD (AKR1C9) structure. Transient transfection indicates that in COS-1 cells, AKR1C enzymes function as ketosteroid reductases due to potent inhibition of their oxidase activity by NADPH. By acting as ketosteroid reductases they may regulate the occupancy of the androgen, estrogen and progesterone receptors. RT-PCR showed that AKRs are discretely localized. AKR1C4 is virtually liver specific, while AKR1C2 and AKR1C3 are dominantly expressed in prostate and mammary gland. AKR1C genes are highly conserved in structure and may be transcriptionally regulated by steroid hormones and stress.
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