Author/Editor		Penning, TM; Jin, Y; Steckelbroeck, S; Lanišnik-Rižner, T; Lewis, M
Title		Structure-function of human 3alpha-hydroxysteroid dehydrogenases: genes and proteins
Type		članek
Source		Mol Cell Endocrinol
Vol. and No.		Letnik 215
Publication year		2004
Volume		str. 63-72
Language		eng
Abstract		Four soluble human 3alpha-hydroxysteroid dehydrogenase (HSD) isoforms exist which are aldo-keto reductase (AKR) superfamily members. They share 86% sequence identity and correspond to: AKR1C1 (20alpha(3alpha)-HSD); AKR1C2 (type 3 3alpha-HSD and bile-acid binding protein); AKR1C3 (type 2 3alpha-HSD and type 5 17beta-HSD); and AKR1C4 (type 1 3alpha-HSD). Each of the homogeneous recombinant enzymes are plastic and display 3-, 17- and 20-ketosteroid reductase and 3alpha- 17beta- and 20alpha-hydroxysteroid oxidase activities with different kcat/Km 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 (beta-face of steroid inverted) relative to the position of 3-ketosteroids in the related rat liver 3alpha-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.
Descriptors		3-HYDROXYSTEROID DEHYDROGENASES STRUCTURE-ACTIVITY RELATIONSHIP ISOMERISM RECOMBINANT PROTEINS TRANSFECTION GENES POLYMERASE CHAIN REACTION RECEPTORS, ANDROGEN RECEPTORS, ESTROGEN RECEPTORS, PROGESTERONE