Structure and function of 17beta-hydroxysteroid dehydrogenase type 1 and type 2.
17beta-Hydroxysteroid dehydrogenases (17HSDs) catalyze the interconversions between high-activity 17beta-hydroxysteroids and low-activity 17-ketosteroids. Several distinct 17HSD isoenzymes have been characterized. They have unique tissue distribution patterns suggesting a specific function for each of the isoenzymes in modifying sex steroid hormone activity. The activities of 17HSDs are essential for gonadal sex steroid biosynthesis and they are also involved in the modulation of steroid hormone action in peripheral tissues. 17HSD type 1 (17HSD1) is needed for estradiol biosynthesis in ovarian granulosa cells and it is also expressed in breast tissue, thus increasing locally estradiol concentration. 17HSD type 2 (17HSD2) is another 17HSD enzyme involved in estrogen metabolism. The type 2 enzyme has an opposite activity catalyzing estradiol to estrone, thereby reducing the exposure of tissues to estrogen action. Preliminary data suggest that 17HSD2 may predominate in human non-malignant breast epithelial cells, while 17HSD type 1 activity prevails in malignant cells. Determination of the three-dimensional structure of human 17HSD1 has led to an atomic level description of the estradiol binding pocket of the enzyme and an understanding of its mechanism of action, and the molecular basis for the estrogen-specificity of the enzyme. Deprivation of an estrogen response by using specific 17HSD1 inhibitors is a tempting approach to treat estrogen-dependent breast cancer.
Vihko
P
P
Biocentre Oulu and WHO Collaborating Centre for Research on Reproductive Health, University of Oulu, P.O. Box 5000, FIN-90014, Oulu, Finland. pvihko@whoccr.oulu.fi
Isomaa
V
V
Ghosh
D
D
D015067:17-Hydroxysteroid Dehydrogenases / Q000737:chemistry* / Q000502:physiology*; D001665:Binding Sites; D001940:Breast / Q000201:enzymology; D001943:Breast Neoplasms / Q000517:prevention & control; D004847:Epithelial Cells / Q000201:enzymology; D004958:Estradiol / Q000096:biosynthesis; D005260:Female; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry* / Q000502:physiology*; D008297:Male; D009928:Organ Specificity; D010053:Ovary / Q000201:enzymology
D012739:Gonadal Steroid Hormones; D007527:Isoenzymes; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases