Characterization of type 12 17β-hydroxysteroid dehydrogenase, an isoform of type 3 17β-hydroxysteroid dehydrogenase responsible for estradiol formation in women

Abstract

A novel 17β-hydroxysteroid dehydrogenase (17β-HSD) chronologically named type 12 17β-HSD (17β-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17β-HSD (17β-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. Both are encoded by large genes spanning 11 exons, most of them showing identical size. Using human embryonic kidney-293 cells stably expressing 17β-HSD12, we have found that the enzyme catalyzes selectively and efficiently the transformation of E1 into E2, thus identifying its role in estrogen formation, in contrast with 17β-HSD3, the enzyme involved in the biosynthesis of the androgen testosterone in the testis. Using realtime PCR to quantify mRNA in a series of human tissues, the expression levels of 17β-HSD12 as well as two other enzymes that perform the same transformation of E1 into E2, namely type 1 17β-HSD and type 7 17β-HSD, it was found that 17β-HSD12 mRNA is the most highly expressed in the ovary and mammary gland. To obtain a better understanding of the structural basis of the difference in substrate specificity between 17β-HSD3 and 17β-HSD12, we have performed tridimensional structure modelization using the coordinates of type 1 17β-HSD and site-directed mutagenesis. The results show the potential role of bulky amino acid F234 in 17β-HSD12 that blocks the entrance of androstenedione. Overall, our results strongly suggest that 17β-HSD12 is the major estrogenic 17β-HSD responsible for the conversion of E1 to E2 in women, especially in the ovary, the predominant source of estrogens before menopause. Copyright © 2006 by The Endocrine Society.