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Characterization of Type 12 17ß-Hydroxysteroid Dehydrogenase, an Isoform of Type 3 17ß-Hydroxysteroid Dehydrogenase Responsible for Estradiol Formation in Women

Oncology and Molecular Endocrinology Research Center, Laval University Medical Center (CHUL) and Laval University, Quebec, Canada G1V 4G2

Address all correspondence and requests for reprints to: Professor Van Luu-The, Oncology and Molecular Endocrinology Research Center, Laval University Medical Center (Centre Hospitalier Universitaire Laval), 2705 Laurier Boulevard, Quebec, Quebec, Canada G1V 4G2.

A novel 17ß-hydroxysteroid dehydrogenase (17ß-HSD) chronologically named type 12 17ß-HSD (17ß-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17ß-HSD (17ß-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 17ß-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 17ß-HSD3, the enzyme involved in the biosynthesis of the androgen testosterone in the testis. Using real-time PCR to quantify mRNA in a series of human tissues, the expression levels of 17ß-HSD12 as well as two other enzymes that perform the same transformation of E1 into E2, namely type 1 17ß-HSD and type 7 17ß-HSD, it was found that 17ß-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 17ß-HSD3 and 17ß-HSD12, we have performed tridimensional structure modelization using the coordinates of type 1 17ß-HSD and site-directed mutagenesis. The results show the potential role of bulky amino acid F234 in 17ß-HSD12 that blocks the entrance of androstenedione. Overall, our results strongly suggest that 17ß-HSD12 is the major estrogenic 17ß-HSD responsible for the conversion of E1 to E2 in women, especially in the ovary, the predominant source of estrogens before menopause.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ

Ligands:   17β-Estradiol  |  Dihydrotestosterone

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