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Publication Abstract from PubMed

Steroids are implicated in many physiological processes, such as reproduction, aging, metabolism, and cancer. To understand the molecular basis for steroid recognition and discrimination, we studied the human estrogenic 17beta-hydroxysteroid dehydrogenase (17beta-HSD1) responsible for the last step in the bioactivation of all estrogens. Here we report the first observation of the conversion of dihydrotestosterone (DHT) into 3beta,17beta-androstanediol (3beta-diol) by 17beta-HSD1, an estrogenic enzyme studied for more than half a century. Kinetic observations demonstrate that both the 3beta-reduction of DHT into 3beta-diol (kcat = 0.040 s(-1)1; Km = 32 +/- 9 microM) and the 17beta-oxidation of DHT into androstandione (A-dione) (kcat = 0.19 s(-1); Km = 26 +/-6 microM) are catalyzed by 17beta-HSD1 via alternative binding orientation of the steroid. The reduction of DHT was also observed in intact cells by using HEK-293 cells stably transformed with 17beta-HSD1. The high-resolution structure of a 17beta-HSD1-C19-steroid (testosterone) complex solved at 1.54 A demonstrates that the steroid is reversibly oriented in the active site, which strongly supports the existence of alternative binding mode. Such a phenomenon can be explained by the pseudo-symmetric structure of C19-steroids. Our results confirm the role of the Leu149 residue in C18/C19-steroid discrimination and suggest a possible mechanism of 17beta-HSD1 in the modulation of DHT levels in tissues, such as the breast, where both the enzyme and DHT are present.

Pseudo-symmetry of C19 steroids, alternative binding orientations, and multispecificity in human estrogenic 17beta-hydroxysteroid dehydrogenase.,Gangloff A, Shi R, Nahoum V, Lin SX FASEB J. 2003 Feb;17(2):274-6. Epub 2002 Dec 17. PMID:12490543^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.