17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1)

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is an enzyme encoded by the HSD17B1 gene that catalyzes the NADPH-dependent reduction of estrone (E1) to the more potent estrogen 17β-estradiol (E2), as well as the interconversion of androstenedione to testosterone, thereby regulating sex steroid potency in tissues like the ovary, breast, and periphery. Structurally, it features a Rossmann fold short-chain dehydrogenase domain, functions as a homodimer of 34.5 kDa subunits, and employs a catalytic triad (Ser142, Tyr155, Lys159) for proton relay in its active site. Overexpression in breast cancer cells elevates local E2 levels, promoting proliferation via estrogen receptor activation, making 17β-HSD1 a key player in estrogen-dependent malignancies. Inhibitors like EM-139 bind the steroid pocket through hydrogen bonds at key residues, blocking E2 formation, though challenges include inhibitor flexibility and family-wide off-target effects. This positions 17β-HSD1 as a therapeutic target for breast cancer, with efforts focused on selective inhibitors to deprive tumors of estrogenic stimuli without disrupting normal steroid balance.

Other names

17-beta-hydroxysteroid dehydrogenase 1HSD17B117β-HSD117-HSD1

Inhibition of E1 to E2 conversion (reductive activity), Competitive inhibition at steroid binding site via hydrogen bonds with Ser142, Tyr155, His221, Glu282