title: Identification of a first enzymatic activator of a 17β-hydroxysteroid dehydrogenase.
abstract: Small molecule activators that directly modulate the activity of an enzyme are uncommon entities, and such activators had never yet been identified for any 17β-hydroxysteroid dehydrogenase (17β-HSD). We hereby report the fortuitous discovery of a steroid derivative that caused an up to 3-fold increase in the activity of 17β-HSD12. The stimulation of estrone to estradiol conversion has been characterized in intact and homogenized stably transfected HEK-293 cells and has also been observed in T47D breast cancer cells. Structure-activity relationships closely linked to the nature of the substituent on the [1,3]oxazinan-2-one ring of an estradiol derivative emerged from this study and may help in the identification of a previously unsuspected endogenous activation of 17β-HSD12. This activator will therefore be a useful tool to study this relatively unknown enzyme as well as the possible activation of other 17β-HSD family members.
authors.affiliation: Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec (CHUL, T4), and Faculty of Medicine, Laval University , Québec, Québec G1V 4G2, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Trottier
authors.forename: René
authors.initials: R
authors.lastname: Maltais
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002474:Cell-Free System; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans
chemical_list: D020536:Enzyme Activators; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase