| Author/Editor | Cassetta, Alberto; Stojan, Jure; Krastanova, Ivet; Kristan, Katja; Brunskole Švegelj, Mojca; Lamba, Doriano; Lanišnik-Rižner, Tea | |
| Title | Structural basis for inhibition of 17[beta]-hydroxysteroid dehydrogenases by phytoestrogens | |
| Type | članek | |
| Vol. and No. | , št. Vol. | |
| Publication year | 2017 | |
| Volume | str. str. | |
| ISSN | 0960-0760 - The Journal of steroid biochemistry and molecular biology | |
| Language | eng | |
| Abstract | Phytoestrogens are plant-derived compounds that functionally and structurally mimic mammalian estrogens. Phytoestrogens have broad inhibitory activities toward several steroidogenic enzymes, such as the 17[beta]-hydroxysteroid dehydrogenases (17[beta]-HSDs), which modulate the biological potency of androgens and estrogens in mammals. However, to date, no crystallographic data are available to explain phytoestrogens binding to mammalian 17[beta]-HSDs. NADP(H)-dependent 17[beta]-HSD from the filamentous fungus Cochliobolus lunatus (17[beta]-HSDcl) has been the subject of extensive biochemical, kinetic and quantitative structure-activity relationship studies that have shown that the flavonols are the most potent inhibitors. In the present study, we investigated the structure-activity relationships of the ternary complexes between the holo form of 17[beta]-HSDcl and the flavonols kaempferol and 3,7-dihydroxyflavone, in comparison with the isoflavones genistein and biochanin A. Crystallographic data are accompanied by kinetic analysis of the inhibition mechanisms for six flavonols (3-hydroxyflavone, 3,7-dihydroxyflavone, kaempferol, quercetin, fisetin, myricetin), one flavanone (naringenin), one flavone (luteolin), and two isoflavones (genistein, biochanin A). The kinetics analysis shows that the degree of hydroxylation of ring B significantly influences the overall inhibitory efficacy of the flavonols. A distinct binding mode defines the interactions between 17[beta]-HSDcl and the flavones and isoflavones. Moreover, the complex with biochanin A reveals an unusual binding mode that appears to account for its greater inhibition of 17[beta]-HSDcl with respect to genistein. Overall, these data provide a blueprint for identification of the distinct molecular determinants that underpin 17[beta]-HSD inhibition by phytoestrogens. | |
| Keywords | phytoestrogens flavonoids structural biology fitoestrogeni flavonoidi strukturna biologija |