17??-hydroxysterold dehydrogenase type 7 (17??-HSD7) is a novel estrogenic hydroxysteroid dehydrogenase from mammals. We modeled the three-dimensional structure of human 17??-HSD7, analyzed the phylogeny of 17??-HSD7 homologues and determined its expression pattern by in silico Northern blotting. Predominant expression is found not only in reproductive tissues (breast, ovary, placenta) but also in liver and developing brain, principal sites of cholesterol synthesis. The substrate binding pocket is opening towards a conserved membrane-associated helix, which is indicative for a conversion of a membrane component. 17??-HSD7 shows significant homology to a yeast 3-ketosteroid reductase (ERG27) involved in ergosterol biosynthesis. Our results lead to the conclusion that 17??-HSD7 is not only involved in estradiol production but plays another (and possibly more important) role as a 3-ketosteroid reductase in cholesterogenesis. This agrees with the striking absence of 17??-HSD7 homologues in the complete genomes of Drosophila and C. elegans which are both auxotrophic for cholesterol. Copyright ?? 2001 Elsevier Science Ireland Ltd.