Molecular and Cellular Endocrinology 171 (2001) 199 – 204 17-hydroxysteroid dehydrogenase type 7 — an ancient 3-ketosteroid reductase of cholesterogenesis R. Breitling, A. Krazeisen, G. Mo ¨ ller, J. Adamski * GSF -National Research Center for Enironment and Health, Institute for Experimental, Genetics, Ingolsta ¨dter Landstr. 1, 85764 Neuherberg, Germany Abstract 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. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: 17-Hydroxysteroid dehydrogenase; 3-Ketosteroid reductase; Cholesterogenesis; Steroidogenesis; Evolution; HSD17B7 www.elsevier.com/locate/mce 1. Introduction 17-hydroxysteroid dehydrogenase type 7 (17- HSD7) is a novel estrogenic hydroxysteroid dehydroge- nase. It was originally identified as a prolactin-receptor associated protein highly expressed in the ovary of pregnant rats (Duan et al., 1996) and has recently been cloned from mouse and humans (Nokelainen et al., 1998; Krazeisen et al., 1999). 17-HSD7 efficiently cata- lyzes the conversion of inactive estrone to its biologi- cally active hydroxy form estradiol (Nokelainen et al., 1998). In the mouse the enzyme is expressed not only in the luteal cells of the ovary, but also in uterus and placenta of pregnant animals (Nokelainen et al., 2000). In this way rodent 17-HSD7 seems to complement the function of the other estrogenic dehydrogenase, namely 17-HSD1, by synthesizing the increasing amounts of estradiol in the second half of pregnancy (Peltoketo et al., 1999). In humans the function of 17-HSD7 has not been determined, but the expression pattern of the enzyme indicates that it might play an additional role in non-reproductive tissues (Krazeisen et al., 1999). The human protein has been mapped to chromosome 10p11.2, close to susceptibility loci for hyperlipidemia, obesity and diabetes, and the syntenous region in the mouse contains the tumour progression locus 2 (Krazeisen et al., 1999). To determine its possible func- tionality we have investigated human 17-HSD7 using a comprehensive bioinformatics approach, including comparative phylogenetic analysis, molecular modeling and in silico Northern blotting. 2. Methods 2.1. Phylogenetic analysis Homologues of 17-HSD7 were identified by an iter- ative PSI-BLAST search (Altschul et al., 1997) of the non-redundant protein database at NCBI. To prevent biased results by the presence of short highly conserved regions, the protein sequence of human 17-HSD7 was * Corresponding author. Tel.: +49-89-31873155; fax: +49-89- 31873225. E-mail address: adamski@gsf.de (J. Adamski). 0303-7207/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII:S0303-7207(00)00416-0