ReviewIntegrated view on 17beta-hydroxysteroid dehydrogenases
Introduction
17beta-hydroxysteroid dehydrogenases (17beta-HSDs) catalyse the interconversion between the active and inactive forms of specific steroidal hormones on the final steps of their biosynthesis. They are named according to their ability to catalyse oxidation or reduction of the 17-hydroxy or 17-keto functions of specific physiologically relevant steroids. This catalysis is co-factor (NAD(P)/NAD(P)H) dependent. Up to now, 14 types of 17beta-HSDs are reported in vertebrates of which 12 are also present in humans, while 17beta-HSD6 and 9 are only reported for rodents. With the exception of 17beta-HSD5, which is a member of the aldoketo-reductase (AKR) family, all 17beta-HSDs belong to the short chain dehydrogenase/reductase (SDR) superfamily. In vertebrates the enzymes show generally low sequence homology (15–20%) but some elements characteristic for SDR members are very similar, e.g. the Rossman fold involved in cofactor binding and several conserved motifs including the active center motif “YXXXK” (Oppermann et al., 2003). Despite this structural conservation, substrate specificities among the family members are diverse and for some 17beta-HSDs substrates such as fatty acids or bile acids are preferred over sex steroids.
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Novel functional aspects of selected 17beta-HSDs
The multifunctionality of 17beta-HSDs was already addressed in an earlier review (Moeller and Adamski, 2006). This report now will focus on latest findings on 17beta-HSD function, mostly for the enzymes with broad substrate specificity, and will mention some aspects concerning the role of 17beta-HSDs in disease.
Crystal structures of 17beta-HSDs
The first report about a 17beta-HSD crystal structure was given in 1993. Zhu and co-workers presented the crystal structure of human 17beta-HSD1 in complex with the cofactor NADP+ (Zhu et al., 1993). The refined structure of the enzyme was afterwards published in 1995 (Ghosh et al., 1995). Since then 14 more 17beta-HSD1 structures were submitted to the protein data bank (PDB), some in complex with cofactor, some with substrate or inhibitor and some in combination with substrate/inhibitor and
Animal models for 17beta-HSDs
The first mouse models for 17beta-HSDs were published in 2000, namely a knockout for 17beta-HSD4 (Baes et al., 2000) and a transgenic mouse over-expressing human 17beta-HSD10 (Du Yan et al., 2000). Since then, two more transgenic mice for human 17beta-HSD type 1 and 2 (Saloniemi et al., 2007, Zhongyi et al., 2007) were generated as well as two knockout mice for 17beta-HSD2 (Rantakari et al., 2008) and 17beta-HSD7 (Shehu et al., 2008). An overview can be found in Table 5.
The phenotype of
Polymorphisms in HSD17B genes in connection to diseases
The physiological significance of steroid hormones in diseases like for example cancer or endometriosis is well known (Kitawaki et al., 2002, Sasano et al., 2008). Therefore, in the last years, more and more efforts were made to predict susceptibility to diseases on the basis of gene variations in HSD17B genes. Up to now, we are aware of at least 35 studies dealing with the analysis of HSD17B polymorphisms in connection with cancer, polycystic ovary syndrome (PCOS), endometriosis as well as
Outlook
Although all the enzymes described here were named as 17beta-HSDs, and therewith suggested to be most important in sex steroid metabolism, we now know that many of the enzymes play more important roles in other metabolic pathways as for example in fatty acid metabolism. Therefore, 17beta-HSDs contribute to our knowledge on the metabolome, specifically the lipidome.
We are awaiting the discovery of more so-called 17beta-HSDs. Indeed, inhibitor studies against estrogenic enzymes suggest the
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