Evolutionary analysis of 11β-hydroxysteroid dehydrogenase-type 1, -type 2, -type 3 and 17β-hydroxysteroid dehydrogenase-type 2 in fish

AbstractSteroid dehydrogenases regulate the access of active steroids to their receptors. In particular, 11β-hydroxysteroid dehydrogenase-type 1 (11β-HSD1) and 11β-HSD2 regulate the levels of glucocorticoids, such as cortisol, and 17β-HSD1 and 17β-HSD2 regulate the levels of androgens and estrogens. Human 11β-HSD1 and 11β-HSD2 are distant homologs, with less than 25% amino acid sequence identity, as are human 17β-HSD1 and 17β-HSD2. In contrast, human 11β-HSD2 and 17β-HSD2 are close homologs, with about 43% sequence identity. Until recently, deciphering early events in the evolution of 11β-HSD2 and 17β-HSD2 was difficult because only mammalian sequences were available. The completely sequenced Takifugu, Tetraodon and medaka genomes and the almost completed zebrafish genome provide an opportunity to investigate the evolution of 11β-HSD2, 17β-HSD2, and 11β-HSD1. Unexpectedly, a search of the Takifugu, Tetraodon and medaka genomes only found an ortholog to 11β-HSD2 and none to 17β-HSD2, while the zebrafish genome contains orthologs of both enzymes. This suggests that 17β-HSD2 was lost in teleosts after the divergence of zebrafish and medaka. Also unexpectedly, searches with 11β-HSD1 only identified several fish 11β-HSD3s, as well as an ortholog in Ciona, indicating that 11β-HSD3 is the ancestor of 11β-HSD1