Evolutionary analysis of 11beta-hydroxysteroid dehydrogenase-type 1, -type 2, -type 3 and 17beta-hydroxysteroid...

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