A key regulator of glucocorticoid action is 11beta-hydroxysteroid dehydrogenase-type 1 (11beta-HSD1), which catalyzes the conversion of cortisone to cortisol, the biologically active glucocorticoid. 11beta-HSD1 is a paralog of 11beta-HSD3, whose physiological function remains unclear. As reported here, 11beta-HSD3 has orthologs in sea urchin, amphioxus and Ciona, while 11beta-HSD1 first appears in sharks. Thus, 11beta-HSD3 arose before the evolution of glucocorticoid signaling, suggesting different ancestral function(s) for 11beta-HSD3. Four perplexing findings arise from this evolutionary analysis: (1) 11beta-HSD1 is not present in a ray-finned fish genome, (2) zebrafish and fathead minnow contain two isoforms of 11beta-HSD3; (3) neither rat nor mouse contain 11beta-HSD3 and (4) amphioxus contains 16 11beta-HSD3 paralogs.
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