11[beta]-hydroxysteroid dehydrogenase-type 2 evolved from an ancestral 17[beta]-hydroxysteroid dehydrogenase-type 2

Abstract

11[beta]-hydroxysteroid dehydrogenase type-2 (11[beta]-HSD2) regulates the local concentration of cortisol that can activate the glucocorticoid receptor and mineralocorticoid receptor, as well as the concentration of 11-keto-testosterone, the active androgen in fish. Similarly, 17[beta]-HSD2 regulates the levels of testosterone and estradiol that activate the androgen receptor and estrogen receptor, respectively. Interestingly, although human 11[beta]-HSD2 and 17[beta]-HSD2 act at different positions on different steroids, these enzymes are paralogs. Despite the physiological importance of 11[beta]-HSD2 and 17[beta]-HSD2, details of their origins and divergence from a common ancestor are not known. An opportunity to understand their evolution is presented by the recent sequencing of genomes from sea urchin, a basal deuterostome, and amphioxus, a basal chordate, and the availability of substantial sequence for acorn worm and elephant shark, which together provide a more complete dataset for analysis of the origins of 11[beta]-HSD2 and 17[beta]-HSD2. BLAST searches find an ancestral sequence of 17[beta]-HSD2 in sea urchin, acorn worm and amphioxus, while an ancestral sequence of 11[beta]-HSD2 first appears in sharks. Sequence analyses indicate that 17[beta]-HSD2 in sea urchin may have a non-enzymatic activity. Evolutionary analyses indicate that if acorn worm 17[beta]-HSD2 is catalytically active, then it metabolizes novel substrate(s).