Evolution of 17b-HSD type 4, a multifunctional protein of b-oxidation

17b-Hydroxysteroid dehydrogenase type 4 (17b-HSD4) is the most unusual among human 17b-HSDs. It is characterized by a multidomain structure, in which the dehydrogenase domain is fused to a hydratase and a lipid transfer domain. 17b-HSD4 not only inactivates estradiol by conversion to estrone but its three protein domains also participate in successive steps of peroxisomal b-oxidation of longand branched-chain fatty acids. We have compared the genomic structure of human 17b-HSD4 and several homologous genes from lower animals and fungi. Our data suggest an evolutionary scenario for the three protein domains and indicate a highly dynamic history of the enzyme but also a very high conservation of multifunctionality. This suggests that the main function of human 17b-HSD4 is still its involvement in fatty-acid metabolism, while steroid conversion is only a secondary and possibly minor activity in vivo. © 2001 Elsevier Science Ireland Ltd. All rights reserved.