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

17β-Hydroxysteroid dehydrogenase type 4 (17β-HSD4) is the most unusual among human 17β-HSDs. It is characterized by a multidomain structure, in which the dehydrogenase domain is fused to a hydratase and a lipid transfer domain. 17β-HSD4 not only inactivates estradiol by conversion to estrone but its three protein domains also participate in successive steps of peroxisomal β-oxidation of long- and branched-chain fatty acids. We have compared the genomic structure of human 17β-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 17β-HSD4 is still its involvement in fatty-acid metabolism, while steroid conversion is only a secondary and possibly minor activity in vivo. Copyright © 2001 Elsevier Science Ireland Ltd.