FUNCTIONS OF 17ß-HYDROXYSTEROID DEHYDROGENASE TYPE 4

Gabriele Möller¹, Frauke Leenders², Monika Markus³, Bettina Husen⁴, Yvan de Launoit⁵, Jerzy Adamski1

¹GSF Research Center for Environment and Health, Institute for Mammalian Genetics, 85764 Neuherberg, ²University Clinic Charité, Institute for Pharmacology and Toxicology, Berlin, ³Medical School Hannover, Hannover, ⁴Institute for Anatomy, University of Greifswald, Greifswald, Germany, ⁵CNRS, Institut Pasteur, Lille, France, Address the correspondence to J. Adamski, email: adamski@gsf.de

Abstract

Five types of 17(beta)-hydroxysteroid dehydro-genases catalyzing the conversion of estrogens and androgens at position C17 have been identified so far. The porcine peroxisomal 17(beta)-hydroxy-steroid dehydro-genase type 4 (17ß-HSD 4) catalyzes the oxidation of estradiol with high preference over the reduction of estrone. The 17ß-HSD 4 reveals only 25% amino acid similarity with 17ß-HSD 1, 2, 3 and 5 enzymes. The highest levels of 17ß-HSD 4 mRNA transcription and specific activity are found in liver and kidney followed by ovary and testes. In porcine gonads the immunofluorescence assigned the 17ß-HSD 4 to granu-losa cells, Leydig and Sertoli cells. A 2.9 kb mRNA codes for an 80 kDa (737 amino acids) protein featuring domains which are not present in the other 17(beta)-HSDs. Although five Asn-Xaa-Ser/Thr (Xaa - unspecified amino acid) sites are found in the 80 kDa protein the enzyme is not glycosylated.The 80 kDa protein is N-terminally cleaved to a 32 kDa enzymatically active fragment. Both the 80 kDa and the N-terminal 32 kDa (amino acids 1-323) protein are the first enzymes that are able to perform the dehydro-ge-nase reaction not only with steroids at the C17 position but also with 3-hydro-xy-acyl-CoA. The central part of the 80 kDa protein (amino acids 324-596) catalyzes the 2-enoyl-acyl--CoA hydratase reaction with high efficiency. The C-terminal part of the 80 kDa protein (amino acids 597-737) facilitates the transfer of 7-dehydrocholesterol and phosphatidylcholine between membranes in vitro. The unique multidomain structure of the 80 kDa protein permits the catalysis of several reactions so far thought to be performed by complexes of different enzymes.