Unique multifunctional HSD17B4 gene product: 17 beta-hydroxysteroid dehydrogenase 4 and D-3-hydroxyacyl-coenzyme A dehydrogenase hydratase involved in Zellweger syndrome

Six types of human 17 beta-hydrosysteroid dehyrogenases catalyzing the conv ersion of estrogens and androgens at position C17 have been identified so f ar. The peroxisomal 17 beta-hydroxysteroid dehydrogenase type 4 (17 beta-HS D ii, gene name HSD17B4) catalyzes the oxidation of estradiol with high pre ference over the reduction of estrone. The highest levels of 17 beta-HSD 4 mRNA transcription and specific activity are found in liver and kidney foll owed by ovary and testes. A 3 kb mRNA codes for an 80 kDa (737 amino acids) protein featuring domains which are not present in the other 17 beta-HSDs. The N-terminal domain of 17 beta-HSD 4 reveals only 25% amino acid similar ity with the other types of 17 beta-HSDs. The 80 kDa protein is N-terminall y cleaved to a 32kDa enzymatically artive fragment. Both the 80 kDa and the N-terminal 32 kDa (amino acids 1-323) protein are able to perform the dehy drogenase reaction not only with steroids at the C17 position but also with D-3-hydrosyacyl-coenzyme A (CoA). The enzyme is not active with L-stereois omers. The central part of the 80 kDa protein (amino acids 324-596) catalyz es the 2-enoyl-acyl-CoA hydratase reaction with high efficiency. The C-term inal part of the 80 kDa protein (amino acids 597-737) facilitates the trans fer of 7-dehydrocholesterol and phosphatidylcholine between membranes in vi tro. The HSD17B4 gene is stimulated by progesterone, and ligands of PPAR al pha (peroxisomal proliferator activated receptor alpha) such as clofibrate, and is down-regulated by phorbol esters. Mutations in the HSD17B4 lead to a fatal form of Zellweger syndrome.