Unique multifunctional HSD17B4 gene product: 17beta-hydroxysteroid dehydrogenase 4 and D-3-hydroxyacyl-coenzyme A dehydrogenase/hydratase involved in Zellweger syndrome.
Six types of human 17beta-hydroxysteroid dehydrogenases catalyzing the conversion of estrogens and androgens at position C17 have been identified so far. The peroxisomal 17beta-hydroxysteroid dehydrogenase type 4 (17beta-HSD 4, gene name HSD17B4) catalyzes the oxidation of estradiol with high preference over the reduction of estrone. The highest levels of 17beta-HSD 4 mRNA transcription and specific activity are found in liver and kidney followed 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 17beta-HSDs. The N-terminal domain of 17beta-HSD 4 reveals only 25% amino acid similarity with the other types of 17beta-HSDs. 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 able to perform the dehydrogenase reaction not only with steroids at the C17 position but also with D-3-hydroxyacyl-coenzyme A (CoA). The enzyme is not active with L-stereoisomers. 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 HSD17B4 gene is stimulated by progesterone, and ligands of PPARalpha (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.
de Launoit
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Y
Virology Unit, Faculty of Medicine, CP 614, Free University Brussels, 808 route de Lennik, 1070 Brussels, Belgium.
Adamski
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J
D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D004746:Enoyl-CoA Hydratase / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006836:Hydro-Lyases; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes; D009154:Mutation; D064029:Peroxisomal Multifunctional Protein-2; D017386:Sequence Homology, Amino Acid; D013347:Subcellular Fractions / Q000201:enzymology; D013552:Swine; D015211:Zellweger Syndrome / Q000201:enzymology*
D009097:Multienzyme Complexes; D015067:17-Hydroxysteroid Dehydrogenases; D015094:3-Hydroxyacyl CoA Dehydrogenases; D006836:Hydro-Lyases; D064029:Peroxisomal Multifunctional Protein-2; C104587:HSD17B4 protein, human; D004746:Enoyl-CoA Hydratase