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Submitted on December 23, 2002
Accepted on June 16, 2003
1 GSF-National Research Center for Environment and Health, Institute of Experimental Genetics, Neuherberg, Germany; Jenapharm GmbH & Co. KG, 07745 Jena, Germany; Deutsches Primatenzentrum, 37077 Göttingen, Germany; Current address: Solvay Pharmaceuticals GmbH, 30173 Hannover, Germany; Department of Biology, San Diego State University, San Diego, CA 92182, USA
* To whom correspondence should be addressed. E-mail: adamski{at}gsf.de.
The protein encoded by the HSD17B7 gene was originally described as a PRL-receptor associated protein and as 17beta-hydroxysteroid dehydrogenase type 7. Its ability to synthesize 17beta-estradiol in vitro has been reported previously. However, we demonstrate that HSD17B7 is the orthologue of the yeast 3-ketosteroid reductase Erg27p and converts zymosterone to zymosterol in vitro, using NAPDH as cofactor. Expression of human and murine HSD17B7 in an Erg27p-deficient yeast strain complements the 3-ketosteroid reductase deficiency of the cells and restores growth on sterol-deficient medium. A fusion of HSD17B7 with green fluorescent protein is located in the endoplasmic reticulum, the site of post-squalene cholesterogenesis. Further critical evidence for a role of HSD17B7 in cholesterol metabolism is provided by the observation that its murine orthologue is a member of the same highly distinct embryonic synexpression group as hydroxymethyl-glutaryl-CoA reductase, the rate-limiting enzyme of sterol biogenesis, and is specifically expressed in tissues that are involved in the pathogenesis of congenital cholesterol-deficiency disorders. We conclude that HSD17B7 participates in post-squalene cholesterol biosynthesis, thus completing the molecular cloning of all genes of this central metabolic pathway. In its function as the 3-ketosteroid reductase of cholesterol biosynthesis HSD17B7 is a novel candidate for inborn errors of cholesterol metabolism.
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