Closing the gap: identification of human 3-ketosteroid reductase, the last unknown enzyme of mammalian cholesterol biosynthesis.
The protein encoded by the HSD17B7 gene was originally described as a prolactin receptor-associated protein and as 17beta-hydroxysteroid dehydrogenase (HSD) type 7. Its ability to synthesize 17beta-estradiol in vitro has been reported previously. However, we demonstrate that HSD17B7 is the ortholog of the yeast 3-ketosteroid reductase Erg27p and converts zymosterone to zymosterol in vitro, using reduced nicotinamide adenine dinucleotide phosphate 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 postsqualene cholesterogenesis. Further critical evidence for a role of HSD17B7 in cholesterol metabolism is provided by the observation that its murine ortholog is a member of the same highly distinct embryonic synexpression group as hydroxymethyl-glutaryl-coenzyme A 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 postsqualene 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.
Marijanovic
Zrinka
Z
GSF-National Research Center for Environment and Health, Institute of Experimental Genetics, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
Laubner
Daniela
D
Moller
Gabriele
G
Gege
Christian
C
Husen
Bettina
B
Adamski
Jerzy
J
Breitling
Rainer
R
D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis*; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D051379:Mice / Q000196:embryology / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics; D010802:Phylogeny; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics
D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D002784:Cholesterol; D010088:Oxidoreductases; D015096:3-Hydroxysteroid Dehydrogenases; C031298:3-ketosteroid reductase; C400426:ERG27 protein, S cerevisiae