This Article Full Text Full Text (PDF) Supporting Figures All Versions of this Article: 17/9/1715    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marijanovic, Z. Articles by Breitling, R. Search for Related Content PubMed PubMed Citation Articles by Marijanovic, Z. Articles by Breitling, R.

Closing the Gap: Identification of Human 3-Ketosteroid Reductase, the Last Unknown Enzyme of Mammalian Cholesterol Biosynthesis

GSF-National Research Center for Environment and Health, Institute of Experimental Genetics (Z.M., D.L., G.M., J.A.), 85764 Neuherberg, Germany; Jenapharm GmbH & Co. KG (C.G.), 07745 Jena, Germany; Deutsches Primatenzentrum (B.H.), 37077 Göttingen, Germany; and Department of Biology (R.B.), San Diego State University, San Diego, California 92182

Address all correspondence and requests for reprints to: Jerzy Adamski, GSF-National Research Center for Environment and Health, Institute of Experimental Genetics, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany. E-mail: adamski{at}gsf.de.

The protein encoded by the HSD17B7 gene was originally described as a prolactin receptor-associated protein and as 17ß-hydroxysteroid dehydrogenase (HSD) type 7. Its ability to synthesize 17ß-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.

This article has been cited by other articles:

				P.-G. Blanchard and V. Luu-The Differential androgen and estrogen substrates specificity in the mouse and primates type 12 17{beta}-hydroxysteroid dehydrogenase J. Endocrinol., August 1, 2007; 194(2): 449 - 455. [Abstract] [Full Text] [PDF]

				N. Zelcer, N. Khanlou, R. Clare, Q. Jiang, E. G. Reed-Geaghan, G. E. Landreth, H. V. Vinters, and P. Tontonoz Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors PNAS, June 19, 2007; 104(25): 10601 - 10606. [Abstract] [Full Text] [PDF]

				T. Ohnesorg, B. Keller, M. H. de Angelis, and J. Adamski Transcriptional regulation of human and murine 17{beta}-hydroxysteroid dehydrogenase type-7 confers its participation in cholesterol biosynthesis. J. Mol. Endocrinol., August 1, 2006; 37(1): 185 - 197. [Abstract] [Full Text] [PDF]

				V. Luu-The, P. Tremblay, and F. Labrie Characterization of Type 12 17{beta}-Hydroxysteroid Dehydrogenase, an Isoform of Type 3 17{beta}-Hydroxysteroid Dehydrogenase Responsible for Estradiol Formation in Women Mol. Endocrinol., February 1, 2006; 20(2): 437 - 443. [Abstract] [Full Text] [PDF]

				M. Germann, C. Gallo, T. Donahue, R. Shirzadi, J. Stukey, S. Lang, C. Ruckenstuhl, S. Oliaro-Bosso, V. McDonough, F. Turnowsky, et al. Characterizing Sterol Defect Suppressors Uncovers a Novel Transcriptional Signaling Pathway Regulating Zymosterol Biosynthesis J. Biol. Chem., October 28, 2005; 280(43): 35904 - 35913. [Abstract] [Full Text] [PDF]

				D. Cunningham, D. Swartzlander, S. Liyanarachchi, R. V. Davuluri, and G. E. Herman Changes in gene expression associated with loss of function of the NSDHL sterol dehydrogenase in mouse embryonic fibroblasts J. Lipid Res., June 1, 2005; 46(6): 1150 - 1162. [Abstract] [Full Text] [PDF]

				T. E. Vaskivuo, M. Maentausta, S. Torn, O. Oduwole, A. Lonnberg, R. Herva, V. Isomaa, and J. S. Tapanainen Estrogen Receptors and Estrogen-Metabolizing Enzymes in Human Ovaries during Fetal Development J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3752 - 3756. [Abstract] [Full Text] [PDF]

				H. Caldas and G. E. Herman NSDHL, an enzyme involved in cholesterol biosynthesis, traffics through the Golgi and accumulates on ER membranes and on the surface of lipid droplets Hum. Mol. Genet., November 15, 2003; 12(22): 2981 - 2991. [Abstract] [Full Text] [PDF]