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J. Biol. Chem., Vol. 281, Issue 38, 28200-28209, September 22, 2006

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The Protozoan Inositol Phosphorylceramide Synthase

A NOVEL DRUG TARGET THAT DEFINES A NEW CLASS OF SPHINGOLIPID SYNTHASE^*

Paul W. Denny¹, Hosam Shams-Eldin, Helen. P. Price^¶2, Deborah F. Smith^¶, and Ralph T. Schwarz^||

From the Centre for Infectious Diseases, Wolfson Research Institute, Durham University, Queen's Campus, Stockton-on-Tees TS17 6BH, United Kingdom, Institute for Virology, Medical Center of Hygiene and Medical Microbiology, Philipps-University Marburg, Hans-Meerwein-Strasse, 35043 Marburg, Germany, ^¶Immunology and Infection Unit, Department of Biology, University of York, Heslington, York YO10 5YW, United Kingdom, and ^||Unité de Glycobiologie Structurale et Fonctionnelle, Unité Mixte de Recherche CNRS/Université des Sciences et Technologies de Lille 8576, Institut Federatif de Recherche 118, Université des Sciences et Technologies de Lille, 59655 Villeneuve D'Ascq cedex, France

Sphingolipids are ubiquitous and essential components of eukaryotic membranes, particularly the plasma membrane. The biosynthetic pathway for the formation of these lipid species is conserved up to the formation of sphinganine. However, a divergence is apparent in the synthesis of complex sphingolipids. In animal cells, ceramide is a substrate for sphingomyelin (SM) production via the enzyme SM synthase. In contrast, fungi utilize phytoceramide in the synthesis of inositol phosphorylceramide (IPC) catalyzed by IPC synthase. Because of the absence of a mammalian equivalent, this essential enzyme represents an attractive target for anti-fungal compounds. In common with the fungi, the kinetoplastid protozoa (and higher plants) synthesize IPC rather than SM. However, orthologues of the gene believed to encode the fungal IPC synthase (AUR1) are not readily identified in the complete genome data bases of these species. By utilizing bioinformatic and functional genetic approaches, we have isolated a functional orthologue of AUR1 in the kinetoplastids, causative agents of a range of important human diseases. Expression of this gene in a mammalian cell line led to the synthesis of an IPC-like species, strongly indicating that IPC synthase activity is reconstituted. Furthermore, the gene product can be specifically inhibited by an anti-fungal-targeting IPC synthase. We propose that the kinetoplastid AUR1 functional orthologue encodes an enzyme that defines a new class of protozoan sphingolipid synthase. The identification and characterization of the protozoan IPC synthase, an enzyme with no mammalian equivalent, will raise the possibility of developing anti-protozoal drugs with minimal toxic side affects.

Received for publication, January 26, 2006 , and in revised form, June 28, 2006.

^* This work was funded by Royal Society (2005/R1) and Biotechnology and Biological Research Council (BB/D52396X/1) grants (to P. W. D.), by Wellcome Trust Grant 077503 (to D. F. S.), and by Deutsche Forschungsgemeinschaft, Bonn, Germany. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Supported by Wellcome Trust Grant 077503.

¹ To whom correspondence should be addressed: Ctr. for Infectious Diseases, Wolfson Research Inst., Durham University, Queen's Campus, Stockton-on-Tees, TS17 6BH, UK. Tel.: 44-191-334-0319; E-mail: p.w.denny{at}durham.ac.uk.

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