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The protozoan inositol phosphorylceramide synthase: A novel drug target that defines a new class of sphingolipid synthase

Denny, P.W.; Shams-Eldin, H.; Price, H.P.; Smith, D.F.; Schwarz, R.T.

The protozoan inositol phosphorylceramide synthase: A novel drug target that defines a new class of sphingolipid synthase Thumbnail


Authors

H. Shams-Eldin

H.P. Price

D.F. Smith

R.T. Schwarz



Abstract

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.

Citation

Denny, P., Shams-Eldin, H., Price, H., Smith, D., & Schwarz, R. (2006). The protozoan inositol phosphorylceramide synthase: A novel drug target that defines a new class of sphingolipid synthase. Journal of Biological Chemistry, 281(38), 28200-28209. https://doi.org/10.1074/jbc.m600796200

Journal Article Type Article
Publication Date Sep 1, 2006
Deposit Date May 28, 2008
Publicly Available Date Mar 29, 2024
Journal Journal of Biological Chemistry
Print ISSN 0021-9258
Electronic ISSN 1083-351X
Publisher American Society for Biochemistry and Molecular Biology
Peer Reviewed Peer Reviewed
Volume 281
Issue 38
Pages 28200-28209
DOI https://doi.org/10.1074/jbc.m600796200
Publisher URL http://www.jbc.org/cgi/content/abstract/281/38/28200

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Copyright Statement
This research was originally published in Journal of biological chemistry.
Denny, P. W. and Shams-Eldin, H. and Price, H. P. and Smith, D. F. and Schwarz, R. T. (2006) 'The protozoan inositol phosphorylceramide synthase : a novel drug target that defines a new class of sphingolipid synthase.', Journal of biological chemistry., 281 (38). pp. 28200-28209 © the American Society for Biochemistry and Molecular Biology"





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