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Papers In Press, published online ahead of print November 1, 2009
J. Lipid Res., doi:10.1194/jlr.M900230-JLR200

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Journal of Lipid Research, Vol. 50, 2270-2277, November 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Sphingomyelin synthase SMS2 displays dual activity as ceramide phosphoethanolamine synthase^[S]

Philipp Ternes^1,2,*, Jos F. H. M. Brouwers, Joep van den Dikkenberg^* and Joost C. M. Holthuis^2,*

^* Membrane Enzymology, Bijvoet Center and Institute of Biomembranes, Utrecht University, 3584 CH Utrecht, The Netherlands
Biochemistry and Cell Biology, Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CM Utrecht, The Netherlands

² To whom correspondence should be addressed. e-mail: pternes{at}uni-goettingen.de (P.T.); (j.c.holthuis{at}uu.nl) (J.H)

Sphingolipids are vital components of eukaryotic membranes involved in the regulation of cell growth, death, intracellular trafficking, and the barrier function of the plasma membrane (PM). While sphingomyelin (SM) is the major sphingolipid in mammals, previous studies indicate that mammalian cells also produce the SM analog ceramide phosphoethanolamine (CPE). Little is known about the biological role of CPE or the enzyme(s) responsible for CPE biosynthesis. SM production is mediated by the SM synthases SMS1 in the Golgi and SMS2 at the PM, while a closely related enzyme, SMSr, has an unknown biochemical function. We now demonstrate that SMS family members display striking differences in substrate specificity, with SMS1 and SMSr being monofunctional enzymes with SM and CPE synthase activity, respectively, and SMS2 acting as a bifunctional enzyme with both SM and CPE synthase activity. In agreement with the PM residency of SMS2, we show that both SM and CPE synthase activities are enhanced at the surface of SMS2-overexpressing HeLa cells. Our findings reveal an unexpected diversity in substrate specificity among SMS family members that should enable the design of specific inhibitors to target the biological role of each enzyme individually.

Supplementary key words bifunctional enzyme • sphingolipid biosynthesis • ceramide homeostasis • cell growth • lipid asymmetry • cervical carcinoma HeLa cells

Abbreviations: CPE, ceramide phosphoethanolamine; ER, endoplasmic reticulum; NBD, 7-nitro-2,1,3-benzoxadiazole; NBD-Cer, 7-nitro-2,1,3-benzoxadiazole ceramide; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PM, plasma membrane; SM, sphingomyelin; TNBS, trinitrobenzenesulfonic acid; TNP, trinitrophenyl

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