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J. Biol. Chem., Vol. 280, Issue 40, 33735-33738, October 7, 2005

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LASS5 Is a Bona Fide Dihydroceramide Synthase That Selectively Utilizes Palmitoyl-CoA as Acyl Donor^*

From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel

We demonstrated recently (Riebeling, C., Allegood, J.C., Wang, E., Merrill, A. H. Jr., and Futerman, A. H. (2003) J. Biol. Chem. 278, 43452–43459) that upon over-expression in human embryonic kidney cells, longevity assurance gene homolog 5 (LASS5, previously named TRH4) elevates the synthesis of (dihydro)ceramides selectively enriched in palmitic acid. To determine whether LASS5 is a bona fide dihydroceramide synthase or, alternatively, whether it modifies an endogenous dihydroceramide synthase, we over-expressed LASS5 with a hemagglutinin (HA) tag at the C terminus, solubilized it using digitonin, and purified it by immunoprecipitation. Solubilized LASS5-HA displays the same fatty acid selectivity as the membrane-bound enzyme. After elution from agarose beads, only one band could be detected by SDS-PAGE, and its identity was confirmed to be LASS5 by mass spectrometry. Dihydroceramide synthase activity of the eluted LASS5-HA protein was totally dependent on exogenously added phospholipids. Moreover, eluted LASS5-HA was highly selective toward palmitoyl-CoA as acyl donor and was inhibited by the (dihydro)ceramide synthase inhibitor, fumonisin B1. This study identifies LASS5 as a genuine dihydroceramide synthase and demonstrates that mammalian dihydroceramide synthases do not require additional subunits for their activity.

Received for publication, June 14, 2005

^* This work was supported by Israel Science Foundation Grant 1047/03. 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.

¹ Joseph Meyerhoff Professor of Biochemistry. To whom correspondence should be addressed: Dept. of Biological Chemistry, Weizmann Inst. of Science, Rehovot 76100, Israel. Tel.: 972-8-9342704; Fax: 972-8-9344112; E-mail: tony.futerman{at}weizmann.ac.il.

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