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Title: Ceramide synthase inhibition causes accumulation of 1-deoxysphinganine: biosynthesis of a novel category of bioactive sphingoid bases in diverse mammalian cell linesa and mice

Author
item PARK, HYEJUNG - SCH.BIOL., GEORGIA TECH
item Zitomer, Nicholas
item Mitchell, Trevor
item Voss, Kenneth
item WANG, ELAINE - SCH.BIOL., GEORGIA TECH
item SULLARDS, CAMERON - SCH.BIOL., GEORGIA TECH
item GARNIER, ETHEL - YERKES LAB., EMORY U.
item LIEBESKIND, LANNY - CHEMISTRY, EMORY U.
item Riley, Ronald
item MERRILL, ALFRED - SCH.BIOL., GEORGIA TECH

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 12/11/2008
Publication Date: 12/11/2008
Citation: Park, H., Zitomer, N.C., Mitchell, T.R., Voss, K.A., Wang, E., Sullards, C., Garnier, E., Liebeskind, L., Riley, R.T., Merrill, A. 2008. Ceramide synthase inhibition causes accumulation of 1-deoxysphinganine: biosynthesis of a novel category of bioactive sphingoid bases in diverse mammalian cell linesa and mice. Southeastern Regional Lipd Conference. November 5 - 7, 2008. Cashiers, NC.

Interpretive Summary: Abstact - no summary required

Technical Abstract: Fumonisins (FB) are mycotoxins that inhibit ceramide synthases (CerS) and cause animal and plant disease. Inhibition of CerS results in a rapid increases in sphinganine (Sa), an intermediate of de novo sphingolipid biosynthesis, sphinganine 1-phosphate, and a previously unidentified metabolite that has been noticed in FB-treated cells in culture. Analysis of the unknown metabolite by mass spectrometry revealed that it has a molecular weight of 285 (m/z = 286.3 in positive ionization mode), which was suggestive of a sphinganine lacking the 1 or 3 hydroxyl-group. Further analysis of the compound and comparison with a synthetic standard established that the structure is 1-deoxysphinganine. The ability of FB to elevate 1-deoxysphinganine was found with a wide variety of mammalian cell lines (e.g., HepG2, HeLa, RAW264.7 and others) as well as in vivo by the finding of this compound in both livers and kidneys from mice fed diets containing purified FB1. We have developed LC-ESI MS/MS assays for free 1-deoxysphanine and the N-acyl-metabolites to facilitate studies of their biosynthesis and functions. This work by the presenting lab (HP/AM) was supported by NIH grant GM69338 (Lipid Maps). We are also grateful to Genevieve Bondy and Sarah Pruett for assistance with portions of this work.