Abstract
Culture materials and grains contaminated with certain isolates of Fusarium moniliforme cause equine leucoencephalomalacia, porcine pulmonary edema syndrome, and liver cancer in rats. The causative agents are thought to be a family of compounds called fumonisins, which bear considerable structural similarity to the long-chain (sphingoid) base backbones of sphingolipids. Incubation of rat hepatocytes with fumonisins inhibited incorporation of [14C]serine into the sphingosine moiety of cellular sphingolipids with an IC50 of 0.1 microM for fumonisin B1. In contrast, fumonisin B1 increased the amount of the biosynthetic intermediate sphinganine, which suggests that fumonisins inhibit the conversion of [14C]sphinganine to N-acyl-[14C]sphinganines, a step that is thought to precede introduction of the 4,5-trans double bond of sphingosine (Merrill, A.H., Jr. and Wang, E. (1986) J. Biol. Chem. 261, 3764-3769). In agreement with this mechanism, fumonisin B1 inhibited the activity of sphingosine N-acyltransferase (ceramide synthase) in rat liver microsomes with 50% inhibition at approximately 0.1 microM and reduced the conversion of [3H]sphingosine to [3H]ceramide by intact hepatocytes. As far as we are aware, this is the first discovery of a naturally occurring inhibitor of this step of sphingolipid metabolism. These findings suggest that disruption of the de novo pathway of sphingolipid biosynthesis may be a critical event in the diseases that have been associated with consumption of fumonisins.
Highlights
From the $Departmentof Biochemistry, Rollins Research Center, Emory University School of Medicine, Atlanta, Georgia 30322 and the 6Toxicolom and Mvcotoxins Research Unitl United States Department of Agriculture-Agricultural Research Service, Athens, Georgia 30613 ”
Culture materials and grains contaminated with ceisro-latedfrom extracts of F. moniliforme [9] andnaturally tain isolates of Fusarium moniliforme cause equine contaminated corn [10, 11].Fumonisin B1 has been shown to leucoencephalomalacia, porcine pulmonary edemsyan- cause equine leucoencephalomalacia [12], porcine pulmonary drome, and liver cancer in rats
Recent are thought to bea family of compounds called fumon- surveys indicate that high levels of fumonisin B1are present isins, which bear considerable structural similarity to in United States feedsassociatedwith field cases of these the long-chain(sphingoid) base backbonesof sphingolipids
Summary
We hypothefumonisin B1 inhibited the activity of sphingosine N- sized that disruption of sphingosine metabolism might be a acyltransferase (ceramide synthase) in rat limveicrro- target of fumonisins This manuscript reports that fumonisins somes with 50% inhibition a t approximately 0.1 p~ inhibit de nouo sphingolipid biosynthesis by rat liver hepatoand reduced the conversion of [3H]sphingosine to [3H] cytes and identifies an important site of inhibition as the ceramide by intact hepatocyteAss. far as we are aware,reaction catalyzed by sphingosine N-acyltransferase (ceramthis is thefirstdiscovery of a naturallyoccurring ide synthase). The abbreviations used are: 1, liter;HPLC, high performance liquid chromatography
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