Sphingolipid metabolism: Roles in signal transduction and disruption by fumonisins

Sphingolipids have important roles in membrane and lipoprotein structure an d in cell regulation as second messengers for growth factors, differentiati on factors, cytokines, and a growing list of agonists. Bioactive sphingolip ids are formed both by the turnover of complex sphingolipids and as interme diates of sphingolipid biosynthesis. Usually, the amounts are highly regula ted; however, by inhibiting ceramide synthase, fumonisins block the biosynt hesis of complex sphingolipids and cause sphinganine land sometimes sphingo sine) to accumulate. Where the mechanism has been studied most thoroughly, the accumulation of sphingoid bases is a primary cause of the toxicity of f umonisin B (FB). Nonetheless, the full effects of fumonisins probably invol ve many biochemical events. The elevations in sphingoid bases also affect t he amounts of other lipids, including the l-phosphates and N-acetyl derivat ives of sphinganine. Furthermore, the aminopentol backbone of FB1 (AP(1)) i s both an inhibitor and a substrate for ceramide synthase, and the resultan t N-palmitoyl-AP(1) (PAP(1)) is an even more potent inhibitor of ceramide s ynthase (presumably as a product analog). PAP(1) is 10 times more toxic tha n FB1 or API for HT-29 cells in culture, and hence may play a role in the t oxicity of nixtamalized fumonisins. All these processes-the effects of fumo nisins on sphingolipid metabolism, the pathways altered by perturbation of sphingolipid metabolism, and the complex cellular behaviors regulated by sp hingolipids-must be borne in mind when evaluating the pathologic effects of fumonisins.