SPHINGOLIPID METABOLISM: ROLES IN SIGNAL TRANSDUCTION AND DISRUPTION BY FUMONISINS

Authors: MERRILL, JR., A - BIOCHEM/EMORY U., ATLANTA; SULLARDS, M - BIOCHEM/EMORY U., ATLANTA; WANG, ELAINE - BIOCHEM/EMORY U., ATLANTA; Voss, Kenneth; Riley, Ronald

Submitted to: Environmental Health Perspectives
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/1/2000
Publication Date: 5/1/2001
Citation: N/A

Interpretive Summary: Fumonisins are a group of chemicals produced by the fungus Fusarium moniliforme that is found on corn wherever it is grown. The fumonisins are known to be the cause of farm animal disease and have been associated with human disease in developing countries where corn is a dietary staple. Recently the fumonisins have been shown to cause cancer in laboratory animals. In all the animal diseases, it has been found that fumonisins cause changes in the way that a unique group of fats are made and metabolized. The group of fats that are changed are called "sphingolipids". They are named after the mysterious sphinx of Greek and Egyptian mythology. They were so named because their function in cells was unknown and they were very difficult to work with. Recently, however, it has become clear that these mysterious fats play a very important role in regulating how cells behave and especially how and when cells are selected to live or die. Fumonisins change the fats by blocking a step in the pathway by which the fats are made. Blocking the step causes many changes in other fats. These other fats can signal changes to occur inside the cells at times, and under conditions, where the changes are not appropriate. When this happens the cell behaves in a way that is not correct. In some situations this can endanger other cells and can be the cause of disease.

Technical Abstract: Sphingolipids have important roles in membrane and lipoprotein structure and in cell regulation as "second messengers" for growth factors, differentiation factors, cytokines and a growing list of agonists. Bioactive sphingolipids are formed both by the turnover of complex sphingolipids and as intermediates of sphingolipid biosynthesis. Usually, the amounts are highly regulated, however, by inhibiting ceramide synthase, fumonisins block the biosynthesis of complex sphingolipids and cause sphinganine (and sometimes sphingosine) to accumulate. Where the mechanism has been studied most thoroughly, the accumulation of sphingoid bases is a primary cause of the toxicity of FB1, nonetheless, the full effects of fumonisins probably involve many biochemical events. The elevations in sphingoid bases also affect the amounts of other lipids, including the 1-phosphates and N-acetyl-derivatives of sphinganine. Furthermore, the aminopentol backbone of FB1 (AP1) is both an inhibitor and a substrate for ceramide synthase, and the resultant N-palmitoyl-AP1 (PAP1) is an even more potent inhibitor of ceramide synthase (presumably as a product analog). PAP1 is 10-times more toxic than FB1 or AP1 for HT29 cells in culture, hence, may play a role in the toxicity of nixtamalized fumonisins. All of these processes, the effects of fumonisins on sphingolipid metabolism, the pathways that are altered by perturbation of sphingolipid metabolism, and the complex cellular behaviors that are regulated by sphingolipids, must be borne in mind when evaluating the pathological effects of fumonisins.