Ceramide synthase inhibition by fumonisins: a perfect storm of perturbed sphingolipid metabolism, signaling, and disease

Fumonisins are mycotoxins that cause diseases of plants and, when consumed by animals, can damage liver, kidney, lung, brain, and other organs, alter immune function, and cause developmental defects and cancer. They structurally resemble sphingolipids (SLs), and studies nearly 30 years ago discovered that the most prevalent fumonisin [fumonisin B-1 (FB1)] potently inhibits ceramide synthases (CerSs), enzymes that use fatty acyl-CoAs to N-acylate sphinganine (Sa), sphingosine (So), and other sphingoid bases. CerS inhibition by FB1 triggers a perfect storm of perturbations in structural and signaling SLs that include: reduced formation of dihydroceramides, ceramides, and complex SLs; elevated Sa and So and their 1-phosphates, novel 1-deoxy-sphingoid bases; and alteration of additional lipid metabolites from interrelated pathways. Moreover, because the initial enzyme of sphingoid base biosynthesis remains active (sometimes with increased activity), the impact is multiplied by the continued production of damaging metabolites. Evidence from many studies, including characterization of knockout mice for specific CerSs and analyses of human blood (which found that FB1 intake is associated with elevated Sa 1-phosphate), has consistently pointed to CerS as the proximate target of FB1. It is also apparent that the changes in multiple bioactive lipids and related biologic processes account for the ensuing spectrum of animal and plant disease. Thus, the diseases caused by fumonisins can be categorized as sphingolipidoses (in these cases, due to defective SL biosynthesis), and the lessons learned about the consequences of CerS inhibition should be borne in mind when contemplating other naturally occurring and synthetic compounds (and genetic manipulations) that interfere with SL metabolism.