Structure Activity Relationship for Fumonisin Phytotoxicity

Fumonisins are mycotoxins produced by a number of species of Fusarium and Aspergillus. They are polyketides that possess a linear polyol structure with two tricarballylic acid side chains and an amine moiety. Toxicity results from their inhibition of Ceramide Synthase (CerS), which perturbs sphingolipid concentrations. The tricarballylic side chains and amine group of fumonisins are key molecular features responsible for inhibiting CerS, however their individual contributions toward overall toxicity are not fully understood. We have recently reported novel, deaminated fumonisins produced by A. niger and have identified an enzyme (AnFAO) responsible for their synthesis. Here we performed a structure/function activity assay to investigate the individual contributions of the tricarballylic acid and amine toward overall fumonisin toxicity. Lemna minor was treated at 40 μM against FB₁, hydrolyzed FB₁ (hFB₁), deaminated FB₁ (FPy₁), or hydrolyzed/deaminated (hFPy₁). Four end points were monitored: plant dry weight, frond surface area, lipidomics, and metabolomics. Overall, hFB₁ was less toxic than FB₁ and FPy₁ was less toxic than hFB₁. hFPy₁ which lacks both the amine group and tricarballylic side chains was also less toxic than FB₁ and hFB₁, however it was not significantly less toxic than FPy₁. Lipidomic analysis showed that FB₁ treatment significantly increased levels of phosphotidylcholines, ceramides, and pheophorbide A, while significantly decreasing the levels of diacylglycerides, sulfoquinovosyl diacylglycerides, and chlorophyll. Metabolomic profiling revealed a number of significantly increased compounds that were unique to FB₁ treatment including phenylalanine, asymmetric dimethylarginine (ADMA), S-methylmethionine, saccharopine, and tyrosine. Conversely, citrulline, N-acetylornithine and ornithine were significantly elevated in the presence of hFB₁ but not any of the other fumonisin analogues. These data provide evidence that although removal of the tricarballylic side chains significantly reduces toxicity of fumonisins, the amine functional group is a key contributor to fumonisin toxicity in L. minor and justify future toxicity studies in mammalian systems.