London Research and Development Centre, Agriculture and Agri-Food Canada, 1391 Sandford Street, London, Ontario N5V 4T3, Canada.
Chem Res Toxicol. 2021 Jun 21;34(6):1604-1611. doi: 10.1021/acs.chemrestox.1c00057. Epub 2021 Apr 23.
Fumonisins are mycotoxins produced by a number of species of and . 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 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. was treated at 40 μM against FB, hydrolyzed FB (hFB), deaminated FB (FPy), or hydrolyzed/deaminated (hFPy). Four end points were monitored: plant dry weight, frond surface area, lipidomics, and metabolomics. Overall, hFB was less toxic than FB and FPy was less toxic than hFB. hFPy which lacks both the amine group and tricarballylic side chains was also less toxic than FB and hFB, however it was not significantly less toxic than FPy. Lipidomic analysis showed that FB 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 FB treatment including phenylalanine, asymmetric dimethylarginine (ADMA), S-methylmethionine, saccharopine, and tyrosine. Conversely, citrulline, -acetylornithine and ornithine were significantly elevated in the presence of hFB 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 and justify future toxicity studies in mammalian systems.
伏马菌素是由多种 和 产生的真菌毒素。它们是具有线性多醇结构的聚酮化合物，带有两个三羧酸侧链和一个胺基部分。毒性是由于它们抑制神经酰胺合酶（CerS），从而扰乱神经鞘脂浓度。伏马菌素的三羧酸侧链和胺基是抑制 CerS 的关键分子特征，但它们对整体毒性的各自贡献尚不完全清楚。我们最近报道了由 产生的新型去胺化伏马菌素，并鉴定出一种负责其合成的酶（AnFAO）。在这里，我们进行了一项结构/功能活性测定，以研究三羧酸和胺对伏马菌素整体毒性的各自贡献。将 用 40 μM 处理 FB、水解 FB（hFB）、去胺化 FB（FPy）或水解/去胺化 FB（hFPy）。监测了四个终点：植物干重、羽片表面积、脂质组学和代谢组学。总的来说，hFB 比 FB 毒性小，FPy 比 hFB 毒性小。缺乏胺基和三羧酸侧链的 hFPy 也比 FB 和 hFB 毒性小，但毒性不比 FPy 小。脂质组学分析表明，FB 处理显著增加了磷酯酰胆碱、神经酰胺和原卟啉 A 的水平，同时显著降低了二酰基甘油、磺基奎诺二酰基甘油和叶绿素的水平。代谢组学分析显示，FB 处理导致许多独特的化合物显著增加，包括苯丙氨酸、不对称二甲基精氨酸（ADMA）、S-甲基蛋氨酸、蔗糖和酪氨酸。相反，在存在 hFB 的情况下，瓜氨酸、 -乙酰鸟氨酸和鸟氨酸显著升高，但在其他伏马菌素类似物中则没有升高。这些数据提供了证据，表明尽管去除三羧酸侧链会显著降低伏马菌素的毒性，但胺基功能团是 中伏马菌素毒性的关键贡献者，并证明了在哺乳动物系统中进行未来毒性研究的合理性。
