College of Public Health, Department of Environmental Health Science, University of Georgia, Athens, GA 30602
School of Biological Sciences and the Parker H. Petit Institute for Bioengineering and Bioscience Georgia Institute of Technology, Atlanta, GA 30332
J Lipid Res. 2019 Jul;60(7):1183-1189. doi: 10.1194/jlr.S093815. Epub 2019 May 2.
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 (FB)] potently inhibits ceramide synthases (CerSs), enzymes that use fatty acyl-CoAs to -acylate sphinganine (Sa), sphingosine (So), and other sphingoid bases. CerS inhibition by FB 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 FB intake is associated with elevated Sa 1-phosphate), has consistently pointed to CerS as the proximate target of FB 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.
伏马菌素是一种真菌毒素，可引起植物疾病，动物摄入后会损害肝脏、肾脏、肺、大脑和其他器官，改变免疫功能，并导致发育缺陷和癌症。它们在结构上类似于鞘脂类（SLs），近 30 年前的研究发现，最常见的伏马菌素[伏马菌素 B（FB）]强烈抑制神经酰胺合酶（CerSs），这些酶使用脂肪酸酰基辅酶 A 将神经酰胺前体（Sa）、鞘氨醇（So）和其他鞘氨醇碱基酰化。FB 对 CerS 的抑制引发了 SL 结构和信号通路的“完美风暴”，包括：二氢神经酰胺、神经酰胺和复杂 SL 的形成减少；Sa 和 So 及其 1-磷酸升高，新型 1-脱氧鞘氨醇碱基；以及来自相关途径的其他脂质代谢物的改变。此外，由于鞘氨醇碱基生物合成的初始酶仍然活跃（有时活性增加），因此由于继续产生有害代谢物，其影响会倍增。许多研究的证据，包括对特定 CerSs 的敲除小鼠的特征描述以及对人类血液的分析（发现 FB 摄入与 Sa 1-磷酸升高有关），一致指出 CerS 是 FB 的直接靶标。很明显，多种生物活性脂质和相关生物过程的变化解释了随后的动植物疾病谱。因此，伏马菌素引起的疾病可以归类为“鞘脂贮积症”（在这些情况下，由于 SL 生物合成缺陷），当考虑其他天然存在和合成化合物（以及遗传操作）干扰 SL 代谢时，应该记住 CerS 抑制的后果。
