|DIVON, HEGE - Norwegian Veterinary Institute|
|UHLIG, SILVIO - Norwegian Veterinary Institute|
Submitted to: BMC Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/6/2020
Publication Date: 7/23/2020
Citation: Kim, H.S., Lohmar, J.M., Busman, M., Brown, D.W., Naumann, T.A., Divon, H.H., Lysoe, E., Uhlig, S., Proctor, R.H. 2020. Identification and distribution of gene clusters required for synthesis of sphingolipid metabolism inhibitors in diverse species of the filamentous fungus Fusarium. Biomed Central (BMC) Genomics. 21:510. https://doi.org/10.1186/s12864-020-06896-1.
Interpretive Summary: Mycotoxins are toxic compounds produced by fungi and pose a health hazard to humans and animals because of their occurrence in food and feed crops. Fumonisins are mycotoxins that inhibit formation of class of lipids (sphingolipids) that are essential for normal functioning of human and animal cells. Fumonisin-induced inhibition of sphingolipid formation in animals, and presumably humans, can cause multiple diseases, including cancer. Because of the health hazards of fumonisins, researchers have elucidated genetic and biochemical processes required for their production in fungi. fumonisin-induced inhibition of sphingolipid formation results from similarities in chemical structures of the mycotoxins and sphinganine, an intermediate in the biochemical pathway that results in sphingolipid formation. Some other fungal compounds also have sphinganine-like structures and inhibit sphingolipid formation. Fumonisins and these other compounds are referred to as sphinganine-analog metabolites (SAMs). With the exception of fumonisins, almost nothing is known about the genetic and biochemical processes required for SAM production. In the current study, therefore, we used knowledge of fumonisin production along with DNA sequencing technology to survey over 300 fungal species for genes involved in SAM production. This research led to the identification of genes that are likely responsible SAM production of in 96 species of Fusarium and 37 species of other fungi. The results will enhance efforts to identify novel SAMs and determine roles they play in fungal biology. The resulting knowledge will contribute to development of strategies that eliminate fumonisin contamination in crops and, thereby, improve food and feed safety.
Technical Abstract: Sphingolipids are structural components and signaling molecules in eukaryotic membranes, and many organisms produce compounds that inhibit sphingolipid metabolism. Some of the inhibitors are structurally similar to the sphingolipid biosynthetic intermediate sphinganine. These sphinganine-analog metabolites (SAMs) include the mycotoxins fumonisins that frequently contaminate maize. Due to food and feed safety concerns, fumonisin biosynthesis has been investigated extensively, including characterization of fumonisin biosynthetic gene clusters in the fungi Aspergillus and Fusarium. Production of several other SAMs has also been reported in fungi, but there is almost no information on their biosynthesis. There is also little information on how widely SAM production occurs in fungi or on the extent of structural variation of fungal SAMs. Using fumonisin biosynthesis as a model, we predicted that SAM biosynthetic gene clusters in fungi should include a polyketide synthase, aminotransferase and dehydrogenase gene. Surveys of genome sequences identified five putative clusters with this three-gene combination in 92 of 186 species of the agriculturally important fungal genus Fusarium. Collectively, the putative SAM clusters were distributed widely but discontinuously among the species. We propose that the SAM5 cluster confers production of 2-amino-14,16-dimethyloctadecan-3-ol, a previously described Fusarium SAM. We also identified SAM clusters in 24 species of other fungal genera, including a putative sphingofungin biosynthetic gene cluster in Aspergillus fumigatus. Our results provide a genomics approach to identify novel SAM biosynthetic gene clusters in fungi, which should in turn contribute to identification of novel SAMs that could have medical and other applications, and provide insights into the role of SAMs in the ecology of fungi. Such insights have potential to contribute to strategies to reduce fumonisin contamination in crops and to control crop diseases caused by SAM-producing fungi.