Natural Voltage‐Gated Sodium Channel Ligands: Biosynthesis and Biology

Natural product biosynthetic pathways are composed of enzymes that use powerful chemistry to assemble complex molecules. Small molecule neurotoxins are examples of natural products with intricate scaffolds which often have high affinities for their biological targets. The focus of this Minireview is small molecule neurotoxins targeting voltage‐gated sodium channels (VGSCs) and the state of knowledge on their associated biosynthetic pathways. There are three small molecule neurotoxin receptor sites on VGSCs associated with three different classes of molecules: guanidinium toxins, alkaloid toxins, and ladder polyethers. Each of these types of toxins have unique structural features which are assembled by biosynthetic enzymes and the extent of information known about these enzymes varies among each class. The biosynthetic enzymes involved in the formation of these toxins have the potential to become useful tools in the efficient synthesis of VGSC probes.Terrific toxins: Living organisms produce highly potent small molecule neurotoxins as forms of self‐defense. A subset of these toxins target voltage‐gated sodium channels, a potential target for non‐opioid pain management in humans. The biosynthetic pathways of these channel‐disrupting ligands are discussed in the context of biocatalytic applications.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149247/1/cbic201800754.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149247/2/cbic201800754-sup-0001-misc_information.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149247/3/cbic201800754_am.pd