Natural Voltage‐Gated Sodium Channel Ligands: Biosynthesis and Biology

Abstract

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.

A review of chemical defense in harlequin toads (Bufonidae: Atelopus)

“…Source. While a bacterial origin of TTX is well-supported for marine taxa ( Campbell et al, 2009 , Chau et al, 2011 , Li et al, 2020 , Magarlamov et al, 2017 , Wu et al, 2005 ), the source of TTX in amphibians remains unresolved (see Hanifin, 2010 ; Stokes et al, 2014 ; Lukowski and Narayan, 2019 ). Although a complete review of all evidence regarding the source of TTX defenses in amphibians is outside the scope of this text, we evaluate existing data from Atelopus considering recent research in Taricha newts.…”

“…The detection of TTX-producing bacteria is complicated by the unknown genetic basis of TTX synthesis ( Lukowski and Narayan, 2019 ). While one early study was unable to detect bacterial DNA in TTX-rich tissues of the salamandrid Taricha granulosa ( Lehman et al, 2004 ), multiple strains of TTX-producing bacteria have recently been cultured from the skin of the same species ( Vaelli et al, 2020 ).…”

“…Given that Atelopus are riparian and possess skin-associated cyanobacteria ( Becker et al, 2014 ), it seems plausible that ZTX AB has a cyanobacterial origin. Unlike TTX, the genetic basis of saxitoxin synthesis is known ( Hackett et al, 2013 ), so metagenomic techniques could be applied to the Atelopus microbiome to test for the presence of bacteria with gene clusters similar to the saxitoxin gene cluster ( Lukowski and Narayan, 2019 ). While A. zeteki from El Valle de Antón, Panama are the most studied sources of ZTX AB ( Table S1 ), the use of metagenomic analyses on the microbiome of this species is complicated by the possible extinction of A. zeteki in the wild, and uncertainty regarding whether captive A. zeteki retain ZTX AB ( Lukowski and Narayan, 2019 ).…”

Linking Genes to Molecules in Eukaryotic Sources: An Endeavor to Expand Our Biosynthetic Repertoire

“…There are limited examples of molecules that are produced by both cyanobacteria and marine eukaryotes, but when this occurs it provides an approach to generate hypotheses about eukaryotic natural product biosynthesis. For example, some paralytic shellfish toxins (PSTs), such as saxitoxin (Figure 3D), are produced by both cyanobacteria and dinoflagellates [64][65][66]. While a putative gene cluster for saxitoxin in cyanobacteria was identified in 2008 [67], biochemical confirmation was lacking until recently.…”

Spider Knottin Pharmacology at Voltage-Gated Sodium Channels and Their Potential to Modulate Pain Pathways

“…Such rapid influx of Na + ions is key to generation and propagation of action potential and underlies transmission of a wide array of somatosensory signals, including touch, smell, temperature, proprioception and pain [21]. A range of molecules discovered from natural sources (e.g., venomous animals) interact with Na V channels to activate or inhibit the influx of Na + ions [16,22]. Na V channels are also expressed in non-excitable cells where they contribute to non-canonical functions [23], such as catecholamine release [24], angiogenesis [25], phagocytosis, endosomal acidification and podosome formation [26,27], production of pro-inflammatory mediators [28] and are key regulators in various human pathologies, such as cancer progression [29], multiple sclerosis [30], epilepsy [31] and pain syndromes [32,33].…”