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.

Keywords: biocatalysis; biosynthesis; enzymes; neurotoxins; voltage-gated sodium channels.

Figure 1.

Diagram of voltage-gated sodium channel structure and binding sites of natural small molecule neurotoxins. Receptor site I is indicated in red and is targeted by the guanidinium toxins. Receptor site II, indicated in green, interacts with alkaloid toxins and receptor site V, indicated in blue, is targeted by the ladder polyethers.

Figure 2.

Examples of saxitoxin and gonyautoxin analogs isolated from natural sources.

Figure 3.

Characterized biosynthetic steps in paralytic shellfish toxin biosynthesis. A) Substrates required for the SxtA reaction. B) Characterized late-stage steps in paralytic shellfish toxin biosynthesis. Inset: In vitro evidence for order of hydroxylation events in saxitoxin (3) biosynthesis. C) Structure of zetekitoxin AB (5).

Figure 4.

Structures of tetrodotoxin (1) and chiriquitoxin (2) and commonly observed derivatives 4-epi-tetrodotoxin (17), 11-deoxytetrodotoxin (18), and 6-epi-tetrodotoxin (19).

Figure 5.

Prominent biosynthetic proposals for tetrodotoxin (1) biosynthesis. A) General biosynthetic proposal by Shimizu for all producing organisms, B) Yotsu-Yamashita proposal for terrestrial tetrodotoxin (1) producers, C) Yotsu-Yamashita proposal for marine tetrodotoxin (1) producers.

Figure 6.

Possible biosynthetic precursors obtained by labeling studies.

Figure 7.

Proposed biosynthesis of aconitine (6) with geranylgeranyl pyrophosphate (34) as a precursor.

Figure 8.

Structures of common batrachotoxin (7) products in poison dart frogs and birds.

Figure 9.

Proposed biosynthesis of ciguatoxin 1 (11).