Abstract
Toxin synergism is a complex biochemical phenomenon, where different animal venom proteins interact either directly or indirectly to potentiate toxicity to a level that is above the sum of the toxicities of the individual toxins. This provides the animals possessing venoms with synergistically enhanced toxicity with a metabolic advantage, since less venom is needed to inflict potent toxic effects in prey and predators. Among the toxins that are known for interacting synergistically are cytotoxins from snake venoms, phospholipases A2 from snake and bee venoms, and melittin from bee venom. These toxins may derive a synergistically enhanced toxicity via formation of toxin complexes by hetero-oligomerization. Using a human keratinocyte assay mimicking human epidermis in vitro, we demonstrate and quantify the level of synergistically enhanced toxicity for 12 cytotoxin/melittin-PLA2 combinations using toxins from elapids, vipers, and bees. Moreover, by utilizing an interaction-based assay and by including a wealth of information obtained via a thorough literature review, we speculate and propose a mechanistic model for how toxin synergism in relation to cytotoxicity may be mediated by cytotoxin/melittin and PLA2 complex formation.
Highlights
The venomous animals that pose a threat to human health are classified in six major groups: cnidarians, venomous fish, scorpions, spiders, hymenopterans, and snakes (Ericsson et al, 2006)
Exposure of N/TERT cells to Naja spp. cytotoxins showed an average of seven-fold higher cytotoxic activity in combination with MII (~62%), five-fold higher in combination with Nmo12 (~50%), and four-fold higher when combined to bvPLA2 (~45%) (Figure 1)
Interspecies toxin combinations were tested, and interestingly, for snakes, we found that Nmo12, an acidic phospholipase A2 (PLA2) from N. mossambica, exhibited less synergistic effects when combined with Naja spp. cytotoxins, compared to when it was combined with MII from the B. asper pit viper
Summary
The venomous animals that pose a threat to human health are classified in six major groups: cnidarians, venomous fish, scorpions, spiders, hymenopterans, and snakes (Ericsson et al, 2006). Their venoms are complex cocktails of toxic proteins, peptides, and small organic and inorganic molecules. Venoms derive their toxicity from proteins known as toxins These toxins are Intraspecies and Interspecies Toxin Synergism in themselves a diverse and complex group, including smaller neurotoxic peptides, larger phospholipases, and venom proteases, along with many other protein families (Ducancel, 2016). The main toxic component of bee venoms, was first identified as a DLF, and as its mechanism closely resembles that of cytotoxins (Dempsey, 1990), it may be considered as a “cytotoxin-like” peptide
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