Functional Variability of Snake Venom Metalloproteinases: Adaptive Advantages in Targeting Different Prey and Implications for Human Envenomation

Abstract

Snake venom metalloproteinases (SVMPs) are major components in most viperid venoms that induce disturbances in the hemostatic system and tissues of animals envenomated by snakes. These disturbances are involved in human pathology of snake bites and appear to be essential for the capture and digestion of snake's prey and avoidance of predators. SVMPs are a versatile family of venom toxins acting on different hemostatic targets which are present in venoms in distinct structural forms. However, the reason why a large number of different SVMPs are expressed in some venoms is still unclear. In this study, we evaluated the interference of five isolated SVMPs in blood coagulation of humans, birds and small rodents. P-III class SVMPs (fractions Ic, IIb and IIc) possess gelatinolytic and hemorrhagic activities, and, of these, two also show fibrinolytic activity. P-I class SVMPs (fractions IVa and IVb) are only fibrinolytic. P-III class SVMPs reduced clotting time of human plasma. Fraction IIc was characterized as prothrombin activator and fraction Ic as factor X activator. In the absence of Ca2+, a firm clot was observed in chicken blood samples with fractions Ic, IIb and partially with fraction IIc. In contrast, without Ca2+, only fraction IIc was able to induce a firm clot in rat blood. In conclusion, functionally distinct forms of SVMPs were found in B. neuwiedi venom that affect distinct mechanisms in the coagulation system of humans, birds and small rodents. Distinct SVMPs appear to be more specialized to rat or chicken blood, strengthening the current hypothesis that toxin diversity enhances the possibilities of the snakes for hunting different prey or evading different predators. This functional diversity also impacts the complexity of human envenoming since different hemostatic mechanisms will be targeted by SVMPs accounting for the complexity of the response of humans to venoms.

Coevolution of Snake Venom Toxic Activities and Diet: Evidence that Ecological Generalism Favours Toxicological Diversity

“…Consistent with the latter suggestion, and another example of prey-specific toxins, two 3FTxs described from the venom of Spilotes sulphureus have contrasting prey-specificity, with one active against mammals but not lizards, and another active against lizards but not mammals [32]. Note that prey-specific toxins are not restricted to 3FTxs; different forms of snake venom metalloproteinases (SVMPs) isolated from Bothrops neuwiedi have been shown to vary greatly in their toxicity to mammals vs birds [33]. Such evidence demonstrates that individual toxins may be selected to target particular prey types and provides a good mechanistic basis for how diet-driven selection of venom could operate.…”

Comparison of venoms from wild and long-term captive Bothrops atrox snakes and characterization of Batroxrhagin, the predominant class PIII metalloproteinase from the venom of this species

“…However, sequence and functional variability within PIII-SVMPs have been reported and may compromise antigen neutralization. Bernardoni and colleagues [24] analyzed different functional forms of Bothrops neuwiedi SVMPs and demonstrated selectivity for different targets in the hemostatic system, affecting distinct mechanisms of coagulation in humans, rodents and birds. In this regard, most of the studies relating intraspecific variability are focused in proteomics data and do not include functional variability within the same toxin group.…”

Structures of N-Glycans of Bothrops Venoms Revealed as Molecular Signatures that Contribute to Venom Phenotype in Viperid Snakes

“…The challenges involved in the complete characterization of snake venoms are related to their complexity. In the case of viperid venoms, this feature is not only because of the number of different toxin classes, but also to various toxin forms with a high degree of variability in primary structure, resulting from gene duplication and non-synonymous mutations (3)(4)(5)(6)(7)(8)(9)(10)(11). On evolution venomous snakes generated different repertoires of toxins to deal with distinct prey types, hence the venom proteome and peptidome may vary at different taxonomic levels, and intraspecifically, because of factors like gender, diet, age, and habitat (12)(13)(14)(15)(16)(17)(18)(19).…”