Multifunctional Toxins in Snake Venoms and Therapeutic Implications: From Pain to Hemorrhage and Necrosis

Venoms have evolved on numerous occasions throughout the animal kingdom. These 'biochemical weapon systems' typically function to facilitate, or protect the producing animal from, predation. Most venomous animals remain unstudied despite venoms providing model systems for investigating predator-prey interactions, molecular evolution, functional convergence, and novel targets for pharmaceutical discovery. Through advances in 'omic' technologies, venom composition data have recently become available for several venomous lineages, revealing considerable complexity in the processes responsible for generating the genetic and functional diversity observed in many venoms. Here, we review these recent advances and highlight the ecological and evolutionary novelty of venom systems. Copyright © 2012 Elsevier Ltd. All rights reserved.

The importance of proteinases in the pathologies associated with Viperid envenoming has long been appreciated. Over the past 40 years substantial research has clearly implicated metalloproteinases in the venom (snake venom metalloproteinases; SVMPs) as playing key roles in the development of such symptoms as hemorrhage, edema, hypotension, hypovolemia, inflammation and necrosis. In spite of this wealth of information there are still many unresolved questions pertaining to the structural basis for the various SVMPS giving rise to the diversity of activities. In this short review we will not attempt to provide an exhaustive collation of structural studies on the SVMPs; however, we will give a brief outline of the structural classification of the SVMPs; as well as relate them to the other members of the reprolysin family of metalloproteinases, the ADAMs. The information put forth in the text does not allow specific conclusions to be drawn on the structural basis for SVMP functional diversity, but it is our goal that it will allow for the development of testable hypotheses that can be experimentally pursued. What the reader will observe is that there are very interesting structural features displayed by the various SVMP classes and subclasses that provide insight into their functional characteristics.

This study analyzed the origin and evolution of snake venom proteome by means of phylogenetic analysis of the amino acid sequences of the toxins and related nonvenom proteins. The snake toxins were shown to have arisen from recruitment events of genes from within the following protein families: acetylcholinesterase, ADAM (disintegrin/metalloproteinase), AVIT, complement C3, crotasin/beta defensin, cystatin, endothelin, factor V, factor X, kallikrein, kunitz-type proteinase inhibitor, LYNX/SLUR, L-amino oxidase, lectin, natriuretic peptide, betanerve growth factor, phospholipase A(2), SPla/Ryanodine, vascular endothelial growth factor, and whey acidic protein/secretory leukoproteinase inhibitor. Toxin recruitment events were found to have occurred at least 24 times in the evolution of snake venom. Two of these toxin derivations (CRISP and kallikrein toxins) appear to have been actually the result of modifications of existing salivary proteins rather than gene recruitment events. One snake toxin type, the waglerin peptides from Tropidolaemus wagleri (Wagler's Viper), did not have a match with known proteins and may be derived from a uniquely reptilian peptide. All of the snake toxin types still possess the bioactivity of the ancestral proteins in at least some of the toxin isoforms. However, this study revealed that the toxin types, where the ancestral protein was extensively cysteine cross-linked, were the ones that flourished into functionally diverse, novel toxin multigene families.