Phospholipase A2 Myotoxins from Bothrops Snake Venoms

Several myotoxins have been isolated from Bothrops snake venoms during the last 10 years. All of them are group II basic phospholipases A2, although some lack enzymatic activity (i.e. Lys-49 variants). These myotoxins appear as an antigenically related family of proteins occurring in many, but not all, Bothrops venoms, bearing a close structural and antigenic relationship to toxins found in other crotalid venoms of the genera Agkistrodon and Trimeresurus. Myotoxins are quantitatively important venom components in some Bothrops species. Intramuscular injection of Bothrops myotoxins leads to a rapid series of drastic degenerative events, probably initiated at the plasma membrane level, which culminate in a selective skeletal muscle necrosis. This in vivo specificity contrasts with the ability of myotoxins to lyse many types of cells in culture. Muscle damage, as well as cytolysis and liposome disruption, occur in conditions where phospholipase A2 activity is inhibited, although enzymatic activity might enhance myotoxin actions. A membrane receptor for Bothrops myotoxins has not been identified yet. A working hypothesis on the mechanism of action is proposed. Current evidence suggests that these toxins interact with biological membranes via a molecular region distinct from their known catalytic site. The active region is likely to be formed by a combination of basic and hydrophobic amino acid residues near the C-terminus of the protein, which allow electrostatic interaction and bilayer penetration. These events may lead to membrane destabilization and loss of selective permeability to ions such as calcium, both of which appear to be important mediators in the process of muscle necrosis.