Modulation of phospholipase A(2) activity generated by molecular evolution

Snake venom oligomeric neurotoxins offer several unique examples of modulat ion of phospholipase A(2) (PLA(2)) activity generated by molecular evolutio n. This phenomenon was found in evolutionary younger snakes and is probably common for representatives of the genus Vipera. At present, the best-studi ed example is the heterodimeric neurotoxin vipoxin from the venom of the so utheast European snake Vipera ammodytes meridionalis. It is a complex betwe en a basic strongly toxic PLA(2) and an acidic and catalytically inactive P LA(2)-like component (Inh). This is the first reported example of a high de gree of structural homology (62%) between an enzyme and its natural protein inhibitor. The inhibitor is a product of the divergent evolution of the un stable PLA(2) in order to stabilize it and to preserve the pharmacological activity/toxicity for a long time. Inh reduces both the catalytic activity and toxicity of PLA(2). Vipoxin also illustrates evolution of the catalytic into a inhibitory function. Vipoxin analogues have been found in the venom of viperid snakes inhabiting diverse regions of the world. An attempt is m ade to explain modulation of the toxic function by the three-dimensional st ructure of vipoxin.