Catalytically Active Snake Venom PLA₂ Enzymes: An Overview of Its Elusive Mechanisms of Reaction

Snake venom-secreted phospholipase A₂ (svPLA₂) enzymes, both catalytically active and inactive, are a central component in envenoming. These are responsible for disrupting the cell membrane's integrity, inducing a wide range of pharmacological effects, such as the necrosis of the bitten limb, cardiorespiratory arrest, edema, and anticoagulation. Although extensively characterized, the reaction mechanisms of enzymatic svPLA₂ are still to be thoroughly understood. This review presents and analyses the most plausible reaction mechanisms for svPLA_2, such as the "single-water mechanism" or the "assisted-water mechanism" initially proposed for the homologous human PLA₂. All of the mechanistic possibilities are characterized by a highly conserved Asp/His/water triad and a Ca²⁺ cofactor. The extraordinary increase in activity induced by binding to a lipid-water interface, known as "interfacial activation," critical for the PLA₂s activity, is also discussed. Finally, a potential catalytic mechanism for the postulated noncatalytic PLA₂-like proteins is anticipated.