Modulation of phospholipase A 2 activity generated by molecular evolution

Abstract

Snake venom oligomeric neurotoxins offer several unique examples of modulation of phospholipase A2 (PLA2) activity generated by molecular evolution. This phenomenon was found in evolutionary younger snakes and is probably common for representatives of the genus Vipera. At present, the best-studied example is the heterodimeric neurotoxin vipoxin from the venom of the southeast European snake Vipera ammodytes meridionalis. It is a complex between a basic strongly toxic PLA2 and an acidic and catalytically inactive PLA2-like component (Inh). This is the first reported example of a high degree of structural homology (62%) between an enzyme and its natural protein inhibitor. The inhibitor is a product of the divergent evolution of the unstable PLA2 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 PLA2. 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 made to explain modulation of the toxic function by the three-dimensional structure of vipoxin.

Toxicity evolution of Vipera aspis aspis venom: identification and molecular modeling of a novel phospholipase A2 heterodimer neurotoxin1

“…The group 2 subunit is identical to the acidic subunit of PLA 2 ‐I from Vaz , 98.3% identical to the vipoxin inhibitor (PDB code 1JLT, the most recently described vipoxin isoform sequence of the PLA 2 , from Vamme venom) and only 92.7% to RV7. In common with the vipoxin inhibitor, His48, essential for catalysis, is replaced by a Gln [28], implying that the group 2 subunit lacks enzymatic activity. RV7 differs from the others by the conservation of the catalytic activity (His48) and eight other amino acid differences.…”

Enzymatic toxins from snake venom: structural characterization and mechanism of catalysis

“…Most probably, Inh is a product of divergent evolution in order to stabilize the relatively unstable PLA 2 and to preserve the pharmacological activity of the toxin for a long period. Vipoxin is the first reported example of a PLA 2 acquiring an inhibitory function [140].…”

Accelerated Evolution of Fetuin Family Proteins inProtobothrops flavoviridis(Habu Snake) Serum and the Discovery of an L1-Like Genomic Element in the Intronic Sequence of a Fetuin-Encoding Gene

“…This significant difference in substitution rates among the structural domains is in contrast to the cases of snake venom isozymes, in which high substitution rates have been found almost uniformly throughout the mature protein-coding regions. [9][10][11][12] In the present case of HSF and HLP, a coordination of abnormally rapid diversification of CY1 and HR and the high conservation of CY2 might have been critical to the appearance of a fetuin isoform with novel physiological activity.…”

“…Accordingly, this evolutionary pattern, specifically observed in snake venom isozyme genes, is an example of accelerated evolution, and is considered to have contributed to the rapid adaptive evolution of snake venoms. [8][9][10][11][12] Since these venom components are also highly toxic to the snakes themselves when accidentally injected into the bloodstream, venomous snakes possess protective proteins that inhibit venomous enzymes in their blood. For example, several isoforms of PLA 2 inhibitors 13,14) and a habu serum factor (HSF) that inhibits venom MPs 15,16) have been isolated and characterized in the habu.…”