Immunochemical Characterization and Role in Toxic Activities of Region 115–129 of Myotoxin II, a Lys49 Phospholipase A2fromBothrops asperSnake Venom

Neutralization of snake venom phospholipase A2 toxins by aqueous extract of Casearia sylvestris (Flacourtiaceae) in mouse neuromuscular preparation

“…The mechanism of the neuromuscular blockade induced by the Lys49 PLA 2 s remains largely unknown, although there is a consensus that their effects take place in the absence of enzymatic activity (Kini, 2003;Lomonte et al, 2003). It has been suggested that a region located at the C-terminal part of the molecule, is responsible for penetration and disorganization of plasma membrane (Calderon and Lomonte, 1998). We have previously shown that heparin is able to neutralize both the muscle damaging and the neuromuscular blocking activities of a Lys49 PLA 2 (BthTX-I) (Gallacci et al, 2006).…”

Inhibition of Myotoxic Activity of Bothrops asper Myotoxin II by the Anti-trypanosomal Drug Suramin

“…Inhibition of B. asper Mytotoxin II by Suramin attempted to identify and to delineate the region or regions important for the expression of myotoxicity in PLA 2 s, 23 on the basis of sequence homology, [36][37][38] charge distribution, [39][40][41] hydrophobicity profiles, 39 chemical modification, 42,43 use of synthetic peptides, 34,44,45 and site-directed mutagenesis. 30,46 With the biochemical and structural information currently available we are now able to probe the structure-function relationship, and the mode of action and inhibition of Lys49 PLA 2 analogues by addressing the roles of the C-terminal region and the nominal active site in myotoxicity.…”

A Molecular Mechanism for Lys49-Phospholipase A2 Activity Based on Ligand-induced Conformational Change

“…The flexibility of the C-terminal region is not unexpected given that peptides corresponding to residues 115-129 of a myotoxin from B. asper have been successfully used to mimic the myotoxic effects of the whole protein (52). Furthermore, the critical role of Lys 122 in this model is supported by its absolute conservation in Lys 49 -PLA 2 myotoxins as well as by site-directed mutagenesis experiments (40,76).…”

“…The sulfate ions in forms II and III are located in similar positions, ϳ6 Å closer to the active site than in form I (Fig. 1), and are bound by the side chains of Arg 34 , Lys 49 , Tyr 52 (not in form III due to a minor difference in the position of the sulfate), and Lys 53 . Significant differences exist in the side chain conformations of Lys 53 and Arg 34 in form I compared with the other two forms, in order to be able to interact with the anion at two distinct sites.…”

“…"SequenceSpace" analysis (42) and x-ray diffraction studies (32)(33)(34)(43)(44)(45)(46) have both clearly shown that, with the exception of Asp 49 itself, the Lys 49 -PLA 2 s conserve all the important residues of the catalytic machinery, as well the nucleophilic water molecule and a hydrogen-bonding network that involves Tyr 52 and Tyr 73 and the N terminus. In addition, crystallographic structures in complex with naturally bound fatty acid molecules (interpreted as the product of catalysis) have been described (46,47).…”