Do chemical modifications dissociate between the enzymatic and pharmacological activities of β bungarotoxin and notexin?

Abstract

P. Rosenberg, A. Ghassemi, E. Condrea, D. Dhillon and C.-C. Yang. Do chemical modifications dissociate between the enzymatic and pharmacological activities of β bungarotoxin and notexin? Toxicon 27, 137–159, 1989.—We have measured enzymatic, hemolytic and anticoagulant activities, lethal potencies and effects on contractions of the phrenic nerve-diaphragm preparation, by chemically modified derivatives of β bungarotoxin (βBuTX) and notexin, two presynaptically acting toxins which have PLA 2 activity. The following chemical modifications of βBuTX were tested: alkylation and methylation of histidine 48, alkylation of tryptophan 19, sulfonylation of tyrosine 68, oxidation of methionines 6 and 8, semicarbazide addition under varied conditions to carboxyl groups, varied extents of carbamylation or trinitrophenylation of lysines and guanidination of all lysines with or without trinitrophenylation of the N-terminal asparagine. Only the histidine, tryptophan and tyrosine residues were modified in notexin. The results obtained were compared with those previously obtained using chemically modified derivatives of Naja nigricollis and Naja naja atra PLA 2 enzymes which do not have a specific presynaptic site of action. The results with oxidized methionine and lysine-modified derivatives of βBuTX are supportive of the suggestions of others that the N-terminal region and basic residues away from the enzymatic active region contribute towards the β type presynaptic neurotoxicity of the PLA 2 toxins. Using modified derivatives of βBuTX and notexin, the dissociations between enzymatic activities and pharmacological properties were not as marked as previously observed with N. nigricollis and N. n. atra PLA 2; nevertheless, several dissociations were noted. We conclude that, just as with non-presynaptically acting PLA 2 enzymes, some pharmacological actions of presynaptically acting PLA 2 toxins may occur independently of phospholipid hydrolysis.