Effect of methylation of histidine-48 on some enzymatic and pharmacological activities of snake venom phospholipases A2.

The effects on some pharmacological and enzymatic properties were determined following methylation of histidine at the enzymatic active site of the basic relatively toxic Naja nigricollis and the acidic relatively non-toxic Naja naja atra phospholipases A2. Following methylation a very low residual enzymatic activity (0.4-1% of control) was accompanied by a parallel loss in intraventricular lethality, anticoagulant potency, direct hemolytic action and ability to block directly and indirectly evoked contractions of the mouse phrenic nerve-diaphragm preparation. Since methylation does not impair the enzyme's ability to bind monomeric or micellar substrates or Ca2+, the results suggest that the pharmacologically active region of the molecule is different from the micellular substrate binding site but strongly influenced by the invariant histidine-48 located at the enzymatic active site.