Accelerated evolution and molecular surface of venom phospholipase A(2) enzymes

Multiple phospholipase A(2) (PLA(2)) isoenzymes found in a single snake ven om induce a variety of pharmacological effects, These multiple forms are fo rmed by gene duplication and accelerated evolution of exons. We examined th e amino acid sequences of 127 snake venom PLA(2) enzymes and their homologu es to study in which location most natural substitutions occur. Our data sh ow that hot spots of amino acid substitutions in this group of proteins occ ur mostly on the surface. A logistic model correlating the substitution rat es of each amino acid residue with their surface accessibility indicates th at the probability of natural substitutions occurring in the fully exposed residue is 2.6-3.5 times greater than that of substitutions occurring in bu ried residues. These surface substitutions play a significant role in the e volution of new PLA(2) isoenzymes by altering the specificity of targeting to various tissues or cells, resulting in distinct pharmacological effects. Thus natural substitutions in PLA(2) enzymes, in contrast to popular belie f, are not random substitutions but appear to be directed toward modifying the molecular surface.