SOURCE AND TARGET ENZYME SIGNATURE IN SERINE-PROTEASE INHIBITOR ACTIVE-SITE SEQUENCES

Amino acid sequences of proteinaceous proteinase inhibitors have been extensively analysed for deriving information regarding the molecular evolution and functional relationship of these proteins. These sequenc es have been grouped into several well defined families. It was found that the phylogeny constructed with the sequences corresponding to the exposed loop responsible for inhibition has several branches that res emble those obtained from comparisons using the entire sequence. The m ajor branches of the unrooted tree corresponded to the families to whi ch the inhibitors belonged. Further branching is related to the enzyme specificity of the inhibitor. Examination of the active site loop seq uences of trypsin inhibitors revealed that there are strong preference s for specific amino acids at different positions of the loop. These p references are inhibitor class specific. Inhibitors active against mor e than one enzyme occur within a class and confirm to class specific s equence in their loops. Hence, only a few positions in the loop seem t o determine the specificity. The ability to inhibit the same enzyme by inhibitors that belong to different classes appears to be a result of convergent evolution.