Effect of enzyme processivity on the efficacy of a competitive chitinase inhibitor

Many glycoside hydrolases, such as chitinases and cellulases, degrade polysaccharides in a processive manner. Inhibition of chitinases is of great interest, because chitin-metabolizing pathogenic organisms such as certain fungi, insects and nematodes need chitinase activity for survival. Here we show how the processivity and the directionality of two chitinases, chitinase A (ChiA) and B (ChiB) from Serratia marcescens, affects the practical inhibition efficacy (IC50) of allosamidin, a general competitive inhibitor of family 18 chitinases. The results show that there is a clear negative correlation between processivity and the efficiency of competitive inhibition, and that this effect of processivity (i.e. reducing inhibitor efficacy) is largest when allosamidin binds to those enzyme subsites that interact with the polymeric part of the substrate. Besides providing further insight into the processivity and directionality of the two Serratia enzymes, these results reveal important aspects of ligand binding that should be taken into account when designing inhibitors of processive enzymes.