Biological roles of specific peptides in enzymes

It has recently been shown (Kunik et al., PLOS Comput Biol 2007;3(8):e167) that the occurrence of specific peptides (SPs) on sequences of enzymes allows for accurate EC classification of enzymes. We inquire whether these SPs play important roles in bringing about the enzymatic function. This is assessed by cross‐checking the occurrence of SPs on enzymes with Swiss‐Prot annotations and PDB spatial structures of enzymes. Analyzing the coverage of functional annotations of enzymes, we demonstrate that SPs contain major fractions of all annotated features. This result is statistically highly significant and associates over 10% of all SPs with important biological markers. Concentrating on DNA binding regions, relevant to LexA repressor enzymes, we find interesting coverage patterns. Moreover, for the same data, we demonstrate that SPs allow for subclassification of the relevant bacteria into phylogenetic classes. An analysis of mutagen annotations on SPs appearing on all enzymes leads to the conclusion that mutations on SPs tend to damage the enzymatic function much more than expected from a background model, hence SPs are of high importance to enzymatic functions. SPs that lie in 3D pockets that are shared by active and binding sites, are shown to be significantly enriched by glycine, leading to the hypothesis that they are responsible for conformational plasticity. Finally we show that SPs can partially resolve outstanding difficult problems of convergent evolution by representing correctly enzyme functions in spite of remote homologies in sequence and in structure. Proteins 2008. © 2008 Wiley‐Liss, Inc.