Research in the Matthews group unites enzymology and chemical biology to develop novel chemical proteomics technologies for the discovery of enzyme cofactors and regulatory post-translational modifications that cannot readily be predicted by gene or protein sequence.

Intrinsic nucleophiles abound among the proteinogenic amino acids, but, interestingly, reactive electrophiles are essentially absent. Therefore, the majority of chemical probes target nucleophilic sites to discover enzymes, inhibitors and drug therapies. However, by acquiring them through post-translational modifications, enzymes do indeed exploit diverse classes of protein-bound electrophiles for catalysis and other essential functions. Owing to this mode of acquisition, functional electrophiles are not generally predictable from sequence; thus, their breadth and prevalence remain to be found. Our group is exploring this unknown to understand the functions of reactive modifications that we have found unexpectedly on drug targets implicated in cancer and Alzheimer’s disease. Such discoveries can be uncovered using the ‘reverse-polarity’ chemical probes that we develop. We expect that this largely un-profiled half of the reactive proteome – the covalent ‘electrophilome’ – will be found to rival its 'nucleophilome' counterpart in functional diversity and disease relevance.