Novel Chemical Tools for High-Energy Phosphoamino Acids

Abstract

Post-translational modification (PTM) plays important roles in adjusting the biological functions of target proteins. One of the most common and extensively studied PTMs is protein phosphorylation. Protein kinases and phosphatases that install or remove the phosphoryl group are essential in controlling most cellular signal transduction pathways, and their misregulation is linked to many diseases including cancer. Our research is focused on studying phosphohistidine (pHis) and phosphoaspartate (pAsp), which are more elusive and labile forms of protein phosphorylation. In prokaryotes and lower eukaryotes, pHis is essential in signaling processes, and it is becoming more widely reported to be relevant to certain human diseases such as cancer and inflammation. In addition, pAsp is a major component of prokaryotic two-component signaling pathways. Accordingly, investigation of the biological function of pHis and pAsp is becoming increasingly important. While it is relatively straightforward to investigate chemically stable phospho-serine (pSer), phospho-threonine (pThr) and phospho-tyrosine (pTyr), studying the functional role of pHis and pAsp has proved much more difficult. It is because most of conventional chemical and biochemical methods are incompatible with these labile PTMs, due to their chemical instability. In order to address this lack of adequate research tools, we have been developing novel chemical tools for pHis and pAsp through synergistic combination of organic chemistry and protein chemistry. Here we report our recent progress on the development of such tools, particularly chemical probes for pHis and pAsp.