Protein pyrophosphorylation is a recently described non-enzymatic post-translational modification. Pyrophosphorylation is mediated by the diphosphoinositol polyphosphate second messengers, a group of high-energy metabolites that has been linked to insulin resistance and obesity. However, due to a dearth of suitable tools, annotation of the pyrophosphoproteome presents a formidable challenge.We have developed a method that provides easy access to pyrophosphopeptides. The solution-based approach takes advantage of the well-established procedures to obtain phosphopeptides and the relatively labile pyrophosphate group is incorporated in the last synthetic step. The remarkable compatibility with functional groups (alcohol, thiol, amine, carboxylic acid) in the peptide substrates suggests that the intrinsic nucleophilicity of the phosphoserine residue is higher than previously appreciated. Because the methodology operates in polar solvents, including water, a broad range of pyrophosphopeptides can be accessed. Progress on employing these peptides for the development of mass spectrometry and antibody-based detection methods for pyrophosphoproteins will be discussed.

Chemical pyrophosphorylation of functionally diverse peptides

248th National Meeting (2014)

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