Dehydroamino acid chemical biology: an example of functional group interconversion on proteins

In nature, dehydroalanine (Dha) and dehydrobutyrine (Dhb) residues are byproducts of protein aging, intermediates in the biosynthesis of lanthipeptides and products of bacterial phospholyases that inactivate host kinase immune responses. Recent chemical biology studies have demonstrated the possibility of mapping dehydroamino acids in complex proteomes in an unbiased manner that could further our understanding of the role of Dha and Dhb in biology and disease more broadly. From a synthetic perspective, chemical mutagenesis through site-selective formation of the unsaturated residue and subsequent addition chemistry has yielded homogeneous proteins bearing a variety of post-translational modifications (PTMs) which have assisted fundamental biological research. This Opinion discusses these recent advances and presents new opportunities for protein engineering and drug discovery. The chemical biology of dehydroalanine and dehydrobutyrine in proteins is summarized and new concepts are presented.