Oxidative stress-mediated N-terminal protein modifications and MS-based approaches for N-terminal proteomics

The N-termini of peptides and proteins can be subjected to highly diverse modifications, including acetylation, myristoylation, pyroglutamylation, and epimerization. These modifications affect protein stability, localization, and activity as well as alter the chemical properties of the N-terminus. Oxidative stress is known to induce the direct oxidation of amino acid side chains and peptide backbones in proteins. Alternatively, polyunsaturated fatty acids can be oxidized to lipid hydroperoxides, which further decompose to form highly reactive aldehydes such as 4-oxo-2(E)-nonenal (ONE) and 4-hydroxy-2(E)-nonenal (HNE). ONE and HNE modify various amino acid residues and induce protein cross-linking. However, there have been few studies on oxidative stress-mediated N-terminal modifications and the resulting functional changes. Our recent studies have reported several novel N-terminal modifications that result in the formation of α-ketoamide, transamination, cyclization, and epimerization. These novel N-terminal modifications are the focus of this review. We also outline recent advances in approaches for N-terminal analysis, which have been developed over the last several decades.