Natural products have applications as biopharmaceuticals, agrochemicals, and other high-value chemicals. However, there are challenges in isolating natural products from their native producers (e.g. b...

The chemoselective incorporation of arginine carbonylation post-translational modification (PTM) within proteins represents an underexplored frontier. This is largely due to the poor nucleophilicity and resistance to chemical oxidation of arginine. Drawing inspiration from the metal catalyzed oxidation (MCO) processes of arginine, we introduce a chemical methodology aimed at generating glutamate-5-semialdehyde from arginine residues within peptides and proteins. This innovative chemical approach capitalizes on the inherent weak nucleophilicity and oxidative properties of arginine. We also demonstrate the application of this strategy to selectively introduce both natural and unnatural post-translational modifications (PTMs) in a targeted manner. Our chemical approach offers a rapid, robust, and highly selective technique, facilitating chemoproteomic profiling of arginine sites prone to forming glutamate-5-semialdehyde PTM within the human proteome. Additionally, this methodology serves as a versatile platform for uncovering microenvironments that are susceptible to undergoing arginine carbonylation PTM, enabling the understanding of the effect of oxidative stress on arginine in proteins and the impact of these PTMs on cellular processes.

The advent of bioorthogonal chemistry has transformed scientific research, offering a powerful tool for selective and noninvasive labeling of (bio)molecules within complex biological environments. Thi...

Broad discussion is needed to chart a path forward.