Lysine Propionylation as a Metabolically Coupled PTM: Mechanisms, Functional Consequences, and Therapeutic Potentials.

Lysine propionylation (Kpr) is a metabolically coupled lysine acylation that links propionyl-CoA availability to the molecular regulation of gene expression and protein function. Although lysine acetylation (Kac) is the most extensively characterized, recent proteomic and metabolic studies suggest that Kpr is more frequent than previously appreciated, occurs at defined lysine sites, and displays tissue-resolved and context-dependent patterns. Kpr often co-varies with other short-chain acylations such as Kac and lysine butyrylation (Kbu); however, emerging genomic-scale evidence indicates mark-biased genomic distributions and functional associations, suggesting that Kpr is not simply an extension or alternative to Kac. Notably, propionyl-CoA, the direct acyl donor for Kpr, can be influenced by microbiome-derived short-chain fatty acids (SCFAs), implying that interventions modulating SCFA availability (e.g., dietary manipulation) may provide an actionable route to tune Kpr and related acylations. Here, we summarize recent advances in propionyl-CoA sources and compartmentalization, the enzymatic writers/erasers/readers, the molecular mechanisms underlying Kpr, and the functional consequences of Kpr in physiology and disease.