Proximal Cysteines that Enhance Lysine N-Acetylation of Cytosolic Proteins in Mice Are Less Conserved in Longer-Living Species

Summary Acetyl-coenzyme A (CoA) is an abundant metabolite that can also alter protein function through non-enzymatic N -acetylation of protein lysines. This N- acetylation is greatly enhanced in vitro if an adjacent cysteine undergoes initial S- acetylation, as this can lead to S→N transfer of the acetyl moiety. Here, using modeled mouse structures of 619 proteins N -acetylated in mouse liver, we show lysine N- acetylation is greater in vivo if a cysteine is within ∼10 A. Extension to the genomes of 52 other mammalian and bird species shows pairs of proximal cysteine and N- acetylated lysines are less conserved, implying most N- acetylation is detrimental. Supporting this, there is less conservation of cytosolic pairs of proximal cysteine and N- acetylated lysines in species with longer lifespans. As acetyl-CoA levels are linked to nutrient supply, these findings suggest how dietary restriction could extend lifespan and how pathologies resulting from dietary excess may occur.