Description

Lysine acylations sit everywhere in biology. Acetylation. Succinylation. Malonylation. Glutarylation. Itaconylation. Crotonylation. Each one can rewrite a protein's surface. It can change charge. It can change shape. It can change who binds, what falls off, and what the protein actually does.

In this work scientists introduced MeOK into a protein: a landing pad for modifications via a masked hydroxylamine handle. From one MeOK-bearing precursor, they build a whole panel of lysine modifications. In ubiquitin alone, they install eleven distinct PTMs. That includes those that have stayed out of reach for direct encoding: malonylation, succinylation, glutarylation, and itaconylation, plus bulky or reactive motifs. They show impact: like how acetylation of E. coli isocitrate dehydrogenase at K242 reduces catalytic performance, and the effect matches a directly encoded acetyl-lysine control.

Citation: Knecht et al., 2025

Post-translational modifications (PTMs) on lysine residues, including acetylation, succinylation, malonylation, and glutarylation, regulate protein function throughout biology. Studying them has been difficult because they are transient, heterogeneous, and hard to install site-specifically.

A non-canonical amino acid called MeOK acts as a universal precursor: once incorporated at a defined site, its masked hydroxylamine handle can be derivatised to generate any of a panel of lysine modifications. From a single MeOK-containing protein, researchers installed 11 distinct PTMs on ubiquitin, including malonylation, succinylation, glutarylation, and itaconylation, modifications previously inaccessible through genetic encoding (Knecht et al., 2025).

For therapeutics, stable PTM mimetics offer a way to lock proteins into specific functional states. Rather than relying on cellular enzymes to add or remove modifications (which creates heterogeneity), the modification is built in during production and remains permanent. This is valuable for producing homogeneous protein therapeutics with defined activity profiles.

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