malonylation

Malonylation is a post-translational modification in which a malonyl group is covalently attached to the ε-amino group of a lysine residue, producing malonyl-lysine. The addition introduces a negative charge and a bulky malonyl moiety, reducing the lysine's positive charge and potentially altering protein conformation, interaction surfaces, and localization. The donor is generally thought to be malonyl-CoA, linking the modification to fatty acid and carbohydrate metabolism. Malonylation can arise via non-enzymatic transfer of the malonyl group, particularly in mitochondria where malonyl-CoA concentrations can be high, though enzymatic mechanisms may also contribute in certain contexts.

Malonylation has been detected on numerous proteins in bacteria, yeast, plants, and animals, including metabolic enzymes and histones. Mass spectrometry–based proteomics and antibodies against malonyl-lysine are used to map the malonylome, revealing that malonylation is widespread and often dynamically regulated in response to cellular energy status.

Reversibility is provided by lysine demalonylases. In mammals, SIRT5 is a well-characterized mitochondrial demalonylase that removes malonyl groups. Other sirtuin family members and deacylases are thought to contribute in a tissue- or context-specific manner. The balance between malonylation and demalonylation reflects metabolic state and nutrient availability.

Functionally, malonylation can modulate enzyme activity, protein stability, and interactions; in mitochondria it has been linked to regulation of metabolic pathways such as fatty acid oxidation and energy production. Crosstalk with other acylations (acetylation, succinylation) adds complexity to metabolic regulation. Continued research aims to define the physiological roles and disease associations.