AMPylates

AMPylation, also known as adenylylation, is a post-translational modification in which an adenosine monophosphate (AMP) moiety is covalently attached to a target molecule, most often a protein. The reaction typically uses ATP as the donor and is catalyzed by AMP transferases.

Among the best-characterized enzymes are Fic-domain proteins, which transfer AMP to selected residues such as serine, threonine, or tyrosine on substrates. The activity is frequently regulated by a conserved autoinhibitory motif and can be modulated by interacting cofactors and cellular conditions. Although Fic-domain proteins form the major class, other enzymes can also carry out AMP transfer.

Biological roles of AMPylation are diverse. In bacteria, AMPylation is used by pathogens to manipulate host cell processes. For example, Legionella pneumophila effector proteins SidM/DrrA AMPylate Rab GTPases to alter vesicle trafficking during infection. In eukaryotic cells, FicD/HYPE can AMPylate the ER chaperone BiP, linking AMPylation to regulation of the unfolded protein response. AMPylation can alter enzyme activity, protein–protein interactions, or subcellular localization. In many systems the modification is reversible, as some organisms possess de-AMPylases that remove AMP, enabling dynamic control of protein function.

Research in this area aims to map substrates, understand regulatory mechanisms, and explore therapeutic potential. Detection and characterization typically rely on mass spectrometry, structural studies, and mutational analyses, and researchers are investigating inhibitors of Fic-domain enzymes as possible antimicrobial or disease-modifying tools.