The rise of AMPylation: from bacterial beginnings to modern implications in health and disease.

Protein AMPylation is a post-translational modification in which adenosine monophosphate (AMP) from ATP is covalently attached to a target protein via a phosphodiester bond. This reaction is catalyzed by AMPylases, a diverse group of enzymes containing adenylyltransferase, filamentation induced by cyclic AMP (FIC), or kinase domains. As a reversible modification, AMPylation is dynamically regulated by both writer enzymes (AMPylases) and eraser enzymes (deAMPylases). Since its initial discovery in bacterial nitrogen metabolism in 1967, AMPylation has been recognized as a critical regulatory mechanism in both prokaryotic and eukaryotic systems. Recent studies link AMPylation to neurological disorders, diabetes, and cancer metastasis, underscoring its physiological and pathological significance. In this review, we present an overview of the discovery of AMPylases and deAMPylases, highlighting their role in cellular signaling, stress response, and host-pathogen interactions.