Life After Catalytic Death: Pseudopeptidases as Key Regulators in Health and Disease

In recent years, researchers have increasingly focused on a special class of proteins – pseudopeptidases, that have lost their catalytic activity while retaining the ability to bind targets with high specificity. The evolutionary transition from an active enzyme to a pseudopeptidase is often driven by point mutations in the active site that “switch off” hydrolysis, paradoxically increasing affinity for substrates or regulatory partners. This process of “functional exaptation” allows the cell to create complex regulatory networks by repurposing existing domains rather than synthesizing new structures. This review analyzes the mechanisms underlying the emergence of pseudopeptidases across all major peptidase families and their roles in signaling cascades as molecular scaffolds, allosteric modulators, or competitive inhibitors. Particular attention is paid to their contribution to pathophysiology: the loss of proteolytic function does not render these proteins “silent”; on the contrary, their dysfunction is critical in the development of cancer, as well as neurodegenerative and inflammatory diseases. The shift from catalytic inertness to active regulation opens new horizons in understanding the molecular mechanisms of pathologies, positioning pseudopeptidases as promising targets for therapeutic intervention.