Metalloendopeptidases

Metalloendopeptidases are a broad class of zinc-dependent proteolytic enzymes that cleave peptide bonds at interior sites within polypeptides (endopeptidases). They require a metal ion at the active site to catalyze hydrolysis and are distinguished from exopeptidases that trim residues from the ends of peptide chains. The most common metal is zinc, coordinated by conserved histidine residues; in many enzymes a catalytic glutamate acts as a general base to activate a bound water molecule, which then performs a nucleophilic attack on the peptide bond.

Subfamilies include matrix metalloproteinases (MMPs), neprilysin and related zinc metallopeptidases, ADAMs and ADAMTS (a disintegrin and metalloproteinase family), and other thermolysin-like enzymes. Many metalloendopeptidases share a characteristic zinc-binding motif, often represented as HEXXH, though the exact sequence varies among families. Some enzymes require additional structural features to recognize substrates, accounting for diverse specificities.

Biological roles and regulation are broad. They participate in extracellular matrix remodeling, processing of signaling peptides, activation or inactivation of cytokines and growth factors, digestion, and immune responses. Many metalloendopeptidases are secreted or membrane-anchored, and their activity is tightly controlled by zymogen activation and endogenous inhibitors such as tissue inhibitors of metalloproteinases (TIMPs) or chelating agents.

Clinical relevance is significant; dysregulation of metalloproteases is associated with cancer invasion and metastasis, arthritis, fibrosis, and cardiovascular disease. Therapeutic approaches include selective inhibitors and modulating endogenous inhibitors, though achieving specificity without adverse effects remains challenging.