Protease: Definition

Detailed Explanation

A protease (also called peptidase, proteinase, or proteolytic enzyme) is any enzyme that catalyzes the hydrolysis of peptide bonds, breaking proteins and peptides into smaller fragments or individual amino acids. Proteases are among the most abundant and functionally diverse enzymes in biology — they constitute approximately 2% of the human genome and participate in virtually every physiological process from digestion to blood clotting to apoptosis.

Proteases are classified by catalytic mechanism into six groups: serine proteases (trypsin, chymotrypsin, thrombin — use a Ser-His-Asp catalytic triad), cysteine proteases (caspases, calpains — use a Cys-His dyad), aspartate proteases (pepsin, HIV protease — use two Asp residues), metalloproteases (ACE, matrix metalloproteinases — use a metal ion, typically zinc), threonine proteases (the proteasome), and glutamic acid proteases (primarily fungal).

For peptide therapeutics, proteases are the central pharmacological obstacle. Native peptides are destroyed in minutes by circulating proteases (DPP-IV cleaves GLP-1), membrane-bound peptidases (aminopeptidases, carboxypeptidases), and digestive proteases (pepsin, trypsin, chymotrypsin). Every major peptide drug design strategy — D-amino acid substitution, N-terminal acetylation, cyclization, PEGylation, acylation — exists to evade protease degradation. Conversely, protease inhibitors are major drug classes: ACE inhibitors for hypertension, HIV protease inhibitors for AIDS, and HCV protease inhibitors for hepatitis C.

Key Facts

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