Unlike proteins, peptides lack protective tertiary structures, making them immediate substrates for peptidases. Understanding degradation is crucial for both physiology and drug development.
Enzymatic Degradation (Proteolysis)
Exopeptidases (Cleave Terminal Residues) - **Aminopeptidases** — Remove N-terminal amino acids sequentially - **Carboxypeptidases** — Remove C-terminal amino acids - **DPP-IV** — Cleaves dipeptides from N-terminus; critical for GLP-1 degradation
Endopeptidases (Cleave Internal Bonds) - **Neprilysin (NEP)** — Degrades natriuretic peptides, enkephalins, Aβ - **Angiotensin-Converting Enzyme (ACE)** — Processes angiotensin I - **Insulin-Degrading Enzyme (IDE)** — Clears insulin and amylin
Chemical Degradation
Deamidation - Asparagine (Asn) and Glutamine (Gln) residues spontaneously convert to aspartate/glutamate - Accelerated at high temperature and pH - Creates charge differences that alter activity
Oxidation - Methionine (Met) and Cysteine (Cys) are vulnerable to reactive oxygen species - Produces sulfoxides and disulfide scrambling - Can inactivate peptides or alter their structure
Diketopiperazine (DKP) Formation - Cyclization of the first two N-terminal residues - Common when Pro or Gly is at position 2 - Leads to chain cleavage
Physiological Context
The Kidney's Central Role - Peptides below 30-40 kDa are freely filtered by glomeruli - Brush border enzymes on proximal tubules degrade filtered peptides - Amino acids are recycled back into circulation
Consequences for Therapeutics Native peptide half-lives are typically **minutes**: - GLP-1: ~2 minutes - Oxytocin: ~3-5 minutes - Insulin: ~5-10 minutes
This necessitates half-life extension strategies for therapeutic peptides.