Cathelicidin family of antimicrobial peptides: proteolytic processing and protease resistance.
Cathelicidins are a gene family of antimicrobial peptides produced as inactive precursors. Signal peptidase removes the N-terminal signal sequence, while peptidylglycine alpha-amidating monooxygenase often amidates and cleaves the C-terminal region. Removal of the cathelin domain liberates the active antimicrobial peptide. For mammalian sequences, this cleavage usually occurs through the action of elastase, but other tissue-specific processing enzymes may also operate. Once released, these bioactive peptides are susceptible to proteolytic degradation. We propose that some mature cathelicidins are naturally resistant to proteases due to their unusual primary structures. Among mammalian cathelicidins, proline-rich sequences should resist attack by serine proteases because proline prevents cleavage of the scissile bond. In hagfish cathelicidins, the unusual amino acid bromotryptophan may make the active peptides less susceptible to proteolysis for steric reasons. Such protease resistance could extend the pharmacokinetic lifetimes of cathelicidins in vivo, sustaining antimicrobial activity.
Shinnar
Ann Eisenberg
AE
Chemistry Department, Barnard College, Columbia University, New York, NY 10027, USA. ashinnar@barnard.edu
Butler
Kathryn L
KL
Park
Hyon Ju
HJ
D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001120:Arginine / Q000737:chemistry; D001665:Binding Sites; D054804:Cathelicidins; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry*; D010450:Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D006196:Hagfishes; D006801:Humans; D006899:Mixed Function Oxygenases / Q000378:metabolism; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism; D005810:Multigene Family; D011392:Proline / Q000737:chemistry; D021382:Protein Sorting Signals; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
C110059:6-bromotryptophan; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D015853:Cysteine Proteinase Inhibitors; D009097:Multienzyme Complexes; D021382:Protein Sorting Signals; D011506:Proteins; C084515:cathelin; D014364:Tryptophan; D001120:Arginine; D011392:Proline; D006899:Mixed Function Oxygenases; C035189:peptidylglycine monooxygenase; D010450:Endopeptidases