Biosynthesis of defensins and other antimicrobial peptides.
Defensins are small (about 30 amino acid residues) cationic antimicrobial peptides with a conserved framework of six disulphide-linked cysteines. Human defensin HNP-1 and the closely related HNP-3 are amphiphilic dimers that act in part by permeabilizing cell membranes. Defensin mRNAs, abundant in neutrophilic promyelocytes, certain non-human macrophages and Paneth cells, encode 94-100 amino acid prepropeptides. PreproHNP-1 is post-translationally processed to inactive proHNP-1 then to mature HNP-1 stored in granules. Bactenecin Bac-5 and perhaps other related neutrophil peptides are also synthesized as prepropeptides but are stored in granules as inactive propeptides. Their conserved cathelin-like propiece inhibits the cysteine protease, cathepsin L, and is removed only during granule release. Charge neutralization of mature peptide by the propiece is seen in both probactenecins and prodefensins. In contrast the propiece of cecropins is very short and proceropins are microbicidal. The pathways that convert myeloid preprodefensins to defensins are specific to myeloid cells but the signal for targeting to granules also functions in non-myeloid granulated cells. The truncation of the anionic propiece by deletion mutagenesis dramatically reduces defensin synthesis, suggesting that the propiece may assist in peptide stabilization, folding or subcellular transport. Despite some similarities in the mechanism of action of the various families of antimicrobial peptides, their precursors differ greatly, presumably owing to differing functions of the propieces.
Ganz
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Department of Medicine, UCLA School of Medicine 90024, USA.
D000595:Amino Acid Sequence; D000818:Animals; D000890:Anti-Infective Agents; D001798:Blood Proteins / Q000096:biosynthesis* / Q000235:genetics; D023082:Defensins; D006801:Humans; D008969:Molecular Sequence Data; D010452:Peptide Biosynthesis; D010455:Peptides / Q000235:genetics / Q000494:pharmacology; D023084:alpha-Defensins
D000890:Anti-Infective Agents; D001798:Blood Proteins; D023082:Defensins; D010455:Peptides; D023084:alpha-Defensins; C406413:human neutrophil peptide 1; C406427:human neutrophil peptide 3