Theta-defensins: cyclic antimicrobial peptides produced by binary ligation of truncated alpha-defensins

• Published in: Current protein & peptide science Vol. 5; no. 5; p. 365
• Main Author: Selsted, Michael E
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01.10.2004
• Subjects: Amino Acid Sequence; Animals; Anti-Bacterial Agents - biosynthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Defensins - chemistry; Defensins - genetics; Defensins - metabolism; Defensins - pharmacology; Humans; Molecular Sequence Data; Peptides, Cyclic - chemistry; Peptides, Cyclic - genetics; Peptides, Cyclic - metabolism; Peptides, Cyclic - pharmacology; Structure-Activity Relationship
• ISSN: 1389-2037
• DOI: 10.2174/1389203043379459

The first cyclic peptide discovered in animals is an antimicrobial octadecapeptide that is expressed in leukocytes of rhesus monkeys. The peptide, termed rhesus Theta-defensin 1 (RTD-1) is the prototype of a new family of antimicrobial peptides, which like the previously characterized alpha- and beta-defensin families, possesses broad spectrum microbicidal activities against bacteria, fungi, and protects mononuclear cells from infection by HIV-1. The cyclic Theta-defensin structure is essential for a number of its antimicrobial properties, as demonstrated by the markedly reduced microbicidal activities of de-cyclized Theta-defensin analogs. Genetic and biochemical experiments disclosed that the biosynthesis of RTD-1 results from the head-to-tail joining of two nine-amino acid peptides, each of which is donated by a separate precursor polypeptide, which are in fact C-terminally truncated pro-alpha-defensins. Alternate combinations of the two nonapeptides generate two additional macaque Theta-defensins, RTD-2 and RTD-3. Humans do not express Theta-defensin peptides, but mRNAs encoding at least two Theta-defensins are expressed in human bone marrow. However, in each case the open reading frame is interrupted by a stop codon in the signal peptide-coding region. The mature Theta-defensin peptide is a two-stranded beta-sheet that, like the alpha- and beta-defensins, is stabilized by three disulfides. However, the parallel orientation of the Theta-defensin disulfide arrangement allows for substantial flexibility around its short axis. Unlike alpha- and beta-defensins, RTD-1 lacks an amphiphilic topology. This may partially explain the unusual interaction between Theta-defensins and phospholipid bilayers.