Circular proteins and mechanisms of cyclization

Abstract

Cyclization via head‐to‐tail linkage of the termini of a peptide chain occurs in only a small percentage of proteins, but engenders the resultant cyclic proteins with exceptional stability. The mechanisms involved are poorly understood and this review attempts to summarize what is known of the events that lead to cyclization. Cyclic proteins are found in both prokaryotic and eukaryotic species. The prokaryotic circular proteins include the bacteriocins and pilins. The eukaryotic circular proteins in mammals include the theta defensins, found in rhesus macaques, and the retrocyclins. Two types of cyclic proteins have been found in plants, the sunflower trypsin inhibitor and the larger, more prolific, group known as cyclotides. The cyclotides from Oldenlandia affinis, the plant in which these cyclotides were first discovered, are processed by an asparaginyl endopeptidase which is a cysteine protease. Cysteine proteases are commonly associated with transpeptidation reactions, which, for suitable substrates can lead to cyclization events. These proteases cleave an amide bond and form an acyl enzyme intermediate before nucleophilic attack by the amine group of the N‐terminal residue to form a peptide bond, resulting in a cyclic peptide. © 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 94: 573–583, 2010. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

Functional Genetic Analysis of the GarML Gene Cluster in Lactococcus garvieae DCC43 Gives New Insights into Circular Bacteriocin Biosynthesis

“…Although several of the circular bacteriocins have now been genetically characterized, the enzymes responsible for the different steps of maturation and the mechanisms and potential coupling of the processes are still unknown (6).…”

Insights into Processing and Cyclization Events Associated with Biosynthesis of the Cyclic Peptide Kalata B1

“…Genes encoding cyclotide precursors from O. affinis, the most studied cyclotide-bearing plant (6), encode proteins that have a conserved motif that flanks the upstream and down-stream processing sites of each cyclotide domain (14). A recent analysis of a large number of cyclotide precursor sequences showed that similar motifs are present in other plant species (15).…”

“…The conserved motifs that flank the cyclotide domains of the precursor proteins have been proposed to have a crucial role in the cyclization reaction ( Fig. 1C) (14,16).…”

“…The second highly conserved residue is a leucine located 2 amino acids downstream of the Asn in the P2Ј position. It has been proposed, but not experimentally verified, that this residue is essential for AEP binding and cyclization (16,18).…”

Mutations near the cleavage site of enterocin NKR-5-3B prepeptide reveal new insights into its biosynthesis

“…Within the family of antimicrobial peptides, a group characterized by the head-to-tail circularization of their backbone, such as circular bacteriocins, has attracted more attention than their linear counterparts due to their superior structural stability [7,8]. They have huge application potential as safe food preservatives because of their exceptional stability and broad antimicrobial spectra [9].…”