Other Circular Peptides

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In recent years several other naturally occurring proteins have been discovered. These are described in a recent review article in Trends in Biochemical Sciences (Trabi and Craik, 2002).

A short list is included to illustrate the rapidly increasing numbers of documented cyclic peptides.

Circular peptides have been found in a wide range of different organisms.
Microcin J25
organism: Escherichia coli AY25
size: 21 amino acids
disulfide bonds: 0
activity: antibiotic
characteristic: highly hydrophobic

Microcin J25 (MccJ25), a highly hydrophobic 21 residue peptide, is excreted by Escherichia coli AY25 in its stationary phase of growth (Blond, 1999). In methanol MccJ25 adopts a highly compact globular structure consisting of a distorted antiparallel ?-sheet which is twisted and folded back onto itself (Blond,2001). The peptide appears to interfere with cell division, since nanomolar concentrations of MccJ25 induce cell filamentation in susceptible cells (Salomón, 1992). Interestingly, the (synthetic) linear form of MccJ25 is less active or even inactive against various tested microorganisms (Blond, 1999), indicating that the circular structure of the backbone is crucial for the peptide's bioactivity.

Bacteriocin AS-48
organism: Enterococcus faecalis subsp. liquefaciens S-48
number of amino acids: 70
disulfide bonds: 0
activity: antibiotic
characteristic: highly basic

Bacteriocin AS-48 was isolated from Enterococcus faecalis subsp. liquefaciens S-48 (Martínez-Bueno, 1994). This highly basic protein consists of 70 amino acids (49% hydrophobic residues) and is active against Gram-positive as well as Gram-negative bacteria. The antimicrobial effect of bacteriocin AS-48 is due to its ability to form pores (with an estimated diameter of 0.7nm) in the membranes of target cells, rendering the membranes permeable to ions and small molecules, causing the release of cytoplasmic material and ultimately the lysis of sensitive cells (Gálvez, 1991). The three dimensional structure of bacteriocin AS-48 consists of a globular arrangement of five ?-helices connected by five short turn regions and enclosing a compact hydrophobic core. Interestingly, the cyclisation occurs within one of the alpha-helices, indicating that the structure of the linear peptide is supposedly vastly different from that of the mature one (Abriouel, 2001).

organism: Helianthus annuus (common sunflower)
size: 14 amino acids
disulfide bonds: 1
activity: trypsin inhibitor
characteristic: Ki value in sub-nanomolar range

With just 14 amino acids SFTI-I (sunflower trypsin inhibitor I) is the smallest circular peptide found so far. It shows both sequence and conformational similarity with the Bowman-Birk inhibitors, a family of small serine proteinase inhibitors found in the seeds of legumes and in several other plants (Luckett, 1999). SFTI-1 exhibits the greatest potency amongst these inhibitors, with a Ki value in the sub-nanomolar range. The crystal structure of SFTI-1 in complex with trypsin revealed that the amino acid residues of the inhibitor form two antiparallel ?-strands connected by an extended loop at the reactive site end and by a hairpin turn at the other end. The two ?-strands are furthermore stabilized by a single disulfide bond (Luckett, 1999). Korsinczky et al. (Korsinczky, 2001) compared the solution structure and inhibitory activity of native, circular SFTI-1 with that of an acyclic analogue with the peptide backbone broken at the hairpin end. The three dimensional structures of the two molecules proved to be almost identical to each other and to the crystal structure of SFTI-1 bound to trypsin, indicating that the circular nature of SFTI-1 has probably evolved to increase the in vivo lifetime rather than to confer additional stability onto the active loop region.

organism: Macaca mulatta (Rhesus monkey)
size: 18 amino acids
disulfide bonds: 3
activity: antibiotic
characteristic: ladder-like disulfide arrangement

The three RTD (Rhesus theta defensin) peptides, being circular and only 18 amino acids in size, represent the first example for a new type of mammalian defensins. In 1999 the first, RTD-1, was isolated from the leukocytes of rhesus macaques (Tang, 1999). It was discovered that the mature peptide was made up of two nine-amino acid segments cut out of two different precursor proteins, meaning that two head-to-tail ligations were necessary for the formation the circular peptide. Recently, the homodimeric products of these two precursor proteins were also discovered (Leonova, 2001; Tran, 2001), although in considerably smaller amounts than RTD-1. The solution structure of RTD-1 consists of two beta-strands connected by two tight turns (Trabi, 2001). Despite the small size of RTD-1 and the constraints imposed by the circular backbone and the three disulfide bonds, the peptide exhibits a fair amount of mobility, tempting to regard its ladder-like cystine arrangement as a waste of disulfide bonds.


Abriouel, H. et al. (2001) Monolayer characteristics of bacteriocin AS-48, pH effect and interactions with dipalmitoyl phosphatic acid at the air-water interface. Journal of Colloid and Interface Science 233, 306-312.

Blond, A. et al. (1999) The cyclic structure of microcin J25, a 21-residue peptide antibiotic from Escherichia coli. European Journal of Biochemistry 259, 747-755.

Blond, A. et al. (2001) Solution structure of microcin J25, the single macrocyclic antimicrobial peptide from Escherichia coli. European Journal of Biochemistry 268, 2124-2133.

Gálvez, A. et al. (1991) Permeation of bacterial cells, permeation of cytoplasmic and artificial membrane vesicles, and channel formation on lipid bilayers by peptide antibiotic AS-48. Journal of Bacteriology 173, 886-892.

Korsinczky, M.L.J. et al. (2001) Solution structures by 1H NMR of the novel cyclic trypsin inhibitor SFTI-1 from sunflower seeds and an acyclic permutant. Journal of Molecular Biology 311 (3), 579-591.

Leonova, L. et al. (2001) Circular minidefensins and posttranslational generation of molecular diversity. Journal of Leukocyte Biology 70, 461-464.

Luckett, S. et al. (1999) High-resolution structure of a potent, cyclic proteinase inhibitor from sunflower seeds. Journal of Molecular Biology 290 (2), 525-533.

Martínez-Bueno, M. et al. (1994) Determination of the gene sequence and the molecular structure of the enterococcal peptide antibiotic AS-48. Journal of Bacteriology 176 (20), 6334-6339.

Salomón, R.A. and Farías, R.N. (1992) Microcin 25, a novel antimicrobial peptide produced by Escherichia coli. Journal of Bacteriology 174, 7428-7435.

Tang, Y.-Q. et al. (1999) A cyclic antimicrobial peptide produced in primate leukocytes by the ligation of two truncated ?-defensins. Science 286, 498-502.

Trabi, M. et al. (2001) Three-dimensional structure of RTD-1, a cyclic antimicrobial defensin from rhesus macaque leukocytes. Biochemistry 40, 4211-4221.

Trabi M and Craik D: Circular proteins - no end in sight. Trends Biochem. Sci. (2002) 27:132-138.

Tran, D. et al. (2001) Homodimeric theta defensins from Rhesus macaque leukocytes: isolation, synthesis, antimicrobial activities and bacterial binding properties of the cyclic peptides. Journal of Biological Chemistry