Discovery, Structure and Biological Activities of the Cyclotides

Craik, David J.; Daly, Norelle L.; Mulvenna, Jason; Plan, Manuel R.; Trabi, Manuela

doi:10.2174/1389203043379512

Cited by 165 publications

(134 citation statements)

References 71 publications

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“…Cyclotides are the largest group of circular peptides containing between 28 and 37 amino acids, and have a well defined three-dimensional structure containing exclusively naturally occurring amino acids (7)(8)(9). Cyclotides are characterized by the combination of a cyclic peptide backbone with an embedded cystine knot, collectively called the cyclic cystine knot (10).…”

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confidence: 99%

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

Conlan

Colgrave

Gillon

et al. 2012

Journal of Biological Chemistry

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Background: Production of insecticidal and nematocidal cyclic peptides is inefficient in transgenic plants. Results: Efficient cyclization requires cleavage of the N-terminal propeptide from the mature cyclotide domain and a C terminus containing a binding motif. Conclusion:The cyclization motif has Asn at position P1, a small amino acid at position P1Ј, and a Leu at position P2Ј. Significance: Understanding substrate requirements will help produce cyclotides in transgenic plants.

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confidence: 99%

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

Conlan

Colgrave

Gillon

et al. 2012

Journal of Biological Chemistry

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“…Additional members of the cyclotide family were subsequently identified in screening studies directed toward discovery of bioactive molecules such as neurotensin antagonists (7), inhibitors of HIV replication (8), and hemolytic agents (9). More than 100 cyclotides have since been isolated from various members of the Rubiaceae, Violaceae, and Cucurbitaceae plant families (10,11). A single plant may have at least 12 cyclotide genes and produce dozens of different cyclotides (12)(13)(14).…”

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Plant cyclotides disrupt epithelial cells in the midgut of lepidopteran larvae

Barbeta¹,

Marshall

Gillon³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

198

199

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Several members of the Rubiaceae and Violaceae plant families produce a series of cyclotides or macrocyclic peptides of 28 -37 aa with an embedded cystine knot. The cyclic peptide backbone together with the knotted and strongly braced structure confers exceptional chemical and biological stability that has attracted attention for potential pharmaceutical applications. Cyclotides display a diverse range of biological activities, such as uterotonic action, anti-HIV activity, and neurotensin antagonism. In plants, their primary role is probably protection from insect attack. Ingestion of the cyclotide kalata B1 severely retards the growth of larvae from the Lepidopteran species Helicoverpa armigera. We examined the gut of these larvae after consumption of kalata B1 by light, scanning, and transmission electron microscopy. We established that kalata B1 induces disruption of the microvilli, blebbing, swelling, and ultimately rupture of the cells of the gut epithelium. The histology of this response is similar to the response of H. armigera larvae to the Bacillus thuringiensis delta-endotoxin, which is widely used to control these insect pests of crops such as cotton. circular peptides ͉ insecticidal ͉ kalata B1 ͉ Lepidoptera ͉ microscopy C yclotides are a series of cyclic minipeptides of 28-37 aa that are expressed at high levels in the leaves, stems, and roots of several plant species (1, 2). They have an unusual topology based on a cyclic peptide backbone together with a cystine knot in which two disulfide bonds are threaded by a third disulfide bond (2, 3). This structure forces hydrophobic amino acids onto the surface of the molecule, creating a hydrophobic face on the otherwise hydrophilic surface. The cyclotides are thus soluble in both organic and aqueous solvents and are very stable at extremes of pH and temperature (4). The absence of free N and C termini, together with the tightly packed cystine knot, also renders the cyclotides resistant to the activity of proteases (4). The cyclotides are the largest family of circular proteins, although others have been described in bacteria, plants, and animals (5).Cyclotides were first isolated from the African plant Oldenlandia affinis. Two peptides, kalata B1 and B2, were recognized as the active components in a traditional medicine used to accelerate childbirth (6). Additional members of the cyclotide family were subsequently identified in screening studies directed toward discovery of bioactive molecules such as neurotensin antagonists (7), inhibitors of HIV replication (8), and hemolytic agents (9). More than 100 cyclotides have since been isolated from various members of the Rubiaceae, Violaceae, and Cucurbitaceae plant families (10, 11). A single plant may have at least 12 cyclotide genes and produce dozens of different cyclotides (12)(13)(14). Although an earlier study reported antimicrobial activity (15), it appears that their predominant activity in plants is insecticidal (13, 16). Jennings et al. (13) demonstrated that Helicoverpa punctigera failed to devel...

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“…[1][2][3] They contain 28 to 37 amino acids, and their head-to-tail cyclic backbone and six conserved cysteine residues form a structural motif referred to as a cyclic cystine knot (CCK). [4] It is believed that the compact CCK motif of cyclotides is responsible for their exceptional resistance against chemical, thermal, and proteolytic degradation.…”

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Structure and Activity of the Leaf-Specific Cyclotide vhl-2

et al. 2010

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Cyclotides are plant-derived macrocyclic peptides with potential applications in the pharmaceutical and agricultural industries. In addition to their presumed natural function as host-defence peptides arising from their insecticidal activity, their other biological activities include antimicrobial, haemolytic, and cytotoxic activities, but at present, only limited information is available on the structural and chemical features that are important for these various activities. In the current study, we determined the three-dimensional structure of vhl-2, a leaf-specific cyclotide. Although the characteristic cyclic cystine knot fold of other cyclotides is maintained in vhl-2, it has more potent haemolytic activity than well-characterized cyclotides such as kalata B1 and kalata B8. Analysis of surface hydrophobicity and haemolytic activity for a range of cyclotides indicates a correlation between them, with increasing hydrophobicity resulting in increased haemolytic activity. This correlation is consistent with membrane binding being a vital step in mediating the various cytotoxic activities of cyclotides. The gene sequence for vhl-2 was determined and indicates that vhl-2 is processed from a multidomain precursor protein that also encodes the cyclotide cycloviolacin H3.

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Discovery, Structure and Biological Activities of the Cyclotides

Cited by 165 publications

References 71 publications

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

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

Plant cyclotides disrupt epithelial cells in the midgut of lepidopteran larvae

Structure and Activity of the Leaf-Specific Cyclotide vhl-2

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