Mechanism of Action of Cytotoxic Cyclotides:  Cycloviolacin O2 Disrupts Lipid Membranes

Svangård, Erika; Burman, Robert; Gunasekera, Sunithi; Lövborg, Henrik; Gullbo, Joachim; Göransson, Ulf

doi:10.1021/np070007v

Cited by 131 publications

(124 citation statements)

References 40 publications

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“…We (29) have also shown that some cyclotides assemble into tetramers and octamers in solution and thus potentially could assemble into pores in membranes. Further evidence for their ability to disrupt membranes is seen from their hemolytic activity (30) and their cytotoxic effect on a human lymphoma cell line (31).…”

Section: Discussionmentioning

confidence: 99%

Plant cyclotides disrupt epithelial cells in the midgut of lepidopteran larvae

Barbeta¹,

Marshall

Gillon³

et al. 2008

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

208

202

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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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Section: Discussionmentioning

confidence: 99%

Plant cyclotides disrupt epithelial cells in the midgut of lepidopteran larvae

Barbeta¹,

Marshall

Gillon³

et al. 2008

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

208

202

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“…Bioassays show that cyclotides belonging to both Möbius and bracelet subfamilies have cytotoxic (9) and hemolytic (19) properties. Studies with model membranes show that kalata B1 (kB1) 6 (20,21), the prototypic Möbius cyclotide, and cycloviolacin O 2 (cyO2) (22), the prototypic bracelet cyclotide, can bind and disrupt lipid bilayers. In addition, the majority of cyclotides have a surface-exposed patch of hydrophobic residues that has been suggested to be required for their bioactivities (23,24).…”

mentioning

confidence: 99%

Phosphatidylethanolamine Binding Is a Conserved Feature of Cyclotide-Membrane Interactions

Henriques

Huang

Castanho

et al. 2012

Journal of Biological Chemistry

122

208

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Background: Cyclotides are a family of plant-expressed pesticidal cyclic peptides. Results: A broad range of cyclotides specifically interact with membranes containing phosphatidylethanolamine (PE)-phospholipids. Conclusion: Cyclotide bioactivity correlates with an ability to target, insert into, and disrupt lipid membranes containing PE-phospholipids. Significance: Cyclotides constitute a new lipid-binding protein family that has potential as a scaffold to target tumor cells.

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“…Cyclotides express a diversity of peptide sequences within their backbone loops and have a broad range of biological activities, including uterotonic (2), anti-HIV (3), antimicrobial (4), and anticancer activities (5). Accordingly, they are of great interest for pharmaceutical applications.…”

mentioning

confidence: 99%

Discovery of an unusual biosynthetic origin for circular proteins in legumes

Poth

Colgrave

Lyons

et al. 2011

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

159

192

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Cyclotides are plant-derived proteins that have a unique cyclic cystine knot topology and are remarkably stable. Their natural function is host defense, but they have a diverse range of pharmaceutically important activities, including uterotonic activity and anti-HIV activity, and have also attracted recent interest as templates in drug design. Here we report an unusual biosynthetic origin of a precursor protein of a cyclotide from the butterfly pea, Clitoria ternatea, a representative member of the Fabaceae plant family. Unlike all previously reported cyclotides, the domain corresponding to the mature cyclotide from this Fabaceae plant is embedded within an albumin precursor protein. We confirmed the expression and correct processing of the cyclotide encoded by the Cter M precursor gene transcript following extraction from C. ternatea leaf and sequencing by tandem mass spectrometry. The sequence was verified by direct chemical synthesis and the peptide was found to adopt a classic knotted cyclotide fold as determined by NMR spectroscopy. Seven additional cyclotide sequences were also identified from C. ternatea leaf and flower, five of which were unique. Cter M displayed insecticidal activity against the cotton budworm Helicoverpa armigera and bound to phospholipid membranes, suggesting its activity is modulated by membrane disruption. The Fabaceae is the third largest family of flowering plants and many Fabaceous plants are of huge significance for human nutrition. Knowledge of Fabaceae cyclotide gene transcripts should enable the production of modified cyclotides in crop plants for a variety of agricultural or pharmaceutical applications, including plant-produced designer peptide drugs.cyclic peptides | structure | cystine knot | kalata B1

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Mechanism of Action of Cytotoxic Cyclotides: Cycloviolacin O2 Disrupts Lipid Membranes

Cited by 131 publications

References 40 publications

Plant cyclotides disrupt epithelial cells in the midgut of lepidopteran larvae

Plant cyclotides disrupt epithelial cells in the midgut of lepidopteran larvae

Phosphatidylethanolamine Binding Is a Conserved Feature of Cyclotide-Membrane Interactions

Discovery of an unusual biosynthetic origin for circular proteins in legumes

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