Structure and Activity of Circular Plant Proteins: Cytotoxic Effects of Viola Cyclotides

Cyclotides are a family of small and macrocyclic proteins that have been found in Violacaee and Rubiaceae plant species. These proteins contain a cystine knot: two disulfides bonds together with their connecting peptide backbone form an embedded ring which is penetrated by a third disulfide bond. The cyclotides have been attributed a wide range of biological activities, which in combination with their chemical stability and structural plasticity have made them attractive tools for pharmaceutical applications.The sequence of eleven novel cyclotides, vibi A-K, from Viola biflora was determined by the use of both chemical (extraction and characterization) and molecular biology (cDNA analyses) approaches. A clear discrepancy in the results from the two methods was observed. Additionally, one novel cyclotide, vodo O, was isolated from Viola odorata. To correlate cytotoxic potency to sequence, vodo O and vibi D, E, G and H were tested on a lymphoma cell line.Based on the presence or absence of a cis-Pro bond, the cyclotides are divided into the Möbius and bracelet subfamilies. The bracelet proteins have a higher net charge and are more cytotoxic potent than the Möbius ones. To explore these differences, charged and hydrophobic residues in varv A (Möbius) and cycloviolacin O2 (bracelet) were chemically modified and tested for their cytotoxicity. The net-charge of the two proteins was not important for the potency…


1. Introduction
Cyclotides – circular plant proteins
Structure of cyclotides
Synthesis and production of cyclotides
History of the cyclotides
Biological activities
Aim of this study
2. Cyclotides in plants
Isolation and characterization of cyclotides
Fractionation protocols
LC-MS profiling
Sequence and structure elucidation
Un-knotting the knot
Enzymatic cleavage and MS/MS sequencing
Sequences predicted from mRNA
Structure elucidation
3. Cytotoxicity
The cytotoxicity assay
Cytotoxic activity of cyclotides
Chemical modifications
4. Discussion
Cyclotides from a plant’s perspective
Cyclotides from a plant’s perspective
Aiming for cyclotide sequences
Structure activity correlations
Potential applications
5. Concluding remarks
7. Acknowledgements
8. References
Appendix A: Alignment of cyclotide sequences
Appendix B: 3D structures of cyclotides

Author: Herrmann, Anders

Source: Uppsala University Library

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