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Key role of glutamic acid for the cytotoxic activity of the cyclotide cycloviolacin O2
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
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2006 (English)In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 63, no 2, 235-245 p.Article in journal (Refereed) Published
Abstract [en]

Cyclotides are cyclic plant proteins with potent cytotoxic effects. Here we systematically probed the importance of surface-exposed charged amino acid residues of the cyclotide cycloviolacin O2, using a strategy involving chemical modifications. We show that the single glutamic acid plays a key role for the cytotoxicity: methylation of this residue produced a 48-fold decrease in potency. Virtually no change in potency was observed when masking the single arginine residue using 1,2-cyclohexanedione, while acetylation of the two lysine residues reduced the potency 3-fold. The derivative with modifications at both arginine and lysine residues showed a 7-fold loss of potency. In addition, we show that the activity is dependent on an intact disulfide network and that the short sequences between the six cysteine residues, that is, the backbone loops, are devoid of cytotoxic activity.

Place, publisher, year, edition, pages
2006. Vol. 63, no 2, 235-245 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96354DOI: 10.1007/s00018-005-5486-4PubMedID: 16389447OAI: oai:DiVA.org:uu-96354DiVA: diva2:170903
Available from: 2007-11-08 Created: 2007-11-08 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Structure and Activity of Circular Plant Proteins: Cytotoxic Effects of Viola Cyclotides
Open this publication in new window or tab >>Structure and Activity of Circular Plant Proteins: Cytotoxic Effects of Viola Cyclotides
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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. The Glu residue in cycloviolacin O2 was crucial, while this residue was of minor importance in varv A. Oxidation of the single Trp residue declined the potency significantly in both proteins. To evaluate how the surface properties correlate to the degree of cytotoxic potency, models of all cyclotides hitherto tested were constructed by homology modelling. Calculations showed that the membrane orientation of varv A and cycloviolacin O2 differed significantly, which might explain their difference in potency

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 64 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 64
Keyword
Pharmacognosy, cyclotide, cytotoxic, anti-tumour, macrocyclic, cyclic cystine knot, Alpine violet, Sweet violet, Viola, Violaceae, chemical modifications, structure-activity studies, mass spectroscopy, cDNA clones, Farmakognosi
Identifiers
urn:nbn:se:uu:diva-8283 (URN)978-91-554-7003-6 (ISBN)
Public defence
2007-11-30, B22, BMC, Husargatan 3, Uppsala, 10:15 (English)
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Available from: 2007-11-08 Created: 2007-11-08 Last updated: 2009-10-07Bibliographically approved

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