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J Proteome Res. 2015 Nov 6;14(11):4851-62. doi: 10.1021/acs.jproteome.5b00681. Epub 2015 Oct 8.

Peptidomics of Circular Cysteine-Rich Plant Peptides: Analysis of the Diversity of Cyclotides from Viola tricolor by Transcriptome and Proteome Mining.

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Center for Physiology and Pharmacology, Medical University of Vienna , Schwarzspanierstrasse 17, 1090 Vienna, Austria.
School of Biomedical Sciences, The University of Queensland , St. Lucia, Queensland 4072, Australia.
Florida Museum of Natural History, University of Florida , Gainesville, Florida 32611, United States.
Department of Biological Sciences, University of Alberta , Edmonton, Alberta T6G 2E9, Canada.
Department of Medicine, University of Alberta , Edmonton, Alberta T6G 2E1, Canada.
BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen 518083, China.


Cyclotides are plant-derived mini proteins. They are genetically encoded as precursor proteins that become post-translationally modified to yield circular cystine-knotted molecules. Because of this structural topology cyclotides resist enzymatic degradation in biological fluids, and hence they are considered as promising lead molecules for pharmaceutical applications. Despite ongoing efforts to discover novel cyclotides and analyze their biodiversity, it is not clear how many individual peptides a single plant specimen can express. Therefore, we investigated the transcriptome and cyclotide peptidome of Viola tricolor. Transcriptome mining enabled the characterization of cyclotide precursor architecture and processing sites important for biosynthesis of mature peptides. The cyclotide peptidome was explored by mass spectrometry and bottom-up proteomics using the extracted peptide sequences as queries for database searching. In total 164 cyclotides were discovered by nucleic acid and peptide analysis in V. tricolor. Therefore, violaceous plants at a global scale may be the source to as many as 150 000 individual cyclotides. Encompassing the diversity of V. tricolor as a combinatorial library of bioactive peptides, this commercially available medicinal herb may be a suitable starting point for future bioactivity-guided screening studies.


1kp; Violaceae; circular peptides; cystine-knot; mass spectrometry; natural products; peptidomics; ribosomally synthesized and post-translationally modified peptides; transcriptome

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