Biosynthetic pathways of cyclotides- ultrastable cyclic peptides from plants with applications in agriculture and medicine David Craik The University of Queensland, Australia Cyclotides are plant cyclic peptides that comprise ~30 amino acids and incorporate three disulfide bonds arranged in a cystine knot topology, which makes them exceptionally stable. 1 Cyclotides occur in all plants from the Violaceae family and in certain plants from the Rubiaceae, Cucurbitaceae, Solanaceae and Fabaceae, where they are present as host defense agents against insects and nematodes. 2 A single plant may contain dozens to hundreds of cyclotides expressed in a wide range of tissues, including leaf, flower, stem and roots. Their stability and compact structure makes cyclotides an attractive protein framework onto which bioactive peptide epitopes can be grafted to stabilise them. 3 Because plants produce cyclotides in large quantities (up to 2g/ kg plant weight) we are using crop plants as expression systems for the production of pharmaceutically active cyclotides. This presentation will give an overview on the biosynthetic pathways that produce cyclotides, with a focus on asparaginyl endoproteinase enzymes implicated in the cyclisation process. I will also describe the use of transgenic plants as vehicles for the production of cyclotide-based drug leads for cancer, cardiovascular disease and pain. 4 References 1. De Veer, SJ, Kan, M-W and Craik D J: Cyclotides. Chemical Reviews , 19 , 12375-12421 (2019). 2. Gilding E K, Jackson M A, Poth A G, Henriques S T, Prentis P J, Mahatmanto T, Craik D J: Gene coevolution and regulation lock cyclic plant defence peptides to their targets. New Phytologist (2016) 210 , 717-730. 3. Wang C K, Craik D J: A designer’s guide to the making of macrocycles. Nature Chemical Biology (2018) 14 , 417-427. 4. Jackson M A, Gilding E K, Shafee T, Harris K, Kaas Q, Poon S, Yap K, Jia H, Guarino R, Chan L Y, Durek T, Anderson M A, Craik D J: Molecular basis for the production of cyclic peptides by plant asparaginyl endopeptidases. Nature Communications (2018) 9 , 2411.
K07
© The Author(s), 2022
Made with FlippingBook Learn more on our blog