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Mol Biol Evol. 2015 Feb;32(2):392-405. doi: 10.1093/molbev/msu307. Epub 2014 Nov 6.

The evolution of Momordica cyclic peptides.

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Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld, Australia.
The University of Western Australia, School of Chemistry and Biochemistry & The ARC Centre of Excellence in Plant Energy Biology, Crawley, Perth, WA, Australia.
Plant Biodiversity Research, Technische Universit√§t M√ľnchen, Freising, Germany.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld, Australia


Cyclic proteins have evolved for millions of years across all kingdoms of life to confer structural stability over their acyclic counterparts while maintaining intrinsic functional properties. Here, we show that cyclic miniproteins (or peptides) from Momordica (Cucurbitaceae) seeds evolved in species that diverged from an African ancestor around 19 Ma. The ability to achieve head-to-tail cyclization of Momordica cyclic peptides appears to have been acquired through a series of mutations in their acyclic precursor coding sequences following recent and independent gene expansion event(s). Evolutionary analysis of Momordica cyclic peptides reveals sites that are under selection, highlighting residues that are presumably constrained for maintaining their function as potent trypsin inhibitors. Molecular dynamics of Momordica cyclic peptides in complex with trypsin reveals site-specific residues involved in target binding. In a broader context, this study provides a basis for selecting Momordica species to further investigate the biosynthesis of the cyclic peptides and for constructing libraries that may be screened against evolutionarily related serine proteases implicated in human diseases.


Momordica seeds; cyclic cystine knot peptides; evolution; serine protease inhibitors

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