A bifunctional asparaginyl endopeptidase efficiently catalyzes both cleavage and cyclization of cyclic trypsin inhibitors

Junqiao Du, Kuok Yap, Lai Yue Chan, Fabian B. H. Rehm, Fong Yang Looi, Aaron G. Poth, Edward K. Gilding, Quentin Kaas, Thomas Durek () and David J. Craik ()
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Junqiao Du: The University of Queensland
Kuok Yap: The University of Queensland
Lai Yue Chan: The University of Queensland
Fabian B. H. Rehm: The University of Queensland
Fong Yang Looi: The University of Queensland
Aaron G. Poth: The University of Queensland
Edward K. Gilding: The University of Queensland
Quentin Kaas: The University of Queensland
Thomas Durek: The University of Queensland
David J. Craik: The University of Queensland

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract Asparaginyl endopeptidases (AEPs) catalyze the key backbone cyclization step during the biosynthesis of plant-derived cyclic peptides. Here, we report the identification of two AEPs from Momordica cochinchinensis and biochemically characterize MCoAEP2 that catalyzes the maturation of trypsin inhibitor cyclotides. Recombinantly produced MCoAEP2 catalyzes the backbone cyclization of a linear cyclotide precursor (MCoTI-II-NAL) with a kcat/Km of 620 mM−1 s−1, making it one of the fastest cyclases reported to date. We show that MCoAEP2 can mediate both the N-terminal excision and C-terminal cyclization of cyclotide precursors in vitro. The rate of cyclization/hydrolysis is primarily influenced by varying pH, which could potentially control the succession of AEP-mediated processing events in vivo. Furthermore, MCoAEP2 efficiently catalyzes the backbone cyclization of an engineered MCoTI-II analog with anti-angiogenic activity. MCoAEP2 provides enhanced synthetic access to structures previously inaccessible by direct chemistry approaches and enables the wider application of trypsin inhibitor cyclotides in biotechnology applications.

Date: 2020
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DOI: 10.1038/s41467-020-15418-2

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