J. Am. Chem. Soc. 144, 7686–7692 (2022)
Now, Roland D. Kersten, Jing-Ke Weng and co-workers report the heterologous biosynthesis of diverse moroidins including celogentin C in Nicotiana benthamiana (N. benthamiana), which is a common model organism in plant research. Previous works had shown that peptides with related chemistry to moroidin are derived from proteins that contain a conserved plant-specific BURP domain. These proteins are ribosomally synthesized and contain both the core peptide of the target compound and a cyclase domain. With this knowledge, Kersten, Weng and co-workers mined hundreds of plant transcriptomes leading to the identification of a moroidin BURP-domain protein precursor gene encoding the moroidin core peptide and the cyclase in Japanese kerria (K. japonica). Mass spectrometric analysis verified the presence of moroidin in this plant. Subsequently, the researchers cloned the moroidin precursor gene, termed KjaBURP, from K. japonica to facilitate heterologous expression in N. benthamiana. This led to the presence of moroidin in the N. benthamiana leaves. Further, the researchers were able to reproduce the moroidin biosynthesis in vitro. Based on these combined results, the authors proposed a biosynthetic route for the synthesis of moroidin peptides in K. japonica (Fig. 1). Hereby, cyclization of the core peptide is followed by proteolytic cleavage of the N-terminus by an endopeptidase. The resulting N-terminal glutamine is then either cyclized spontaneously or by a glutamine cyclotransferase, and the C-terminus of moroidin is cleaved by an exopeptidase. Moreover, the authors showed that the system can also processes core substrates with varied size and residues, providing moroidin-like peptide libraries.
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