| Autor: |
Kersten RD; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States., Mydy LS; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States., Fallon TR; Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, Massachusetts 02142, United States.; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, United States., de Waal F; Bioinformatics Group, Wageningen University, Wageningen 6700AP, The Netherlands., Shafiq K; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States., Wotring JW; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States., Sexton JZ; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States., Weng JK; Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, Massachusetts 02142, United States.; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, United States. |
| Abstrakt: |
Moroidin is a bicyclic plant octapeptide with tryptophan side-chain cross-links, originally isolated as a pain-causing agent from the Australian stinging tree Dendrocnide moroides . Moroidin and its analog celogentin C, derived from Celosia argentea , are inhibitors of tubulin polymerization and, thus, lead structures for cancer therapy. However, low isolation yields from source plants and challenging organic synthesis hinder moroidin-based drug development. Here, we present biosynthesis as an alternative route to moroidin-type bicyclic peptides and report that they are ribosomally synthesized and posttranslationally modified peptides (RiPPs) derived from BURP-domain peptide cyclases in plants. By mining 793 plant transcriptomes for moroidin core peptide motifs within BURP-domain precursor peptides, we identified a moroidin cyclase in Japanese kerria, which catalyzes the installation of the tryptophan-indole-centered macrocyclic bonds of the moroidin bicyclic motif in the presence of cupric ions. Based on the kerria moroidin cyclase, we demonstrate the feasibility of producing diverse moroidins including celogentin C in transgenic tobacco plants and report specific cytotoxicity of celogentin C against a lung adenocarcinoma cancer cell line. Our study sets the stage for future biosynthetic development of moroidin-based therapeutics and highlights that mining plant transcriptomes can reveal bioactive cyclic peptides and their underlying cyclases from new source plants. |
