Biosynthesis of a moroidin peptide library for biomedical characterization
Introduction to Topic
Moroidin is a biologically active bicyclic plant octapeptide, with unusual leucine-tryptophan and tryptophan-histidine cross-links that form its two rings. It was initially isolated as a pain-causing agent, which has been shown to be responsible for the painful sting of Dendrocnide moroides, an Australian stinging tree of the Urticaceae family. Moroidin and its structural analog celogentin C, extracted from Celosia argentea of the Amaranthaceae family, have demonstrated anti-mitotic properties, specifically through inhibition of tubulin polymerization, and, thus, they represent an interesting lead structure for cancer therapeutics. However, low efficiency of extraction from source plants and hurdles in organic synthesis impede moroidin-based drug development. Here, we seek another route, biosynthesis, to make moroidin-type bicyclic peptides. Moroidins have recently been characterized as ribosomally synthesized and post-translationally modified peptides (RiPPs) in Japanese Kerria (Kerria japonica).3 Moroidin biosynthesis in K. japonica involves a BURP domain gene, KjaBURP, which encodes a hypothetical peptide cyclase that helps install the indole-derived C-C and C-N bonds, which are essential for moroidinrsquo;s bicyclic structure. Transient expression of KjaBURP in the model plant Nicotiana benthamiana yields moroidin and suggests the feasibility of producing analogs of moroidins in transgenic tobacco plants for further evaluation of moroidins as cancer therapeutics.
My interest in genetics and biosynthesis of plant natural products lead me into this area. As we all know, China is famous for traditional Chinese medicine, whose value is underscored due to the lack of standard scientific proof. Dr. Kerstenrsquo;s previous paper related to gene-guided discovery of cyclic ACE-inhibitor peptides called lyciumins2 impressed me a lot and triggered my curiosity on how to build a plant peptide library for therapeutic characterization. A method to create a lyciumin library has already been established. In this research, we are going to develop a biosynthetic system to diversify moroidins and test which moroidin analogs of the sequence motif QLLVWxxH (with x being any proteinogenic amino acid) can be made in Nicotiana benthamiana by the hypothetical KjaBURP peptide cyclase. Ultimately, we will build a moroidin peptide library for biomedical characterization, for example tubulin polymerization inhibition and optimization of these compounds. Besides, we can also test if the isolation yield of moroidin analogs can be improved through heterologous precursor optimization.
Literature Review
In the plant kingdom, Dendrocnide moroides or lsquo;gympie gympiersquo; is reported to be one of the most painful plants upon contact. All aerial parts of this plant are covered with small trichomes. When contacted with this plant, the trichomes will pierce the skin and cause pain for days up to several weeks. Because of its painful activity, people have conducted corresponding phytotoxin studies on it, and a peptide natural product called moroidin was isolated from it as one of the main active compounds.4 In addition to the pain-causing attribute, moroidin and celogentin C also show potent inhibitory activity against tubulin polymerization, which makes them promising lead structure for cancer therapeutics. Celogentin C was four times more potent than moroidin in the inhibitory activity.1
As a bicyclic octapeptide, moroidin is characterized by an N-terminal pyroglutamate and two side-chain macrocyclic linkages. Interestingly, moroidin and some structural derivatives called celogentins have been isolated from the seeds of Celosia argentea. The bicyclic ring system characteristic of celogentins and moroidin includes unusual connections between Leu, Trp, and His residues.(Figure 1) The ring size and peptide sequence, especially of the second ring between tryptophan and C-terminal histidine, appear to be important for interaction with tubulin and are necessary for biological activity of moroidin peptides.1
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