Gene-guided discovery and ribosomal biosynthesis of anticancer moroidin peptides

Moroidin is a bicyclic plant octapeptide with tryptophan side-chain crosslinks, originally isolated as a pain-causing agent from 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. This submission includes the 793 plant transcriptomes from the 1kp databases [1] of Table S2 which were assembled de novo by rnaSPAdes [2,3] and searched for moroidin peptide cyclases. Yan, Z., Carpenter, E.J., Wickett, N.J., Mirarab, S., Nguyen, N., Warnow, T., Ayyampalayam, S., Barker, M. and Burleigh, J.G., 2014. Data access for the 1,000 Plants (1KP) project. Gigascience, 3(1), pp.2047-217X. Bankevich, A., Nurk, S., Antipov, D., Gurevich, A.A., Dvorkin, M., Kulikov, A.S., Lesin, V.M., Nikolenko, S.I., Pham, S., Prjibelski, A.D. and Pyshkin, A.V., 2012. SPAdes: a new genome assembly algorithm and its applications to single-cell sequencing. Journal of computational biology, 19(5), pp.455-477. Bushmanova, E., Antipov, D., Lapidus, A. and Prjibelski, A.D., 2019. rnaSPAdes: a de novo transcriptome assembler and its application to RNA-Seq data. GigaScience, 8(9), p.giz100.

莫罗伊丁（Moroidin）是一种带有色氨酸侧链交联的双环植物八肽，最初作为致痛活性物质从澳大利亚刺树（Dendrocnide moroides）中分离得到。莫罗伊丁及其从青葙（Celosia argentea）中提取的类似物西洛森汀C（celogentin C）均为微管蛋白聚合抑制剂，因此是癌症治疗的先导化合物。然而，从源植物中分离的产率极低，且有机合成难度极大，阻碍了基于莫罗伊丁的药物开发。本研究开发了生物合成作为获取莫罗伊丁类双环肽的替代途径，并证实此类肽属于植物中BURP结构域肽环化酶衍生的核糖体合成与翻译后修饰肽（ribosomally synthesized and posttranslationally modified peptides，RiPPs）。

本提交包含来自1000种植物（1KP）项目数据库表S2中的793个植物转录组，这些转录组通过rnaSPAdes[2,3]进行从头组装，并用于检索莫罗伊丁肽环化酶。

参考文献：
[1] Yan Z, Carpenter E J, Wickett N J, et al. Data access for the 1,000 Plants (1KP) project[J]. GigaScience, 2014, 3(1): 2047-217X.
[2] Bankevich A, Nurk S, Antipov D, et al. SPAdes: A new genome assembly algorithm and its applications to single-cell sequencing[J]. 计算生物学杂志, 2012, 19(5): 455-477.
[3] Bushmanova E, Antipov D, Lapidus A, et al. rnaSPAdes: A de novo transcriptome assembler and its application to RNA-Seq data[J]. GigaScience, 2019, 8(9): giz100.