Genome mining of novel rubiginones from Streptomyces sp. CB02414 and characterization of the post-PKS modification steps in rubiginone biosynthesis

Autor:	Yeji Wang, Xin Chen, Lu Xue, Xiaohui Yan, Xiangcheng Zhu, Jingjing Zhang, Jingyan Zhang, Ying Sun, Yanwen Duan
Jazyk:	angličtina
Rok vydání:	2021
Předmět:	Mutant Secondary Metabolism Anthraquinones Bioengineering Computational biology ENCODE Biosynthesis Applied Microbiology and Biotechnology Streptomyces Genome Microbiology Cytochrome P450 hydroxylase Polyketide chemistry.chemical_compound Bacterial Proteins Genome mining Gene cluster Gene Rubiginones biology Chemistry Research biology.organism_classification QR1-502 Biosynthetic Pathways Multigene Family Biotechnology
Zdroj:	Microbial Cell Factories, Vol 20, Iss 1, Pp 1-14 (2021) Microbial Cell Factories
ISSN:	1475-2859
Popis:	Background Rubiginones belong to the angucycline family of aromatic polyketides, and they have been shown to potentiate the vincristine (VCR)-induced cytotoxicity against VCR-resistant cancer cell lines. However, the biosynthetic gene clusters (BGCs) and biosynthetic pathways for rubiginones have not been reported yet. Results In this study, based on bioinformatics analysis of the genome of Streptomyces sp. CB02414, we predicted the functions of the two type II polyketide synthases (PKSs) BGCs. The rub gene cluster was predicted to encode metabolites of the angucycline family. Scale-up fermentation of the CB02414 wild-type strain led to the discovery of eight rubiginones, including five new ones (rubiginones J, K, L, M, and N). Rubiginone J was proposed to be the final product of the rub gene cluster, which features extensive oxidation on the A-ring of the angucycline skeleton. Based on the production profiles of the CB02414 wild-type and the mutant strains, we proposed a biosynthetic pathway for the rubiginones in CB02414. Conclusions A genome mining strategy enabled the efficient discovery of new rubiginones from Streptomyces sp. CB02414. Based on the isolated biosynthetic intermediates, a plausible biosynthetic pathway for the rubiginones was proposed. Our research lays the foundation for further studies on the mechanism of the cytochrome P450-catalyzed oxidation of angucyclines and for the generation of novel angucyclines using combinatorial biosynthesis strategies.
Databáze:	OpenAIRE
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