Xiangya International Academy of Translational Medicine, Central South University, Tongzipo Road, #172, Yuelu District, Changsha, 410013, Hunan, China.
State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
Microb Cell Fact. 2021 Oct 2;20(1):192. doi: 10.1186/s12934-021-01681-5.
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.
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.
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.
Rubiginones 属于蒽环类芳香聚酮化合物，已被证明能增强长春新碱（VCR）对 VCR 耐药癌细胞系的细胞毒性。然而，Rubiginones 的生物合成基因簇（BGCs）和生物合成途径尚未报道。
在这项研究中，基于对链霉菌 sp.CB02414 基因组的生物信息学分析，我们预测了两个 II 型聚酮合酶（PKSs） BGC 的功能。Rub 基因簇被预测编码蒽环类家族的代谢物。CB02414 野生型菌株的大规模发酵导致发现了八种 Rubiginones，包括五种新的 Rubiginones（Rubiginones J、K、L、M 和 N）。Rubiginone J 被提议为 Rub 基因簇的最终产物，其特征在于蒽环骨架 A 环上广泛氧化。基于 CB02414 野生型和突变株的生产谱，我们提出了 CB02414 中 Rubiginones 的生物合成途径。
一种基因组挖掘策略使我们能够从链霉菌 sp.CB02414 中高效发现新的 Rubiginones。基于分离的生物合成中间体，提出了 Rubiginones 的合理生物合成途径。我们的研究为进一步研究细胞色素 P450 催化的蒽环类化合物氧化机制以及利用组合生物合成策略生成新型蒽环类化合物奠定了基础。
