Abstract
BackgroundRubiginones 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.ResultsIn 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.ConclusionsA 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.
Highlights
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
The benz[a]anthracene scaffold of angucycline is formed by folding a decaketide chain, which is biosynthesized by the type II polyketide synthases (PKSs), to generate the UWM6 intermediate [3]
We investigated the functions of two cytochrome P450 hydroxylases (RubN1 and RubN2) in the rub cluster of CB02414 and confirmed that they are responsible for the introduction of the hydroxyl groups at C-2 and C-4 of rubiginones, respectively
Summary
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. Angucyclines are aromatic polyketides with an angular tetracyclic benz[a]anthracene skeleton [1]. The benz[a]anthracene scaffold of angucycline is formed by folding a decaketide chain, which is biosynthesized by the type II polyketide synthases (PKSs), to generate the UWM6 intermediate [3]. This common intermediate is decorated by various post-PKS modifications, such as oxidations [4, 5], ring rearrangement/contraction [6], and glycosylations [7, 8], to form numerous angucyclines.
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