Biosynthesis of trioxacarcin revealing a different starter unit and complex tailoring steps for type II polyketide synthase
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| Authors: | Mei Zhang Xian-Feng Hou Li-Hua Qi Yue Yin Qing Li Hai-Xue Pan Xin-Ya Chen Gong-Li Tang |
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| Institution: | a State Key Laboratory of Bio-organic and Natural Products Chemistry , Shanghai Institute of Organic Chemistry , Chinese Academy of Sciences , 345 Lingling Road , Shanghai 200032 , China . Email: ;b Shanghai Collaborative Innovation Center for Biomanufacturing Technology , 130 Meilong Road , Shanghai 200237 , China |
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| Abstract: | Trioxacarcins (TXNs) are highly oxygenated, polycyclic aromatic natural products with remarkable biological activity and structural complexity. Evidence from 13C-labelled precursor feeding studies demonstrated that the scaffold was biosynthesized from one unit of l-isoleucine and nine units of malonyl-CoA, which suggested a different starter unit in the biosynthesis. Genetic analysis of the biosynthetic gene cluster revealed 56 genes encoding a type II polyketide synthase (PKS), combined with a large amount of tailoring enzymes. Inactivation of seven post-PKS modification enzymes resulted in the production of a series of new TXN analogues, intermediates, and shunt products, most of which show high anti-cancer activity. Structural elucidation of these new compounds not only helps us to propose the biosynthetic pathway, featuring a type II PKS using a novel starter unit, but also set the stage for further characterization of the enzymatic reactions and combinatorial biosynthesis. |
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