In vivo investigation of the role of SfmO2 in saframycin A biosynthesis by structural characterization of the analogue saframycin O |
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Authors: | Chao Peng Yu-Min Tang Lei Li Wei Ding Wei Deng Jin-Yue Pu Wen Liu Gong-Li Tang |
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Institution: | PENG Chao,TANG Yu-Min,LI Lei,DING Wei,DENG Wei,PU Jin-Yue,LIU Wen & TANG Gong-Li* State Key Laboratory of Bio-organic and Natural Products Chemistry;Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences,Shanghai 200032,China |
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Abstract: | Saframycin A(SFM-A),a tetrahydroisoquinoline antibiotic isolated from Streptomyces lavendulae,shows potent anti-proliferation activities against a variety of tumor cell lines,and shares the core structure with ecteinascidin 743(ET-743),the anticancer drug for soft-tissue sarcoma.Characterization of the SFM-A biosynthetic gene cluster revealed three nonribosomal peptide synthetase genes and a series of genes encoding oxygenases.To investigate the function of sfmO2 gene,encoding a FAD-dependent monooxygenase/hydroxylase,we constructed the gene replacement mutant(△sfmO2) strain S.lavendulae TL2007 and the corresponding gene complementation mutant strain S.lavendulae TL2008.A novel compound,SFM-O,was isolated from the △sfmO2 replacement mutant strain and its structure was characterized by comparison to the HRMS and NMR spectra of SFM-A.These findings indicated that SfmO2 is responsible for the oxidation of ring A in the biosynthetic pathway of SFM-A,and the new compound SFM-O could be considered as an advanced intermediate in the semisynthesis of ET-743. |
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Keywords: | saframycin A biosynthesis SfmO2 oxygenase saframycin O |
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