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  • Title: Discovery and characterization of the tubercidin biosynthetic pathway from Streptomyces tubercidicus NBRC 13090.
    Author: Liu Y, Gong R, Liu X, Zhang P, Zhang Q, Cai YS, Deng Z, Winkler M, Wu J, Chen W.
    Journal: Microb Cell Fact; 2018 Aug 28; 17(1):131. PubMed ID: 30153835.
    Abstract:
    BACKGROUND: Tubercidin (TBN), an adenosine analog with potent antimycobacteria and antitumor bioactivities, highlights an intriguing structure, in which a 7-deazapurine core is linked to the ribose moiety by an N-glycosidic bond. However, the molecular logic underlying the biosynthesis of this antibiotic has remained poorly understood. RESULTS: Here, we report the discovery and characterization of the TBN biosynthetic pathway from Streptomyces tubercidicus NBRC 13090 via reconstitution of its production in a heterologous host. We demonstrated that TubE specifically utilizes phosphoribosylpyrophosphate and 7-carboxy-7-deazaguanine for the precise construction of the deazapurine nucleoside scaffold. Moreover, we provided biochemical evidence that TubD functions as an NADPH-dependent reductase, catalyzing irreversible reductive deamination. Finally, we verified that TubG acts as a Nudix hydrolase, preferring Co2+ for the maintenance of maximal activity, and is responsible for the tailoring hydrolysis step leading to TBN. CONCLUSIONS: These findings lay a foundation for the rational generation of TBN analogs through synthetic biology strategy, and also open the way for the target-directed search of TBN-related antibiotics.
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