Abstract
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. 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. 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.
References
Dec 1, 1988·The Journal of Antibiotics·K Isono
Aug 1, 1963·Chemical & Pharmaceutical Bulletin·Y MizunoS Suzaki
Oct 11, 1996·The Journal of Biological Chemistry·M J BessmanS F O'Handley
Dec 30, 1998·Archives of Pharmacal Research·J C YooH J Bang
Dec 29, 2000·Molecular & General Genetics : MGG·N WeisschuhA Engels
Sep 16, 2003·The Journal of Biological Chemistry·Mark E DrewPaul T Englund
Aug 30, 2008·Chemistry & Biology·Reid M McCarty, Vahe Bandarian
Mar 6, 2010·The Journal of Biological Chemistry·Zhaoyong YangSteven G Van Lanen
Dec 25, 2010·Molecular BioSystems·Lin ChengZixin Deng
Feb 24, 2011·Microbial Biotechnology·Juan Pablo Gomez-Escribano, Mervyn J Bibb
Dec 18, 2013·Journal of Industrial Microbiology & Biotechnology·Brian O BachmannRichard H Baltz
Dec 24, 2013·Nature Chemical Biology·Daniel P DowlingCatherine L Drennan
Feb 4, 2015·ACS Chemical Biology·Fengming LinE Neil G Marsh
Jun 18, 2015·Nature·Mark D WhiteDavid Leys
Jun 18, 2015·Nature·Karl A P PayneDavid Leys
Aug 1, 2015·Angewandte Chemie·Micah T Nelp, Vahe Bandarian
Sep 24, 2015·Chembiochem : a European Journal of Chemical Biology·Margit WinklerBirgit Wilding
Dec 9, 2015·Current Opinion in Structural Biology·Vahe Bandarian, Catherine L Drennan
Jan 24, 2017·Cell Chemical Biology·Pan WuWenqing Chen
Mar 5, 2017·Applied and Environmental Microbiology·Yaojie GaoWenqing Chen
Jul 30, 2017·Archives of Biochemistry and Biophysics·Stephen A MarshallDavid Leys
Nov 12, 2017·Current Opinion in Chemical Biology·Margit Winkler
Citations
Dec 2, 2020·Nature Chemical Biology·Matthew M DraelosKenichi Yokoyama
Feb 10, 2021·Biochemistry·Aoshu ZhongHung-Wen Liu
Feb 2, 2021·Fungal Biology·C StrubS Schorr-Galindo
Mar 26, 2021·ACS Catalysis·Karl A P PayneDavid Leys
Jul 30, 2021·Frontiers in Bioengineering and Biotechnology·Heung-Soon ParkEung-Soo Kim