Enzymatic Synthesis of the Ribosylated Glycyl-Uridine Disaccharide Core of Peptidyl Nucleoside Antibiotics

Zheng Cui, Xiaodong Liu, Jonathan Overbay, Wenlong Cai, Xiachang Wang, Anke Lemke, Daniel Wiegmann, Giuliana Niro, Jon S. Thorson, Christian Ducho, Steven G. Van Lanen

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9 Scopus citations


Muraymycins belong to a family of nucleoside antibiotics that have a distinctive disaccharide core consisting of 5-amino-5-deoxyribofuranose (ADR) attached to 6′-N-alkyl-5′-C-glycyluridine (GlyU). Here, we functionally assign and characterize six enzymes from the muraymycin biosynthetic pathway involved in the core assembly that starts from uridine monophosphate (UMP). The biosynthesis is initiated by Mur16, a nonheme Fe(II)- and α-ketoglutarate-dependent dioxygenase, followed by four transferase enzymes: Mur17, a pyridoxal-5′-phosphate (PLP)-dependent transaldolase; Mur20, an aminotransferase; Mur26, a pyrimidine phosphorylase; and Mur18, a nucleotidylyltransferase. The pathway culminates in glycosidic bond formation in a reaction catalyzed by an additional transferase enzyme, Mur19, a ribosyltransferase. Analysis of the biochemical properties revealed several noteworthy discoveries including that (i) Mur16 and downstream enzymes can also process 2′-deoxy-UMP to generate a 2-deoxy-ADR, which is consistent with the structure of some muraymycin congeners; (ii) Mur20 prefers l-Tyr as the amino donor source; (iii) Mur18 activity absolutely depends on the amine functionality of the ADR precursor consistent with the nucleotidyltransfer reaction occurring after the Mur20-catalyzed aminotransfer reaction; and (iv) the bona fide sugar acceptor for Mur19 is (5′S,6′S)-GlyU, suggesting that ribosyltransfer occurs prior to N-alkylation of GlyU. Finally, a one-pot, six-enzyme reaction was utilized to generate the ADR-GlyU disaccharide core starting from UMP.

Original languageEnglish
Pages (from-to)7239-7249
Number of pages11
JournalJournal of Organic Chemistry
Issue number13
StatePublished - Jul 6 2018

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health (NIH) grants R01 AI087849 (SVL) and R01 GM115261 (JST), the University of Kentucky College of Pharmacy, the University of Kentucky Markey Cancer Center, the National Center for Advancing Translational Sciences (UL1TR001998), the Deutsche Forschungsgemeinschaft (DFG, grant DU 1095/5-1), the state of Lower Saxony [Lichtenberg doctoral fellowship (CaSuS program) for A.L.], the Konrad-Adenauer-Stiftung (doctoral fellowship for D.W.), and the Fonds der Chemischen Industrie (doctoral fellowship for G.N.).

Publisher Copyright:
© 2018 American Chemical Society.

ASJC Scopus subject areas

  • Organic Chemistry


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