Abstract
Tunicamycins (TUN) are potent inhibitors of polyprenyl phosphate N-acetylhexosamine 1-phosphate transferases (PPHP), including essential eukaryotic GPT enzymes and bacterial HexNAc 1-P translocases. Hence, TUN blocks the formation of eukaryotic N-glycoproteins and the assembly of bacterial call wall polysaccharides. The genetic requirement for TUN production is well-established. Using two genes unique to the TUN pathway (tunB and tunD) as probes we identified four new prospective TUN-producing strains. Chemical analysis showed that one strain, Streptomyces niger NRRL B-3857, produces TUN plus new compounds, named quinovosamycins (QVMs). QVMs are structurally akin to TUN, but uniquely in the 1″,11′-HexNAc sugar head group, which is invariably d-GlcNAc for the known TUN, but is d-QuiNAc for the QVM. Surprisingly, this modification has only a minor effect on either the inhibitory or antimicrobial properties of QVM and TUN. These findings have unexpected consequences for TUN/QVM biosynthesis, and for the specificity of the PPHP enzyme family.
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Acknowledgements
We thank Trina Hartman for technical assistance, Euan Price for help with drafting figures, and Dr Joseph Rich (USDA, NCAUR, Peoria, IL, USA) for pre-review of the manuscript. Mention of trade names or commercial products in this publication is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the U.S. Department of Agriculture. USDA is an equal opportunity provider and employer.
Author contributions
DPL, TAN and WWM designed, administered and performed the genomic database and searches. TAN also undertook the protein N-glycosylation assays. KEV provided analysis by NMR. MJB and MAB undertook permethylation and MS analysis. KMB designed and performed the antimicrobial assays. NPJP conceived the experiments, analyzed data and wrote the paper.
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Price, N., Labeda, D., Naumann, T. et al. Quinovosamycins: new tunicamycin-type antibiotics in which the α, β-1″,11′-linked N-acetylglucosamine residue is replaced by N-acetylquinovosamine. J Antibiot 69, 637–646 (2016). https://doi.org/10.1038/ja.2016.49
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DOI: https://doi.org/10.1038/ja.2016.49
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