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De novo biosynthesis of terminal alkyne-labeled natural products

Abstract

The terminal alkyne is a functionality widely used in organic synthesis, pharmaceutical science, material science and bioorthogonal chemistry. This functionality is also found in acetylenic natural products, but the underlying biosynthetic pathways for its formation are not well understood. Here we report the characterization of what is to our knowledge the first carrier protein–dependent terminal alkyne biosynthetic machinery in microbes. We further demonstrate that this enzymatic machinery can be exploited for the in situ generation and incorporation of terminal alkynes into two natural product scaffolds in Escherichia coli. These results highlight the prospect for tagging major classes of natural products, including polyketides and polyketide/nonribosomal peptide hybrids, using biosynthetic pathway engineering.

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Figure 1
Figure 2: Biochemical characterization of JamA, JamB and JamC.
Figure 3: Substrate specificity of JamB.
Figure 4: Biosynthesis of 3 through starter unit engineering.
Figure 5: Biosynthesis of 5 through extender unit engineering.

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GenBank/EMBL/DDBJ

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Acknowledgements

This research was financially supported by the Pew Scholars Program and University of California Cancer Research Coordinating Committee funds. We thank I. Abe (University of Tokyo) for providing hspks1, S. Bauer (University of California–Berkeley) for assisting with LC/HRMS analysis, J. Pelton (University of California–Berkeley) for helping with NMR spectroscopic analysis, J. Chung (University of California–Berkeley) for helping with compound purification and L. Zhang (University of California–Berkeley) for providing scACP.

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X.Z. designed the experiments, performed all experiments, analyzed the data and wrote the manuscript. J.L. constructed plasmids for antimycin production in E. coli. W.Z. designed the experiments, analyzed the data and wrote the manuscript.

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Correspondence to Wenjun Zhang.

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The authors declare no competing financial interests.

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Supplementary Results, Supplementary Tables 1–4 and Supplementary Figures 1–23. (PDF 4454 kb)

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Zhu, X., Liu, J. & Zhang, W. De novo biosynthesis of terminal alkyne-labeled natural products. Nat Chem Biol 11, 115–120 (2015). https://doi.org/10.1038/nchembio.1718

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