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Natural products

Getting a handle on peptides

Nature Chemistry volume 6, pages 1037–1038 (2014)Cite this article

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Enhancing the structural diversity of peptide natural products relies on synthetic modifications that are typically not chemo- or regioselective. A nonribosomal peptide synthetase has now been engineered to incorporate a non-natural amino acid containing a reactive bio-orthogonal handle.

Many recent endeavours to enhance the structural variability of natural products have focused on developing strategies to biosynthetically incorporate non-native alkynyl and azide functional groups into natural product scaffolds. Once introduced, these bio-orthogonal handles can undergo Cu(I)-catalysed azide–alkyne Huisgen cycloaddition 'click' reactions, which can be used to derivatize and diversify parent compounds for medicinal chemistry applications. Alkyne and azide functionalities have been selectively incorporated into natural products using substrate analogues1, chemical probes2, engineered domains3,4,5 and non-natural co-factors6,7. Although such bio-orthogonal handles have been successfully introduced into polyketides2,3,4,5,6, indole alkaloids1 and sugars7, a general method for enabling a click reaction in nonribosomal peptides does not exist. Writing in Angewandte Chemie International Edition, Hilvert and co-workers8 show that a single tryptophan-to-serine (Trp-to-Ser) point mutation in the adenylation domain of a nonribosomal peptide synthetase (NRPS) allows for the efficient incorporation of propargylated amino acids into a nonribosomal peptide.

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Figure 1: Biosynthesis of diketopiperazines (DKPs) using the wild-type or Trp239Ser-engineered nonribosomal peptide synthetase modules GrsA or TycA.

References

  1. Galan, M. C., McCoy, E. & O'Connor, S. E. Chem. Commun. 3249–3251 (2007).

  2. Riva, E. et al. Angew. Chem. Int. Ed. 53, 1–7 (2014).

    Article  Google Scholar 

  3. Sundermann, U. et al. ACS Chem. Biol. 8, 443–450 (2013).

    Article  CAS  Google Scholar 

  4. Hughes, A. J., Detelich, J. F. & Keatinge-Clay, A. T. Med. Chem. Commun. 3, 956–959 (2012).

    Article  CAS  Google Scholar 

  5. Koryakina, I., McArthur, J. B., Draelos, M. M. & Williams, G. J. Org. Biomol. Chem. 11, 4449–4458 (2013).

    Article  CAS  Google Scholar 

  6. Winter, J. M. et al. Org. Lett. 15, 3774–3777 (2013).

    Article  CAS  Google Scholar 

  7. Singh, S. et al. Angew. Chem. Int. Ed. 53, 3965–3969 (2014).

    Article  CAS  Google Scholar 

  8. Kries, H. et al. Angew. Chem. Int. Ed. 53, 10105–10108 (2014).

    Article  CAS  Google Scholar 

  9. Challis, G. L., Ravel, J. & Townsend, C. A. Chem. Biol. 7, 211–224 (2000).

    Article  CAS  Google Scholar 

  10. Eppelmann, K., Stachelhaus, T. & Marahiel, M. A. Biochemistry 41, 9718–9726 (2002).

    Article  CAS  Google Scholar 

  11. Conti, E., Stachelhaus, T., Marahiel, M. A. & Brick, P. EMBO J. 16, 4174–4183 (1997).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Jaclyn M. Winter and Yi Tang are in the Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California 90095, USA,

    Jaclyn M. Winter & Yi Tang

  2. Yi Tang is also in the Department of Chemistry at the University of California, Los Angeles, California 90095, USA,

    Yi Tang

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  1. Jaclyn M. Winter
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  2. Yi Tang
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Correspondence to Jaclyn M. Winter or Yi Tang.

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Winter, J., Tang, Y. Getting a handle on peptides. Nature Chem 6, 1037–1038 (2014). https://doi.org/10.1038/nchem.2117

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