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Structure and specificity of a permissive bacterial C-prenyltransferase

Nature Chemical Biology volume 13, pages 366–368 (2017)Cite this article

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Abstract

This study highlights the biochemical and structural characterization of the L-tryptophan C6 C-prenyltransferase (C-PT) PriB from Streptomyces sp. RM-5-8. PriB was found to be uniquely permissive to a diverse array of prenyl donors and acceptors including daptomycin. Two additional PTs also produced novel prenylated daptomycins with improved antibacterial activities over the parent drug.

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Figure 1: PriB discovery and permissiveness of PriB and other indole PTs.
Figure 2: Prenylated daptomycins (DAPs) and the crystal structure of PriB.

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Acknowledgements

This work was supported by NIH grants R37 AI52188 and R01 CA203257 (J.S.T.), U01 GM098248 (G.N.P.) and NCATS (UL1TR001998). Daptomycin (Cubicin) was generously provided by Merck. We are grateful to J. Rohr, S. Van Lanen and J. Chappell (College of Pharmacy, University of Kentucky) for helpful discussion and facilitating access to shared equipment and/or reagents. We thank the University of Kentucky Mass Spectrometry Facility for the HR–ESI–MS support. This research also used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science user facility operated by Argonne National Laboratory (DE-AC02-06CH11357). Use of the Lilly Research Laboratories Collaborative Access Team (LRL-CAT) beamline at Sector 31 of the Advanced Photon Source was provided by Eli Lilly and Company.

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Author notes

  1. Shanteri Singh

    Present address: Present address: Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, USA.,

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA

    Sherif I Elshahawi, Khaled A Shaaban, Larissa V Ponomareva & Jon S Thorson

  2. Center for Pharmaceutical Research and Innovation (CPRI), University of Kentucky, Lexington, Kentucky, USA

    Sherif I Elshahawi, Khaled A Shaaban, Larissa V Ponomareva, Jon S Thorson & Shanteri Singh

  3. Department of Biosciences, Rice University, Houston, Texas, USA

    Hongnan Cao & George N Phillips Jr

  4. Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA

    Thangaiah Subramanian & H Peter Spielmann

  5. Department of Plant Pathology, University of Kentucky, Lexington, Kentucky, USA

    Mark L Farman

  6. Department of Chemistry, Markey Cancer Center, Kentucky Center for Structural Biology, University of Kentucky, Lexington, Kentucky, USA

    H Peter Spielmann

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  1. Sherif I Elshahawi
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Contributions

S.I.E. and H.C. contributed to the experimental design and execution and manuscript preparation; K.A.S. and L.V.P. contributed to experimental design and execution; T.S. and H.P.S. contributed experimental reagents and consultation; M.L.F. contributed to experimental design and execution and provided key consultation; G.N.P. and J.S.T. contributed to the experimental design, project oversight and manuscript preparation; S.S. contributed to the experimental design and execution, project oversight and manuscript preparation.

Corresponding authors

Correspondence to George N Phillips Jr, Jon S Thorson or Shanteri Singh.

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Competing interests

J.S.T. is a cofounder of Centrose (Madison, Wisonsin, USA).

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Figures 1–28 and Supplementary Tables 1–11. (PDF 2642 kb)

Supplementary Note

NMR and mass spectral data supporting the structural elucidation of compounds 1, 66, 67, 68, 69, 70 and the prenylated analogs of 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65. (PDF 15278 kb)

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Elshahawi, S., Cao, H., Shaaban, K. et al. Structure and specificity of a permissive bacterial C-prenyltransferase. Nat Chem Biol 13, 366–368 (2017). https://doi.org/10.1038/nchembio.2285

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