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Structural and mechanistic basis for a new mode of glycosyltransferase inhibition

Nature Chemical Biology volume 6, pages 321–323 (2010)Cite this article

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Abstract

Glycosyltransferases are carbohydrate-active enzymes with essential roles in numerous important biological processes. We have developed a new donor analog for galactosyltransferases that locks a representative target enzyme in a catalytically inactive conformation, thus almost completely abolishing sugar transfer. Results with other galactosyltransferases suggest that this unique mode of glycosyltransferase inhibition may also be generally applicable to other members of this important enzyme family.

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Figure 1: GalT structures.

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Acknowledgements

We thank D.D. Djurhuus, D. Adlercreutz and M.H. Bien for excellent technical assistance during this research. The plasmid for the Neisseria meningitidis α-1,4-GalT was a generous gift from W.W. Wakarchuk (National Research Council of Canada). AA(Gly)B was cloned by H.J. Lee (University of Alberta) and N.O.L. Seto (National Research Council of Canada). We also thank A. Henriksen (Carlsberg Laboratory) for supplying equipment and tools for protein crystallography and for helpful discussions. We are grateful for the help with X-ray data collection provided by the beamline staff at I-911 at MAX-lab (Lund, Sweden) and at X12 at Deutsches Elektronen-Synchrotron (European Molecular Biology Laboratory, Hamburg, Germany). This work was supported by the UK Engineering and Physical Sciences Research Council (First Grant EP/D059186/1 to G.K.W.), the UK Medical Research Council (Discipline Hopping Award G0701861 to G.K.W.), the Leverhulme Trust (Research Fellowship RF/4/RFG/2008/0544 to G.K.W.) and the Danish Agency for Science, Technology and Innovation (grant 272-08-0449 to M.M.P.). We thank the Engineering and Physical Sciences Research Council National Mass Spectrometry Service Centre, Swansea, for the recording of mass spectra.

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Author notes

  1. Thomas Pesnot and Rene Jørgensen: These authors contributed equally to this work.

Authors and Affiliations

  1. School of Pharmacy, University of East Anglia, Norwich, UK

    Thomas Pesnot & Gerd K Wagner

  2. Carlsberg Laboratory, Copenhagen, Denmark

    Rene Jørgensen & Monica M Palcic

Authors
  1. Thomas Pesnot
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  2. Rene Jørgensen
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  3. Monica M Palcic
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  4. Gerd K Wagner
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Contributions

T.P. carried out the synthetic work; R.J. carried out the crystallographic analyses; T.P. and R.J. carried out enzymological studies; G.K.W. and M.M.P. designed the study and, together with the other authors, analyzed the data and discussed the results. G.K.W. wrote the paper, with contributions from the other authors. All authors commented on the manuscript.

Corresponding author

Correspondence to Gerd K Wagner.

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The authors declare no competing financial interests.

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Supplementary Methods, Supplementary Schemes 1 and 2, Supplementary Figures 1 and 2 and Supplementary Table 1 (PDF 1945 kb)

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Pesnot, T., Jørgensen, R., Palcic, M. et al. Structural and mechanistic basis for a new mode of glycosyltransferase inhibition. Nat Chem Biol 6, 321–323 (2010). https://doi.org/10.1038/nchembio.343

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