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Structure of dehydroquinate synthase reveals an active site capable of multistep catalysis

Nature volume 394, pages 299–302 (1998)Cite this article

Abstract

Dehydroquinate synthase (DHQS) has long been regarded as a catalytic marvel because of its ability to perform several consecutive chemical reactions in one active site1,2,3,4,5,6,7. There has been considerable debate as to whether DHQS is actively involved in all these steps1,2, or whether several steps occur spontaneously, making DHQS a spectator in its own mechanism3,4,5. DHQS performs the second step in the shikimate pathway, which is required for the synthesis of aromatic compounds in bacteria, microbial eukaryotes and plants8. This enzyme is a potential target for new antifungal and antibacterial drugs9,10 as the shikimate pathway is absent from mammals and DHQS is required for pathogen virulence11. Here we report the crystal structure of DHQS, which has several unexpected features, including a previously unobserved mode for NAD+-binding and an active-site organization that is surprisingly similar to that of alcohol dehydrogenase, in a new protein fold. The structure reveals interactions between the active site and a substrate-analogue inhibitor, which indicate how DHQS can perform multistep catalysis without the formation of unwanted by-products.

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Figure 1: Ribbon diagram of the DHQS dimer showing the inhibitor carbaphosphonate4 (yellow), NAD+ (green) and Zn2+ (orange).
Figure 2: Stereo view of the active site of DHQS.
Figure 3: The proposed mechanism for conversion of DAHP to dehydroquinate by DHQS.

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Acknowledgements

We thank the support staff at the Synchrotron Radiation Source at Daresbury Laboratory, UK, for assistance; D. R. Swatman, F.T.F. Tsai, R. R. Patel and Y. S. Li for technical assistance; G. G. Dodson for support and encouragement; K. Henrick, S. Gamblin, M. Hirschberg, J. O. Baum, W.Taylor and J. D. Moore for discussion; and P. Bartlett for helpful comments. This work was supported by BBSRC. E.P.C. was supported by the UK MRC and K.A.B. received a BBSRC Advanced Fellowship.

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Authors and Affiliations

  1. Division for Protein Structure, National Institute for Medical Research, The Ridgeway, London, NW7 1AA, Mill Hill, UK

    Elisabeth P. Carpenter

  2. Department of Biochemistry and Genetics, Catherine Cookson Building, New Medical School, University of Newcastle upon Tyne, NE2 4HH, UK

    Alastair R. Hawkins

  3. Department of Chemistry, Michigan State University, East Lansing, 48824-1322, Michigan, USA

    John W. Frost

  4. Department of Biochemistry, Imperial College of Science, Technology and Medicine, Exhibition Road, London, SW7 2AY, UK

    Katherine A. Brown

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  1. Elisabeth P. Carpenter
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  4. Katherine A. Brown
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Correspondence to Katherine A. Brown.

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Carpenter, E., Hawkins, A., Frost, J. et al. Structure of dehydroquinate synthase reveals an active site capable of multistep catalysis. Nature 394, 299–302 (1998). https://doi.org/10.1038/28431

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