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The two types of 3-dehydroquinase have distinct structures but catalyze the same overall reaction

Nature Structural Biology volume 6, pages 521–525 (1999)Cite this article

Abstract

The structures of enzymes catalyzing the reactions in central metabolic pathways are generally well conserved as are their catalytic mechanisms. The two types of 3-dehydroquinate dehydratase (DHQase) are therefore most unusual since they are unrelated at the sequence level and they utilize completely different mechanisms to catalyze the same overall reaction. The type I enzymes catalyze a cis-dehydration of 3-dehydroquinate via a covalent imine intermediate, while the type II enzymes catalyze a trans-dehydration via an enolate intermediate. Here we report the three-dimensional structures of a representative member of each type of biosynthetic DHQase. Both enzymes function as part of the shikimate pathway, which is essential in microorganisms and plants for the biosynthesis of aromatic compounds including folate, ubiquinone and the aromatic amino acids. An explanation for the presence of two different enzymes catalyzing the same reaction is presented. The absence of the shikimate pathway in animals makes it an attractive target for antimicrobial agents. The availability of these two structures opens the way for the design of highly specific enzyme inhibitors with potential importance as selective therapeutic agents.

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Figure 1: The different stereochemistry and reaction mechanisms of the type I and II DHQases.
Figure 2: Stereodiagrams of the electron density maps for the types I and II 3-dehydroquinase.
Figure 3: The structure of an enzyme subunit.
Figure 4: Subunit arrangement of the two types of DHQases: a, The dimer of type I DHQase from Salmonella typhi; the molecular noncrystallographic dyad is vertical in the plane of the paper.

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Acknowledgements

We thank S. Bury, B. Boys, A. Lapthorn, J. Milner-White, G. Murshudov and L.A.A. Meira for help at various stages of the work and the staff at the SRS Daresbury, Warrington, UK and the EMBL Outstation, DESY, Hamburg for providing data collection facilities. This work was supported by the Biotechnology and Biological Science Research Council.

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Author notes

  1. David G. Gourley

    Present address: Biochemistry Department, University of Dundee, Dundee, DD1 4HN, UK

  2. Annette K. Shrive

    Present address: Physics Department, Keele University, Keele, Staffs, ST5 5BG, UK

  3. Igor Polikarpov

    Present address: LNLS, C.P. 6192, 13083-970, Campinas, Brazil

  4. Tino Krell

    Present address: Institute of Biology & Chemistry of Proteins, CNRS-UPR 412, 69367, Lyon, France

  5. David G. Gourley, Annette K. Shrive and Igor Polikarpov: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, G12 8QQ, Glasgow, Scotland, UK

    David G. Gourley, Tino Krell & John R. Coggins

  2. Structural Biochemistry Group, ICMB, University of Edinburgh, Michael Swann Building, King's Buildings, Mayfield Road, Edinburgh, EH9 3JR, UK

    Annette K. Shrive, Igor Polikarpov & Lindsay Sawyer

  3. Department of Biochemistry and Genetics, New Medical School, Framlington Place, University of Newcastle upon Tyne, Newcastle upon, NE2 4HH, Tyne, UK

    Alastair R. Hawkins

  4. Department of Chemistry, University of Glasgow, Glasgow, G12 8QQ, Scotland, UK

    Neil W. Isaacs

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Correspondence to John R. Coggins or Lindsay Sawyer.

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Gourley, D., Shrive, A., Polikarpov, I. et al. The two types of 3-dehydroquinase have distinct structures but catalyze the same overall reaction. Nat Struct Mol Biol 6, 521–525 (1999). https://doi.org/10.1038/9287

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