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Letter
Nature Structural Biology  6, 521 - 525 (1999)
doi:10.1038/9287

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

David G. Gourley1, 2, 3, Annette K. Shrive1, 4, 5, Igor Polikarpov1, 4, 6, Tino Krell2, 7, John R. Coggins2, Alastair R. Hawkins8, Neil W. Isaacs9 & Lindsay Sawyer4

1  These authors contributed equally to this work.

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

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

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

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

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

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

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

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

Correspondence should be addressed to Lindsay Sawyer L.Sawyer@ed.ac.uk or John R. Coggins j.coggins@bio.gla.ac.uk
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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Nature Structural & Molecular Biology
ISSN: 1545-9993
EISSN: 1545-9985
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