title: The two types of 3-dehydroquinase have distinct structures but catalyze the same overall reaction.
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.
authors.affiliation: Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Scotland, UK.
authors.forename: D G
authors.initials: DG
authors.lastname: Gourley
authors.forename: A K
authors.initials: AK
authors.lastname: Shrive
authors.forename: I
authors.initials: I
authors.lastname: Polikarpov
authors.forename: T
authors.initials: T
authors.lastname: Krell
authors.forename: J R
authors.initials: JR
authors.lastname: Coggins
authors.forename: A R
authors.initials: AR
authors.lastname: Hawkins
authors.forename: N W
authors.initials: NW
authors.lastname: Isaacs
authors.forename: L
authors.initials: L
authors.lastname: Sawyer
mesh_terms: D001665:Binding Sites; D001894:Borohydrides / Q000378:metabolism; D002384:Catalysis; D003460:Crystallization; D018360:Crystallography, X-Ray; D019281:Dimerization; D015195:Drug Design; D004791:Enzyme Inhibitors; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D012485:Salmonella typhi / Q000201:enzymology*; D012765:Shikimic Acid / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001894:Borohydrides; D004791:Enzyme Inhibitors; D012765:Shikimic Acid; D006836:Hydro-Lyases; C020000:3-dehydroquinate dehydratase