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

@article{Carpenter1998StructureOD,
  title={Structure of dehydroquinate synthase reveals an active site capable of multistep catalysis},
  author={Elisabeth P. Carpenter and Alastair R. Hawkins and John W. Frost and Katherine A. Brown},
  journal={Nature},
  year={1998},
  volume={394},
  pages={299-302}
}
Dehydroquinate synthase (DHQS) has long been regarded as a catalytic marvel because of its ability to perform several consecutive chemical reactions in one active site. There has been considerable debate as to whether DHQS is actively involved in all these steps,, or whether several steps occur spontaneously, making DHQS a spectator in its own mechanism. DHQS performs the second step in the shikimate pathway, which is required for the synthesis of aromatic compounds in bacteria, microbial… 
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Structure of a Sedoheptulose 7-Phosphate Cyclase: ValA from Streptomyces hygroscopicus
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ValA has a fold and active site organization resembling those of the sugar phosphate cyclase dehydroquinate synthase (DHQS) and contains two notable, previously unrecognized interactions between NAD+ and Asp side chains conserved in all sugar phosphatecyclases that may influence catalysis.
Studies on bacterial type II dehydroquinases and shikimate dehydrogenases
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The work in this thesis investigates the active sites and overall structure of bacterial type II dehydroquinases, shikimate dehydrogenases and related proteins using biochemical and biophysical techniques to help to explain the relative potencies of rationally designed inhibitors.
Structural studies of shikimate dehydrogenase from Bacillus anthracis complexed with cofactor NADP
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The molecular modeling of shikimate dehydrogenase from Bacillus anthracis complexed with the cofactor NADP was able to identify the main residues of the NADP binding site responsible for ligand affinities and can be used in the design of more specific drugs against infectious diseases.
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References

SHOWING 1-10 OF 37 REFERENCES
Dehydroquinate synthase: the use of substrate analogues to probe the early steps of the catalyzed reaction.
TLDR
Results suggest that the enzyme exploits this substrate base in the enolization, which occurs through an intramolecular proton transfer of the C-6 proton with the solvent.
Dehydroquinate synthase: the use of substrate analogues to probe the late steps of the catalyzed reaction.
TLDR
The present finding of a syn elimination of the overall stereochemical course of the transformation mediated by dehydroquinate synthase suggests that the transition state for the subsequent intramolecular aldol reaction has a chairlike geometry.
Divergence between the enzyme-catalyzed and noncatalyzed synthesis of 3-dehydroquinate
Synthesis of 1-epi-dehydroquinate, 9, provided an authentic sample of this material and allowed its identification as a minor product in the noncatalyzed rearrangement of enolpyranose 4a to
Efficient independent activity of a monomeric, monofunctional dehydroquinate synthase derived from the N-terminus of the pentafunctional AROM protein of Aspergillus nidulans.
TLDR
The monofunctional DHQ synthase domain is inactivated by treatment with chelating agents in the absence of substrates and is re-activated by the addition of metal ions; among those tested, Zn2+ gave the highest kcat./Km value.
The 3-dehydroquinate synthase activity of the pentafunctional arom enzyme complex of Neurospora crassa is Zn2+-dependent.
TLDR
The co-purification in constant ratio of all five activities of the pentafunctional arom enzyme complex from Neurospora crassa is demonstrated, with results that indicate that the intact enzyme complex contained 1 atom per subunit of tightly bound zinc.
Overproduction in Escherichia coli of the dehydroquinate synthase domain of the Aspergillus nidulans pentafunctional AROM protein.
TLDR
The pentafunctional AROM protein of Aspergillus nidulans is encoded by the complex aromA locus and catalyses steps 2-6 in the synthesis of chorismate, the common precursor for the aromatic amino acids and p-aminobenzoic acid, and the DHQ synthase domain is overproduced in E. coli.
NAD-binding domains of dehydrogenases.
  • A. Lesk
  • Biology
    Current opinion in structural biology
  • 1995
Cyclohexenyl and Cyclohexylidene Inhibitors of 3-Dehydroquinate Synthase: Active Site Interactions Relevant to Enzyme Mechanism and Inhibitor Design
TLDR
Three newly synthesized inhibitors of DHQ synthase binds to 3-dehydroquinate (DHQ) synthase more tightly than similarly substituted cyclohexyl inhibitors and is the first example of a nanomolar-level inhibitor possessing neither a phosphate monoester nor a phosphonic acid.
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