The Structure and Mechanism of the Type II Dehydroquinase from Streptomyces coelicolor

The structure of the type II DHQase from Streptomyces coelicolor has been solved and refined to high resolution in complexes with a number of ligands, including dehydroshikimate and a rationally designed transition state analogue, 2,3-anhydro-quinic acid. These structures define the active site of t...

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Bibliographic Details
Published in:	Structure (London) Vol. 10; no. 4; pp. 493 - 503
Main Authors:	Roszak, Aleksander W., Robinson, David A., Krell, Tino, Hunter, Iain S., Fredrickson, Martyn, Abell, Chris, Coggins, John R., Lapthorn, Adrian J.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-04-2002
Subjects:	Amino Acid Sequence Animals Bacterial Proteins - chemistry Bacterial Proteins - genetics Bacterial Proteins - isolation & purification Bacterial Proteins - metabolism Binding Sites Crystallography, X-Ray dehydroquinase enzyme mechanism Hydro-Lyases - chemistry Hydro-Lyases - genetics Hydro-Lyases - isolation & purification Hydro-Lyases - metabolism Models, Molecular Molecular Sequence Data Molecular Structure Protein Folding Protein Structure, Quaternary Protein Structure, Tertiary rational drug design Sequence Alignment shikimate pathway Shikimic Acid - metabolism Streptomyces - enzymology transition state analog X-ray structure rational drug design shikimate pathway enzyme mechanism transition state analog dehydroquinase X-ray structure
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Summary:	The structure of the type II DHQase from Streptomyces coelicolor has been solved and refined to high resolution in complexes with a number of ligands, including dehydroshikimate and a rationally designed transition state analogue, 2,3-anhydro-quinic acid. These structures define the active site of the enzyme and the role of key amino acid residues and provide snap shots of the catalytic cycle. The resolution of the flexible lid domain (residues 21–31) shows that the invariant residues Arg23 and Tyr28 close over the active site cleft. The tyrosine acts as the base in the initial proton abstraction, and evidence is provided that the reaction proceeds via an enol intermediate. The active site of the structure of DHQase in complex with the transition state analog also includes molecules of tartrate and glycerol, which provide a basis for further inhibitor design.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0969-2126 1878-4186
DOI:	10.1016/S0969-2126(02)00747-5