3M7W

Crystal Structure of Type I 3-Dehydroquinate Dehydratase (aroD) from Salmonella typhimurium LT2 in Covalent Complex with Dehydroquinate

Summary for 3M7W

• Entry DOI: 10.2210/pdb3m7w/pdb
• Related: 3L2I 3LB0
• Descriptor: 3-dehydroquinate dehydratase, 1,3,4-TRIHYDROXY-5-OXO-CYCLOHEXANECARBOXYLIC ACID, GLYCEROL, ... (4 entities in total)
• Functional Keywords: type i 3-dehydroquinase, dhqase_i, dehydroquinate, idp90922, amino-acid biosynthesis, aromatic amino acid biosynthesis, lyase, schiff base, center for structural genomics of infectious diseases, csgid
• Biological source: Salmonella enterica subsp. enterica serovar Typhimurium
• Total number of polymer chains: 6
• Total formula weight: 168208.13

Authors

Minasov, G.,Light, S.H.,Shuvalova, L.,Papazisi, L.,Anderson, W.F.,Center for Structural Genomics of Infectious Diseases (CSGID) (deposition date: 2010-03-17, release date: 2010-04-07, Last modification date: 2023-09-06)

Primary citation

Light, S.H.,Minasov, G.,Shuvalova, L.,Duban, M.E.,Caffrey, M.,Anderson, W.F.,Lavie, A.
Insights into the mechanism of type I dehydroquinate dehydratases from structures of reaction intermediates.
J.Biol.Chem., 286:3531-3539, 2011

PubMed Abstract: The biosynthetic shikimate pathway consists of seven enzymes that catalyze sequential reactions to generate chorismate, a critical branch point in the synthesis of the aromatic amino acids. The third enzyme in the pathway, dehydroquinate dehydratase (DHQD), catalyzes the dehydration of 3-dehydroquinate to 3-dehydroshikimate. We present three crystal structures of the type I DHQD from the intestinal pathogens Clostridium difficile and Salmonella enterica. Structures of the enzyme with substrate and covalent pre- and post-dehydration reaction intermediates provide snapshots of successive steps along the type I DHQD-catalyzed reaction coordinate. These structures reveal that the position of the substrate within the active site does not appreciably change upon Schiff base formation. The intermediate state structures reveal a reaction state-dependent behavior of His-143 in which the residue adopts a conformation proximal to the site of catalytic dehydration only when the leaving group is present. We speculate that His-143 is likely to assume differing catalytic roles in each of its observed conformations. One conformation of His-143 positions the residue for the formation/hydrolysis of the covalent Schiff base intermediates, whereas the other conformation positions the residue for a role in the catalytic dehydration event. The fact that the shikimate pathway is absent from humans makes the enzymes of the pathway potential targets for the development of non-toxic antimicrobials. The structures and mechanistic insight presented here may inform the design of type I DHQD enzyme inhibitors.

PubMed: 21087925
DOI: 10.1074/jbc.M110.192831

Experimental method

X-RAY DIFFRACTION (1.95 Å)