4UMC

Structural analysis of substrate-mimicking inhibitors in complex with Neisseria meningitidis 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase - the importance of accommodating the active site water

Summary for 4UMC

• Entry DOI: 10.2210/pdb4umc/pdb
• Related: 4UMA 4UMB
• Descriptor: PHOSPHO-2-DEHYDRO-3-DEOXYHEPTONATE ALDOLASE, MANGANESE (II) ION, PHOSPHATE ION, ... (5 entities in total)
• Functional Keywords: transferase, dah7ps, dahps, aromatic amino acids, shikimate pathway, oxocarbenium ion, enzyme inhibitors, meningitis
• Biological source: NEISSERIA MENINGITIDIS
• Total number of polymer chains: 4
• Total formula weight: 156128.40

Authors

Heyes, L.C.,Reichau, S.,Cross, P.J.,Parker, E.J. (deposition date: 2014-05-16, release date: 2014-10-08, Last modification date: 2024-01-10)

Primary citation

Heyes, L.C.,Reichau, S.,Cross, P.J.,Jameson, G.B.,Parker, E.J.
Structural Analysis of Substrate-Mimicking Inhibitors in Complex with Neisseria Meningitidis 3-Deoxy-D-Arabino-Heptulosonate 7-Phosphate Synthase - the Importance of Accommodating the Active Site Water.
Bioorg.Chem., 57:242-, 2014

PubMed Abstract: 3-Deoxy-d-arabino-heptulosonate 7-phosphate synthase (DAH7PS) catalyses the first committed step of the shikimate pathway, which produces the aromatic amino acids as well as many other aromatic metabolites. DAH7PS catalyses an aldol-like reaction between phosphoenolpyruvate and erythrose 4-phosphate. Three phosphoenolpyruvate mimics, (R)-phospholactate, (S)-phospholactate and vinyl phosphonate [(E)-2-methyl-3-phosphonoacrylate], were found to competitively inhibit DAH7PS from Neisseria meningitidis, which is the pathogen responsible for bacterial meningitis. The most potent inhibitor was the vinyl phosphonate with a Ki value of 3.9±0.4μM. We report for the first time crystal structures of these compounds bound in the active site of a DAH7PS enzyme which reveals that the inhibitors bind to the active site of the enzyme in binding modes that mimic those of the predicted oxocarbenium and tetrahedral intermediates of the enzyme-catalysed reaction. Furthermore, the inhibitors accommodate the binding of a key active site water molecule. Together, these observations provide strong evidence that this active site water participates directly in the DAH7PS reaction, enabling the facial selectivity of the enzyme-catalysed reaction sequence to be delineated.

PubMed: 25245459
DOI: 10.1016/J.BIOORG.2014.08.003

Experimental method

X-RAY DIFFRACTION (2.34 Å)