title: Identification of Novel Polyphenolic Inhibitors of Shikimate Dehydrogenase (AroE).
abstract: Shikimate dehydrogenase (AroE) is an attractive target for herbicides and antimicrobial agents due to its conserved and essential nature in plants, fungi, and bacteria. Here, we have performed an in vitro screen using a collection of more than 5500 compounds and identified 24 novel inhibitors of AroE from Pseudomonas putida The IC50 values for the two most potent inhibitors we identified, epigallocatechin gallate (EGCG) and epicatechin gallate (ECG), were 3.0 ± 0.2 µM and 3.7 ± 0.5 µM, respectively. Based on the high level of structural conservation between AroE orthologs, we predicted that the identified compounds would also inhibit AroE enzymes from other organisms. Consistent with this hypothesis, we found that EGCG and ECG inhibit the AroE domain of the bifunctional dehydroquinate dehydratase-shikimate dehydrogenase (DHQ-SDH) from Arabidopsis thaliana with IC50 values of 2.1 ± 0.3 µM and 2.0 ± 0.2 µM, respectively.
authors.affiliation: Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Peek
authors.affiliation: Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Shi
authors.affiliation: Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada Centre for the Analysis of Genome Evolution and Function, University of Toronto, Toronto, ON, Canada dinesh.christendat@utoronto.ca.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Christendat
mesh_terms: D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors*; D017360:Arabidopsis / Q000201:enzymology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001665:Binding Sites; D002392:Catechin / Q000031:analogs & derivatives / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D059808:Polyphenols / Q000737:chemistry*; D000072417:Protein Domains; D016958:Pseudomonas putida / Q000737:chemistry; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013053:Spectrophotometry
chemical_list: C000612630:AroE protein, Pseudomonas putida; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D059808:Polyphenols; D002392:Catechin; C062669:epicatechin gallate; C045651:epigallocatechin gallate; D000429:Alcohol Oxidoreductases; C022641:Shikimate dehydrogenase
keywords: Pseudomonas putida; dehydroquinate dehydratase-shikimate dehydrogenase; enzyme inhibition; epigallocatechin gallate; shikimate pathway