Molecular basis for the glyphosate-insensitivity of the reaction of 5-enolpyruvylshikimate 3-phosphate synthase with shikimate.
The shikimate pathway enzyme 5-enolpyruvyl shikimate-3-phosphate synthase (EPSP synthase) has received attention in the past because it is the target of the broad-spectrum herbicide glyphosate. The natural substrate of EPSP synthase is shikimate-3-phosphate. However, this enzyme can also utilize shikimate as substrate. Remarkably, this reaction is insensitive to inhibition by glyphosate. Crystallographic analysis of EPSP synthase from Escherichia coli, in complex with shikimate/glyphosate at 1.5 Angstroms resolution, revealed that binding of shikimate induces changes around the backbone of the active site, which in turn impact the efficient binding of glyphosate. The implications from these findings with respect to the design of novel glyphosate-insensitive EPSP synthase enzymes are discussed.
Priestman
Melanie A
MA
Department of Medicinal Chemistry, University of Kansas, 4040a Malott Hall, Lawrence, 66045, USA.
Healy
Martha L
ML
Funke
Todd
T
Becker
Andreas
A
Schönbrunn
Ernst
E
D051229:3-Phosphoshikimate 1-Carboxyvinyltransferase / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D001665:Binding Sites; D003461:Crystallography; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D012765:Shikimic Acid / Q000737:chemistry / Q000378:metabolism*; D000097797:Glyphosate
D051229:3-Phosphoshikimate 1-Carboxyvinyltransferase; D004791:Enzyme Inhibitors; D005998:Glycine; D012765:Shikimic Acid; D000097797:Glyphosate