Substrate conformational transitions in the active site of chorismate mutase: their role in the catalytic mechanism.
Chorismate mutase acts at the first branch-point of aromatic amino acid biosynthesis and catalyzes the conversion of chorismate to prephenate. The results of molecular dynamics simulations of the substrate in solution and in the active site of chorismate mutase are reported. Two nonreactive conformers of chorismate are found to be more stable than the reactive pseudodiaxial chair conformer in solution. It is shown by QM/MM molecular dynamics simulations, which take into account the motions of the enzyme, that when these inactive conformers are bound to the active site, they are rapidly converted to the reactive chair conformer. This result suggests that one contribution of the enzyme is to bind the more prevalent nonreactive conformers and transform them into the active form in a step before the chemical reaction. The motion of the reactive chair conformer in the active site calculated by using the QM/MM potential generates transient structures that are closer to the transition state than is the stable CHAIR conformer.
Guo
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Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
Cui
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Lipscomb
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Karplus
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D001665:Binding Sites; D002384:Catalysis; D002826:Chorismate Mutase / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D011487:Protein Conformation; D011789:Quantum Theory; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D012996:Solutions; D013379:Substrate Specificity
D012996:Solutions; D002826:Chorismate Mutase