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Dihydrofolate reductase: structural aspects of mechanisms of enzyme catalysis and inhibition

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Abstract

The mechanism of catalytic reduction of folic and dihydrofolic acids to tetrahydrofolate, which proceeds under the action of dihydrofolate reductase and the coenzyme NADPH, is considered. The roles of the enzyme active site, the coenzyme, individual amino acid residues of the enzyme, and water molecules in the catalytic reaction are discussed. Interactions of the enzyme with competitive inhibitors many of which are widely used in medicine as antitumor and antibacterial drugs are examined. The factors controlling the selectivity of inhibitor binding to bacterial forms of the enzyme are analyzed. The results of X-ray diffraction and NMR spectroscopic studies of the structures of the enzyme and its complexes with the substrate and inhibitors are surveyed. The role of specific interactions and molecular motions of the protein and ligands in the mechanism of catalysis and in the binding of the ligands to the enzyme is discussed.

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Polshakov, V.I. Dihydrofolate reductase: structural aspects of mechanisms of enzyme catalysis and inhibition. Russian Chemical Bulletin 50, 1733–1751 (2001). https://doi.org/10.1023/A:1014313625350

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