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J. Biol. Chem., Vol. 262, Issue 33, 15908-15914, Nov, 1987

Kinetic analysis of the mechanism of Escherichia coli dihydrofolate reductase

MH Penner and C Frieden
Department of Biological Chemistry, Washington University School of Medicine, St. Louis, Missouri 63110.

A kinetic mechanism is presented for Escherichia coli dihydrofolate reductase which describes the full time course of the enzymatic reaction over a wide range of substrate and enzyme concentrations at pH 7.2 and 20 degrees C. Specific rate constants were estimated by computer simulation of the full time course of single turnover, burst, and steady-state experiments using both nondeuterated and deuterated NADPH. The mechanism involves the random addition of substrates, but the substrates and enzyme are not at equilibrium prior to the chemical transformation step. The rate-limiting step follows the chemical transformation, and the maximum velocity of the reaction is limited by the release of the product tetrahydrofolate. The full time course of the reaction is markedly affected by the formation of the enzyme-NADPH- tetrahydrofolate abortive complex, but not by the enzyme-NADP- dihydrofolate abortive complex.
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