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J. Biol. Chem., Vol. 262, Issue 6, 2485-2493, 02, 1987
DA Jencks and RG Mathews
In this paper we report on the allosteric regulation of the dimeric
flavoprotein methylenetetrahydrofolate reductase (E.C. 1.5.1.20) by the
inhibitor, AdoMet, and by one of the substrates, NADPH. These metabolites
play antagonistic roles in this regulation, with NADPH recruiting active
forms of the enzyme and AdoMet recruiting inactive forms. At high NADPH
concentrations, activity dependence on AdoMet is sigmoidal, indicating
cooperativity. The kinetics of inhibition induced by AdoMet are slow enough
to be studied by conventional methods and exhibit marked biphasicity. Both
the extents and rates of these phases are again affected antagonistically
by the ligands, AdoMet increasing the extent of the faster phase, and NADPH
decreasing the extent of the faster phase and the rate of the slower phase.
We present a model consistent with these observations. Our model postulates
two states of the enzyme, R and T. NADPH and AdoMet exhibit antagonistic
binding to a given subunit, so that occupancy by one ligand decreases or
abolishes affinity for the other ligand. However, within a given state, the
subunits do not interact with each other, so the ligation of one does not
affect the affinities of its neighbor. R-T transitions occur between all
similarly ligated states. The ligands have different affinities for the R
and T states, and AdoMet binding to a given subunit is measurably slow.
This model predicts the observed features of the equilibrium and kinetic
data noted above. We also present a system for simulation of reaction
schemes in which each step is pseudo first order that is fast and versatile
enough to allow least squares fitting of microscopic rate constants to
kinetic data.
Allosteric inhibition of methylenetetrahydrofolate reductase by adenosylmethionine. Effects of adenosylmethionine and NADPH on the equilibrium between active and inactive forms of the enzyme and on the kinetics of approach to equilibrium
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