Noncompetitive inhibition illustration

Figure 8.38. Noncompetitive Inhibition Illustrated on a Double-Reciprocal Plot. A double-reciprocal plot of enzyme kinetics in the presence ( and absence of a noncompetitive inhibitor shows thatiT is unaltered and...

Figure 9-12 shows a plot of 1 /v against 1 / [S] at a series of fixed values of [I]. For the case that fC, = K2 (classical noncompetitive inhibition), a family of reciprocal plots that intersect on the horizontal axis at a value of -1 / Km is obtained. On the other hand, if K1 and K2 differ (the general case of noncompetitive inhibition), the family of curves intersect at some other point to the left of the vertical axis and, depending upon the relative values of fC, and K2, either above or below the horizontal axis. The example illustrated is for K2 = 0.5/C, that is, for the binding of M to ES being twice as strong as that to E. 

In some instances, Kie = Khy that is, the extent of combination of inhibitor with the E and ES forms of the enzyme are identical. The left panel of Figure II-11 illustrates a plot of such data. In other cases of noncompetitive inhibition, KJc is different (usually larger) than Kjs as illustrated in the right panel of Figure II-11. 

Lineweaver-Burk plots provide a good illustration of competitive inhibition and pure noncompetitive inhibition (Fig. 9.18). In competitive inhibition, plots of 1/v vs 1/[S] at a series of inhibitor concentrations intersect on the ordinate. Thus, at infinite substrate concentration, or 1/[S] = 0, there is no effect of the inhibitor. In pure noncompetitive inhibition, the inhibitor decreases the velocity even when [S] has been extrapolated to an infinite concentration. However, if the inhibitor has no effect on the binding of the substrate, the is the same for every concentration of inhibitor, and the lines intersect on the abcissa. 

Fig. 6.41 Illustration of noncompetitive inhibition. (From bttp //2.bp.blogspot.com/-Z89cvT vrxY/ UIF49dFyTKI/AAAAAAAAABQ/4GB2pbdFgLg/s 7 600/nonComp.gif).

Fromm and Rudolph have discussed the practical limitations on interpreting product inhibition experiments. The table below illustrates the distinctive kinetic patterns observed with bisubstrate enzymes in the absence or presence of abortive complex formation. It should also be noted that the random mechanisms in this table (and in similar tables in other texts) are usually for rapid equilibrium random mechanism schemes. Steady-state random mechanisms will contain squared terms in the product concentrations in the overall rate expression. The presence of these terms would predict nonhnearity in product inhibition studies. This nonlin-earity might not be obvious under standard initial rate protocols, but products that would be competitive in rapid equilibrium systems might appear to be noncompetitive in steady-state random schemes , depending on the relative magnitude of those squared terms. See Abortive Complex... 

The characteristics of the double reciprocal plots given by Equation (5.149), Equation (5.154), and Equation (5.155) determine what kind of enzyme inhibition may occur competitive, noncompetitive, or uncompetitive. In a given concentration of enzyme and inhibitor, the substrate concentration is changed and the double reciprocal plot of 1/V against 1/[A] is drawn. Figure 5.24a illustrates the double... 

Mechanisms of CYP inhibition can be broadly divided into two categories reversible inhibition and mechanism-based inactivation. Depending on the mode of interaction between CYP enzymes and inhibitors, reversible CYP inhibition is further characterized as competitive, noncompetitive, uncompetitive, and mixed (Ito et al., 1998b). Evaluation of reversible inhibition of CYP reactions is often conducted under conditions where M-M kinetics is obeyed. Based on the scheme illustrated in Fig. 5.1, various types of reversible inhibition are summarized in Table 5.1. Figure 5.1 depicts a simple substrate-enzyme complex during catalysis. In the presence of a reversible inhibitor, such a complex can be disrupted leading to enzyme inhibition. 

Initially, the first and last enzymes of the lysine branch of the aspartate pathway illustrated in Fig. 1 were isolated from higher plants. The first enzyme, dihydrodipicolinate synthase (10), is sensitive to inhibition by the pathway product, lysine (Wallsgrove and Mazelis, 1981). Results obtained with extensively purified DHDP synthase from wheat suspension cultures indicate that lysine is a competitive inhibitor with respect to aspartate semialdehyde and a noncompetitive inhibitor with respect to pyruvate (Kumpaisal et ai, 1987). In vivo regulation of this enzyme by feedback inhibition is supported by the isolation of mutants which overproduce lysine and are characterized by a lysine-insensitive DHDP synthase (Negrutiu et ai, 1984). 

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