Heterotropic modulation

Figures 5.11A and B show the characteristic sigmoid curves obtained as a result of interaction between the substrate site, the stimulating modulator site, and the inhibitory modulator site for K and M classes of enzymes. The curves in the absence of modulators are homotropic effects caused by cooperative binding of the substrate. Heterotropic modulators, which can be either positive or negative in their actions, are molecules other than the substrate.

Hemoglobin binding of oxygen is a classic example of the homotropic effect. Hemoglobin also shows heterotropic effects with specific molecules in its environment. These effects are intimately related to the function of hemoglobin as a carrier not only of oxygen but of H+ and CO2 (Chapters 1 and 28). The heterotropic modulators are H+, CO2, and... 

For heterotropic allosteric enzymes, those whose modulators are metabolites other than the normal substrate, it is difficult to generalize about the shape of the substrate-saturation curve. An activator may cause the curve to become more nearly hyperbolic, with a decrease in Z0.5 but no change in Fmax, resulting in an increased reaction velocity at a fixed substrate concentration (V0 is higher for any value of [S] Fig. 6-29b, upper curve). 

Other heterotropic allosteric enzymes respond to an activator by an increase in Fmax with little change in if0i5 (Fig. 6-29c). A negative modulator (an inhibitor) may produce a more sigmoid substrate-saturation curve,... 

Relationship between the initial velocity (v) and the substrate concentration [S] for an allosteric enzyme that shows a heterotropic effect with constant Vmax but with varying ATq.s- Curve a is obtained in the absence of any modulators, curve b in the presence of a positive modulator, and curve c in the presence of a negative modulator. Regulation is achieved by modulation of ATq.s without change in F ax. 

Another aspect and possibly another solution to the issue comes from work by Friedman using flash photolysis kinetics (of CO rebinding after photodissociation from ferrous P450 3A4). The kinetics were multiphasic and were selectively altered by the presence of different substrates. Heterotropic effects were observed with benzo[a]-pyrene and aNF. The interpretation of the results is that different substrates differentially modulate these kinetics by (a) changing the P450... 

Enzyme activity can also be affected by binding of substrate and nonsubstrate Mgands, which can act as activators or inhibitors, at a site other than the active site. These enzymes are called allosteric. These responses can be homotropic or heterotropic. Homotropic responses refer to the allosteric modulation of enzyme activity strictly by substrate molecules heterotropic responses refer to the allosteric modulation of enzyme activity by nonsubstrate molecules or combinations of substrate and nonsubstrate molecules. The allosteric modulation can be positive (activation) or negative (inhibition). Many allosteric enzymes also display cooperativity, making a clear differentiation between allosterism and cooperativity somewhat difficult. 

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