Allosteric enzymes concerted model

FIGURE 16.7 Concerted model for allosteric enzymes. The major steps are (a) and (b). An equilibrium exists between the tight (a) and relaxed (b) forms of the allosteric enzyme. The reactant molecule(s) approaches the reactive site of one of the enzyme sites present in the relaxed form (c). Binding occurs, shifting the equilibrium to the relaxed form(s). The second site is bound (d). 

Allosteric switching. A substrate binds 100 times as tightly to the R state of an allosteric enzyme as to its T state. Assume that the concerted (MWC) model applies to this enzyme. 

Distinguishing between models. The graph below shows the fraction of an allosteric enzyme in the R state (f r) and the fraction of active sites bound to substrate (T) as a function of substrate concentration. Which model, the concerted or sequential, best explains these results ... 

Two major models for allosteric enzymes have been proposed. These are the sequential interaction model and the concerted-symmetry ... 

Schematic diagram of conformational changes of concerted model for a dimeric allosteric enzyme. All subunits are either in the T-form with low affinity for the substrate or in the R-form with high affinity for the substrate.

Two theoretical models that attempt to explain the behavior of allosteric enzymes are the concerted model and the sequential model. In the concerted (or symmetry) model, it is assumed that the enzyme exists in only two states T(aut) and R(elaxed). Substrates and activators bind more easily to the R conformation, whereas inhibitors favor the T conformation. The term concerted is applied to this model because the conformations of all the protein s protomers are believed to change simultaneously when the first effector binds. (This rapid concerted change in conformation maintains the protein s overall symmmetry.) The binding of an activator shifts the equilibrium in favor of the R form. An inhibitor shifts the equilibrium toward the T conformation. 

Fig. 2.10. Scheme of an autocatalytic enzyme reaction. The allosteric enzyme catalysing the reaction is formed by several subunits (not shown), which exist in the conformational states R and T. These states differ in their affinity for the substrate and/or in their catalytic activity. In the model by Monod et al. (1965), the transition between the two conformational states is concerted for all subunits. Here the product is a positive effector, i.e. an activator, as it binds in an exclusive or preferential manner to the most active, R state, of the enzyme. The system is open as the substrate S is injected at a constant rate while the product P disappears as a result of its utilization in a subsequent enzyme reaction. 

Goldbeter, A. 1976. Kinetic cooperativity in the concerted model for allosteric enzymes. Biophys. Chem. 4 159-69. 

The two principal models for the behavior of allosteric enzymes are the concerted model and the sequential model. They were proposed in 1965 and 1966, respectively, and both are currently used as a basis for interpreting experimental results. The concerted model has the advantage of comparative simplicity, and it describes the behavior of some enzyme systems very well. 

In the concerted model, the effects of inhibitors and activators can also be considered in terms of shifting the equilibrium between the T and R forms of the enzyme. The binding of inhibitors to allosteric enzymes is cooperative allosteric inhibitors bind to and stabilize the T form of the enzyme. The binding of activators to allosteric enzymes is also cooperative allosteric activators bind to and stabilize the R form of the enzyme. When an activator, A, is present, the cooperative binding of A shifts the equilibrium between the T and R forms, with the R form favored (Figure 7.6). As a result, there is less need for substrate, S, to shift the equilibrium in favor of the R form, and less cooperativity in the binding of S is seen. 

The two principal models for allosteric enzyme behavior are called the concerted model and the sequential model. 

Recall Distinguish between the concerted and sequential models for the behavior of allosteric enzymes. 

In the concerted model, all the subunits in an allosteric enzyme are found in the same form, either the T form or the R form. They are in equilibrium, with each enzyme having a characteristic ratio of the T/R. In the sequential model, the subunits change individually from T to R. 

The concerted symmetry model is much more versatile than simple sequential models described by Adair or Hill. This model is endowed by the variable values of Kr, L, and c, and therefore may provide explanations for many properties of allosteric enzymes and proteins, including... 

The MWC concerted-symmetry and KNF sequential interaction models may be considered as extreme cases of the more general model shown in Fig. 19. A general model for a four-site allosteric enzyme involves the hybrid oligomers. The first and the fourth column in Fig. 19 represent the concerted-symmetry model. The diagonal represents the sequential interaction model. As shown, there are 25 different types of enzyme forms. If the potential nonequivalent complexes are included (such as, e.g., two different T3RS2), the number raises to 44 possible enzyme forms (Hammes Wu, 1971). 

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