Effect allosteric

The allosteric effect is seen in hemoglobin which can exist in two quaternary stmctural states oxygenated (R) or deoxygenated (T). The binding of one O2 or some other effector to one of the subunits stabilizes the R form as compared to the T form. Binding of a second and third O2 stabilizes it even further. 

FIGURE 15.11 Heterotropic allosteric effects A and I binding to R and T, respectively. The linked equilibria lead to changes in the relative amounts of R and T and, therefore, shifts in the substrate saturation curve. This behavior, depicted by the graph, defines an allosteric K system. The parameters of such a system are (1) S and A (or I) have different affinities for R and T and (2) A (or I) modifies the apparent for S by shifting the relative R versus T population. 

A more sensitive and rigorous method of detecting and quantifying allosteric effects is through observation of the kinetics of binding. 

Allosteric antagonism is characterized by the fact that it attains a maximal value. A sensitive method for the detection of allosteric effects is through studying the kinetics of binding. 

Another possible allosteric effect is to render the receptor insensitive to agonist stimulation (i.e., remove the capacity for agonist response). This may or may not be accompanied by a change in the affinity of the receptor for the agonist. This can be simulated by setting , = 0 in Equation 7.3 to yield... 

Modulators can be classified as potentiators of effect or antagonists. If potentiation is observed, it is clearly an allosteric effect as orthosteric obfuscation of the agonist binding site cannot lead to potentiation of agonism. 

Allosteric modulators possess properties different from orthosteric ligands. Specifically, allosteric effects are saturable and probe dependent (i.e., the modulator produces different effects for different probes). 

Allosteric effects can result in changes in affinity and or efficacy of agonists. 

As discussed in Chapter 7, antagonists may bind to a separate loci on the receptor and thereby allosterically modify the affinity of the receptor for the agonist. The maximal change in the agonist affinity is denoted by a term a. It is useful to distinguish allosteric effects in terms of whether the modulator affects signaling and affinity or just affinity. In the latter situation, the modulator produces parallel shifts to the right of the concentration response curve up to a maximal point. This is discussed in Section 7.4.1 (t, = 1). Under these circumstances, the curve for... 

Figure 17-6. Regulation of pyruvate dehydrogenase (PDH). Arrows with wavy shafts indicate allosteric effects. A Regulation by end-product inhibition. B Regulation by interconversion of active and inactive forms.

Ghanges in the availability of substrates are responsible for most changes in metabolism either directly or indirectly acting via changes in hormone secretion. Three mechanisms are responsible for regulating the activity of enzymes in carbohydrate metabolism (1) changes in the rate of enzyme synthesis, (2) covalent modification by reversible phosphorylation, and (3) allosteric effects. 

Furthermore, these allosteric effects were shown to be truly subtype specific, depending on the nature of the allosteric modulating compound. Thus, alcuronium exerts positive copperativity with [3H]NMS at the M2 and M4 but not at the Mi and M3 receptors [26,27], while other neuromuscular junction blockers such as stercuronium, pancuronium, and d-tubocurarine have been shown to exhibit their effects via an allosteric mechanism specifically on the M2 receptors [28-30]. 

Clarke RJ, Apell H-J, Kong BY (2007) Allosteric effect of ATP on Na+,K+-ATPase conformational kinetics. Biochemistry 46 7034-7044... 

---