Heterotropic allosteric effect

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. 

Ikeda, Y. Taniguchi, N. Noguchi, T. Dominant negative role of the glutamic add residue conserved in the pyruvate kinase M-1 isoz3nne in the heterotropic allosteric effect... 

We first generalize the model treated in section 3.2. Instead of two equivalent sites, we assume that one site, say the left-hand site in Fig. 3.6, can bind the substrate A and the second site can bind the activator or inhibitor B. This is the simplest model of a heterotropic allosteric effect, i.e., two different ligands communicating through the polymer. 

Homotropic allosteric effect appears in the system with identical ligands, and heterotropic allosteric effect is manifested for interaction between different ligands. 

It was pointed out in Section 6.8 that the term allosteric as coined by MCJ and MWC has been used with three different meanings. In Chapter 6 we discussed the allosteric effect in hemoglobin (Hb). There, the two allosteric sites were identical this has been referred to as the homotropic effect. When the two sites bind different ligands, the heterotropic effect, the induced fit by one ligand can either enhance or diminish the binding affinity of the second ligand (see the example in Section 4.5). 

Unlike the midpoint slope (//1/2) of an ideal Nernstian plot, the slope of a non-Nernstian response cannot be interpreted as the number of electrons involved in the oxidation/reduction process. For the Hbs, the n parameter is influenced by site-site heterogeneity and allosteric effects.The n parameter is an indicator of the level of cooperativity that is operative high n values indicate a high level of cooperativity, while low n values indicate reduced cooperativity. The sensitivity of the n parameter to heterotropic effectors may be seen in Figure 2.11. The trend illustrated is consistent with the two-state (R and T) model for Hb. Maximum cooperativity is indicated by the highest values for max (defined in Figure 2.4) as illustrated for Hb o the absence of a heterotropic effector. The T-state is stabilised by heterotropic effectors (data points 1-4), which results in an increase in ease of reduction (increase in 1/2) and a decrease in cooperativity (decrease in max) due to a diminished ease of T R shift as a result of T-state stabilisation. R-state stabilisation occurs in HbCPA and horse Hb (data points 6-9), which is characterised by an increase in ease of oxidation (lower Eijf) and reduced cooperativity as illustrated by diminished max values. 

Homotropic effect refers to allosteric effects produced by enzyme s own substrate and heterotropic effects are due to metabohtes that are not stmcturaUy related to enzyme s substrates. Positive effects are related to enzyme activation and negative effects to enzyme inhibition. Thus, fmctose-diphosphate is a positive allosteric effector of pymvate kinase. 

Allosteric Effect The binding of a guest at one binding site that is influenced by the binding of a second guest, either the same species (homotropic effect) or a different kind of guest (heterotropic effect), bound elsewhere within the host. 

The separation between allosteric effectors and cooperativity lies in the molecule doing the affecting. If the effector molecule acts at another site and the effector is not the substrate, the effect is deemed allosteric and heterotropic. If the effector molecule is the substrate itself, the effect is called cooperative and/or homotropic. 

STEREOCHEMICAL TERMINOLOGY, lUPAC RECOMMENDATIONS HETEROTROPIC EFFECT MONOD-WYMAN-CHANGEUX MODEL HEMOGLOBIN ALLOSTERISM... 

Heterotropic effectors The effector may be different from the substrate, in which case the effect is said to be heterotropic. For example, consider the feedback inhibition shown in Figure 5.17. The enzyme that converts A to B has an allosteric site that binds the end-product, E. If the concentration of E increases (for example, because it is not used as rapidly as it is synthesized), the initial enzyme in the pathway is inhibited. Feedback inhibition provides the cell with a product it needs by regulating the flow of substrate molecules through the pathway that synthesizes that product. [Note Heterotropic effectors are commonly encountered, for example, the glycolytic enzyme phosphofructokinases allosterically inhibited by citrate, which is not a substrate for the enzyme (see p. 97).]... 

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. 

According to the concerted model, an allosteric activator shifts the conformational equilibrium of all subunits toward the R state, whereas an allosteric inhibitor shifts it toward the T state. Thus, ATP (an allosteric activator) shifted the equilibrium to the R form, resulting in an absorption change similar to that obtained when substrate is bound. CTP had a different effect. Hence, this allosteric inhibitor shifted the equilibrium to theT form. Thus, the concerted model accounts for the ATP-induced and CTP-induced (heterotropic), as well as for the substrate-induced (homotropic), allosteric interactions of ATGase. 

Many proteins are regulated by molecules which bind somewhere other than at the active site and either inerease or decrease protein activity. These allosteric ejfectors are often quite specific and may have either a positive or negative effect upon protein activity. C ass cdX feedback inhibition cycles in metabolism generally involve heterotropic allostery, in which a molecule produced near the end of a metabolic pathway acts as an allosteric effector to regulate a protein active earlier in the same pathway. Because of the need for very precise control of the energy charge of the cell, ATP and ADP serve as allosteric effectors for several of the proteins of glucose metabolism. Protons and ions act as allosteric effectors in many... 

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