Heterotropic effects

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). 

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

The symmetry model (fig. 2.4) of allostery can describe the cooperative binding of substrate to enzyme (homotropic effect), as well as the influence of effector molecules on the activity of enzymes (heterotropic effect). 

The MWC model of the previous section accounts only for homotropic effects, as occur, for example, with 02 binding to hemoglobin, but heterotropic effects are frequently observed with regulatory enzymes. To incorporate these effects into the MWC model, we must introduce the binding... 

J.O. Newell, D.W. Markby, and H.K. Schachman. 1989. Cooperative binding of the bisubstrate analog A-(phosphonacetyl)-l-aspartate to aspartate transcarbamoylase and the heterotropic effects of ATP and CTP J. Biol. Chem. 264 2476-2481. (PubMed)... 

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. 

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... 

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... 

Let us first define two terms. Homotropic effects are allosteric interactions that occur when several identical molecules are bound to a protein. The binding of substrate molecules to different sites on an enzyme, such as the binding of aspartate to ATGase, is an example of a homotropic effect. Heterotropic effects are allosteric interactions that occur when different substances (such as inhibitor and substrate) are bound to the protein. In the ATGase reaction, inhibition by GTP and activation by ATP are both heterotropic effects. 

Recall What is a homotropic effect What is a heterotropic effect ... 

The inhibitor displays negative heterotropic effect and elevated cooperativity of the substrate The presence of inhibitor (P > 0), which only binds to the T state, reduces the binding affinity for the substrate by decreasing the concentration of the R state to which the substrate binds (negative hetereotropic effect). Since the substrate must counter this deficit in the equiUbrium concentration of the R state, the cooperativity of the substrate increases in the presence of inhibitor. 

The activator displays a positive heterotropic effect and suppressed cooperativity of the substrate The presence of activator (y > 0) increases the concentration of the substrate-binding R state and therefore increases the substrate binding affinity for the enzyme (positive hetereotropic effect). The advantage of the equilibrium concentration of the R state decreases the substrate cooperativity in the presence of the activator. 

Heterotropic transition Heterotropic interactions may be transmitted to the regulatory sites by the tower helices and by changes at the subunit contacts. The simultaneous binding of allosteric activator and allosteric inhibitor gives rise to a structure intermediate between the T and the R structures. The heterotropic effect is exerted throughout the subunit interface contacts. 

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. 

According to the model, heterotropic effects would be due exclusively to displacement of the equilibrium between the R and T states of the protein. TTius, the saturation function for substrate in the presence of activator and inhibitor may be written as... 

Figure 13. Theoretical curves showing the heterotropic effects of an allosteric activator (y) or inhibitor ( ) upon the shape of the saturation function, drawn according to Eq. (13-60).

This equation expresses the second fundamental property of the MWC model, namely, that the heterotropic effect of an allosteric ligand upon the saturation function for another allosteric ligand should be to modify the homotropic interaction of the latter. 

Obach RS (2012) Heterotropic effects on drug-metabolizing enzyme activities in vitro curiosity emerges as a clinically meaningful phenomenon (perhaps ). Clin Pharmacol Ther 91 385-387... 

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. 

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