Heterotropic Cooperativity

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. 

Mattera, R., Pitts, B. J., Entman, M. L., and Bimbaumer, L. (1985) Guanine nucleotide regulation of a mammalian myocardial muscarinic receptor system. Evidence for homo-and heterotropic cooperativity in ligand binding analyzed by computer-assisted curve fitting. J. Biol. Chem. 260,7410-7421. 

Tang, W. and Stearns, R.A. (2001) Heterotropic cooperativity of cytochrome P450 3A4 and potential drug-drug interactions. Current Drug Metabolism, 2, 185-198. 

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). 

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.

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)... 

A typical allosteric inhibitor therefore cooperates in a heterotropic, negative fashion. 

He YA, Roussel F, Halpert JR. Analysis of homo tropic and heterotropic cooperativity of diazepam oxidation by CYP3A4 using site-directed mutagenesis and kinetic modeling. Arch Biochem Biophys 2003 409 92-101. 

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. 

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