Cooperativity positive

If the binding of one substrate molecule to an enzyme induces stmctural changes that result in altered affinities for the vacant sites, Ae velocity curve will no longer obey the Michaelis-Menten kinetics. Let us consider an enzyme with two identical substrate binding sites (Adair, 1925). 

If the binding of one substrate molecule changes the dissociation constant, Ka. by a factor , and the cat is the same at each site regardless whether the other site is occupied, the reaction sequence is 

If Vmax = afccatEo. and the derivation of the velocity equation is based on a rapid equilibrium assumption, we shall obtain 

An enzyme with four identical sites may be treated similarly. If the binding of the first substrate molecule changes the dissodafion constants of the vacant sites by a factor, a, the binding of the second substrate molecule changes the dissociation constant for the remaining vacant sites by a factor, b, and the third substrate molecule introduces an interaction factor, c, than the effective dissociation constants for the binding of first, second, and the third substrate molecule are 

Note that the change induced by the first molecule of substrate is retained, so is the change induced by the second and the third molecule of substrate that is, the interactions are cumulative (DeLand, 1994 final, 1994 Johnson, 1994). 

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Fig. 5. Protein folding. The unfolded polypeptide chain coUapses and assembles to form simple stmctural motifs such as -sheets and a-hehces by nucleation-condensation mechanisms involving the formation of hydrogen bonds and van der Waal s interactions. Small proteins (eg, chymotrypsin inhibitor 2) attain their final (tertiary) stmcture in this way. Larger proteins and multiple protein assembhes aggregate by recognition and docking of multiple domains (eg, -barrels, a-helix bundles), often displaying positive cooperativity. Many noncovalent interactions, including hydrogen bonding, van der Waal s and electrostatic interactions, and the hydrophobic effect are exploited to create the final, compact protein assembly. Further stmctural...

Positive cooperativity of acetylcholine and other agonists with allosteric ligands on muscarinic acetylcholine receptors. Mol. Pharmacol. 52 172—179. 

Jakubic, J., Bacakova, I., El-Fakahany, E. E., and Tucek, S. (1997). Positive cooperativity of acetylcholine and other agonists with allosteric ligands on muscarinic acetylcholine receptors. Mot. Pharmacol. 52 172-179. 

For this kind of cooperative processes, it is characteristic that the formation of the nucleus is thermodynamically more difficult than for further propagation steps (positive cooperativity). This implies that the elementary transition step of an individual chain segment (tripeptide unit) is influenced by the state of adjacent segments through intramolecular interactions. 

The simplest model that can describe allosteric interactions at GPCRs is the ternary complex allosteric model [9], As shown in Figure 1, according to this model two parameters define the actions of allosteric agent (X) its affinity for the unoccupied receptor (Kx) and its cooperativity (a) with the ligand (A) that interacts at the primary binding site a < 1 represents negative cooperativity a = 1, no cooperativity a > 1, positive cooperativity. 

Birdsall NJ, Farries T, Gharagozloo P, Kobayashi S, Lazareno S, Sugimoto M. Subtype-selective positive cooperative interactions between brucine analogs and acetylcholine at muscarinic receptors functional studies. Mol Pharmacol 1999 55 778-786. 

Tucek S, Musilkova J, Neduoma J, Proska J, Shelkovnikov SW, Vorlicek J. Positive cooperativity in the binding of alcuronium and A-methy lscopolamine to muscarinic acetylcholine receptors. Mol Pharmacol 1990 38 674-680. 

The Hill plot is log (B (Bnu>. - B)) vs. log [L], As noted earlier, the slope of the Hill plot (the Hill coefficient, H) is of particular utility. If the equation holds, a straight line of slope = 1 should be obtained. A value greater than 1 may indicate positive cooperativity, and a slope less than 1 either negative cooperativity or commonly the presence of sites with different affinities. The data of Problem 5.1 are also presented as a Hill plot in Figure 5.10. 

In Chapter 1 (Section 1.2.4.3), the Hill equation and the Hill coefficient, nH, are described. Hill coefficients greater than or less than unity are often interpreted as indicating positive or negative cooperativity, respectively, in the relationship between receptor occupancy and response. For example, positive cooperativity could arise due to amplification in a transduction mechanism mediated by G-proteins and changes in cell calcium concentration. 

Both secondary active transport and positive cooperativity effects enhance carrier-mediated solute flux, in contrast to negative cooperativity and inhibition phenomena, which depress this flux. Most secondary active transport in intestinal epithelia is driven by transmembrane ion gradients in which an inorganic cation is cotransported with the solute (usually a nutrient or inorganic anion). Carriers which translocate more than one solute species in the same direction across the membrane are referred to as cotransporters. Carriers which translocate different solutes in opposite directions across the membrane are called countertransporters or exchangers (Figs. 10 and 11). 

Positive cooperativity means that the reaction of substrate with one active site makes it easier for another substrate to react at another active site. Negative cooperativity means that the reaction of a substrate with one active site makes it harder for substrate to react at the other active site(s). 

COOPERATIVE ENZYMES do not show a hyperbolic dependence of the velocity on substrate concentration. If the binding of one substrate increases the affinity of an oligomeric enzyme for binding of the next substrate, the enzyme shows positive cooperativity. If the first substrate makes it harder to bind the second substrate, the enzyme is negatively cooperative. 

Vmax is S0.5. Enzymes that are positively cooperative are very sensitive to changes of substrate near the S0 5. This makes the enzyme behave more like an on-off switch and is useful metabolically to provide a large change in velocity in response to a small change in substrate concentration. Negative cooperativity causes the velocity to be rather insensitive to changes in substrate concentration near the S0.5-... 

PHOSPHOFRUCTOKINASE shows positive cooperativity with fructose-e-phosphate as the substrate. ATP, an allosteric inhibitor, binds to the T state and decreases the velocity. AMP, a signal for low energy, binds to the R state and increases the velocity of the reaction. 

The formation of ER dimers can be favored once the first monomer has bound to the DNA, since this presents positive cooperation in binding the next monomer. In any case, DNA binding creates a greater compaction of the dimer that results in a subsequent spatial restructuring of the receptor molecules. 

In this part, two series of 44 copolymers with coiled main-chain structures and 45 copolymers with stiff main-chain conformations were described. It was concluded that both optically inactive 42 and 43 adopt helical conformations with an equal proportion of P and M screw senses by means of UV and CD spectra as well as molecular mechanics calculations. A marked positive cooperative induction effect of the preferential screw sense in 44 and 45 copolymers was found. However, there is a marked difference in the helical cooperativity between 44 and 45, probably because of the differences in their global and local conformations. This difference can be related to the persistence of the helical conformation against defects allowing change of... 

Boyer, J. L Martinez-Carcamo, M Monroy-Sanchez, J. A., Posadas, C., and Garcia-Sainz, J. A. (1986) Guanine nucleotide-induced positive cooperativity in muscarinic-cholinergic antagonist binding. Biochem. Biophys. Res. Commun. 134,172-177. 

Schrag, M.L. and Wienkers, L.C. (2005) Catalytic turnover of pyrene by CYP3 A4 evidence that cytochrome b5 directly induces positive cooperativity. Archives of Biochemistry and Biophysics, 438 (1), 21-28. 

To account for positive cooperativity and sigmoidal rate equations, a number of theoretical models for allosteric regulation have been developed. Common to most models is the assumption (and requirement) that enzymes act as multimers and exhibit interactions between the units. We briefly mention the most... 

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