Allosteric phenomena

Allosteric interactions on GPCRs have been observed for the muscarinic [11-13], adenosine Ai [14], a2A-adrenergic [15-17], and dopamine D2 receptor [18]. This chapter focuses only on two allosteric phenomena, as well as their potential for therapeutic exploitation that on the muscarinic receptor and that on the adenosine receptor. 

On this occasion, we would like to emphasize that so-called cooperative phenomena or allosteric phenomena are not characteristic of biological systems alone but are often observed also in synthetic polymer systems. For example, we cite Fig. 25, which shows the adsorption of metal ions on a synthetic polymer ligand112. The adsorption of Cu ions on the polymer ligand is sigmoidal. This cooperative binding of metal ions is easily understood by following Scheme 12. 

Feedback inhibition, activation, and allosteric phenomena are extremely rapid modes of regulating enzyme activity in all types of cells. Repression... 

Hlavica, P. and D.F. Lewis (2001). Allosteric phenomena in cytochrome P450-catalyzed monooxygenations. Ear. J. BioChem. 268, 4817-4832. 

Table 1. Different types of cooperative and allosteric phenomena...

Some of the vacuum theories treated earlier in the book are repeated in Chapter 8. Examples are chemical equilibrium, allosteric phenomena, and helix-coil transition. The general procedure to transform a vacuum theory into a solution theory is developed. Then we emphasize possible large solvent effects that can significantly alter the vacuum theory, especially when the solvent is water. A detailed account of the thermodynamics of protein folding and protein association is also presented. 

The kinetics of substrate hydrolysis by both AChEs and BuChEs deviates from Michaelis-Menten kinciic.s, A.s implicated in Fig. 2 for acetylthiocholinc, only at substrate concentrations lower than 1 mM docs the rise in enzyme activity follow MichaeliS -Mentcn kinetics. At higher concentrations, AChE activity decreases, inhibited by the excess. substrate, whereas BuChE activity increases, activated by the excess substrate. Hence, the terms substrate inhibition and substrate activation are respective hallmarks of catalysi,s hy AChE and BuChE, Both phenomena can be simply described as a consequence of the formation of a ternary complex between the enzyme and two substrate molecules and thus as an allosteric phenomenon. The ternary complex in AChE has reduced or no activity compared to the Michaelis-Mcntcn complex, whereas it appears more active in BuChE hydrolysis. It is imponant to emphasize that this is a substrate-specific phenomenon. Not all AChE and BuChE substrates exhibit substrate inhibition and sub-... 

In die metabolic pathway to an amino add several steps are involved. Each step is die result of an enzymatic activity. The key enzymatic activity (usually die first enzyme in the synthesis) is regulated by one of its products (usually die end product, eg die amino add). If die concentration of die amino add is too high die enzymatic activity is decreased by interaction of die inhibitor with the regulatory site of die enzyme (allosteric enzyme). This phenomenon is called feedback inhibition. 

When the initial LA concentration is large, the quantity of substrate transferred to the aqueous phase allows the lipoxygenation to progress. This reaction consumes LA and produces HP, which favor the transfer of residual substrate between the two phases. Then catalysis and transfer have a reciprocal influence on each other. We demonstrated that the use of a non-allosteric enzyme in a compartmentalized medium permits the simulation of a co-operativity phenomenon. The optimal reaction rate in the two-phase system is reached for a high initial LA concentration 14 mM. Inhibition by substrate excess is observed in two-phase medium. 

When binding of a substrate molecule at an enzyme active site promotes substrate binding at other sites, this is called positive homotropic behavior (one of the allosteric interactions). When this co-operative phenomenon is caused by a compound other than the substrate, the behavior is designated as a positive heterotropic response. Equation (6) explains some of the profile of rate constant vs. detergent concentration. Thus, Piszkiewicz claims that micelle-catalyzed reactions can be conceived as models of allosteric enzymes. A major factor which causes the different kinetic behavior [i.e. (4) vs. (5)] will be the hydrophobic nature of substrate. If a substrate molecule does not perturb the micellar structure extensively, the classical formulation of (4) is derived. On the other hand, the allosteric kinetics of (5) will be found if a hydrophobic substrate molecule can induce micellization. 

The third type of inhibition is called allosteric inhibition, and is particularly important in the control of intermediary metabolism This refers to the ability of enzymes to change their shape (tertiary and quaternary structure, see Section 13.3) when exposed to certain molecules. This sometimes leads to inhibition, whereas in other cases it may actually activate the enzyme. The process allows subtle control of enzyme activity according to an organism s demands. Further consideration of this complex phenomenon is outside our immediate needs. 

Leis AA, Kofler M, Stokic DS, et al Effect of the inhibitory phenomenon following magnetic stimulation of cortex on brainstem motor neuron excitability and on the cortical control of brainstem reflexes. Muscle Nerve 16 1351-1358, 1993 Lemke MR Effect of carbamazepine on agitation in Alzheimer s inpatients refractory to neuroleptics. J Clin Psychiatry 56 354-357, 1995 Lemus CZ, Robinson DG, Kronig M, et al Behavioral responses to a dopaminergic challenge in obsessive-compulsive disorder. J Anxiety Disord 5 369-373, 1991 Lena C, Changeux JP Allosteric modulations of the nicotinic acetylchohne receptor. Trends Neurosci 16 181-186, 1993... 

Non-competitive inhibitors. These inhibitors bind to the enzyme or the enzyme-substrate complex at a site other than the active site. This results in a decrease in the maximum rate of reaction, but the substrate can still bind to the enzyme. An analogous concept is that of allosteric inhibition. The site of binding of an allosteric inhibitor is distinct from the substrate binding site. In this case, the inhibitor is not a steric analog of the substrate and instead binds to the allosteric site (the phenomenon was termed thus by Monod and Jacob). 

The helical structure of PLL plays an important role in transferring information on oxygenation to the neighboring heme groups. We call this cooperative phenomenon the pseudo-allosteric effect of the PLL-heme complex. 

There are essentially two types of control mechanisms for biochemical switching allosteric cooperative transition and reversible chemical modification. Allosteric cooperativity, which was discussed in Chapter 4, was discovered in 1965 by Jacques Monod, Jefferies Wyman, and Jean-Picrrc Changeux [143], and independently by Daniel Koshland, George Nemethy and David Filmer [116]. The molecular basis of this phenomenon, which is well understood in terms of three-dimensional protein crystal structures and protein-ligand interaction, is covered in every biochemistry textbook [147] as well as special treatises [215],... 

Even though in vitro experiments necessarily remove biomolecules from the cellular environment, the structures and dynamics of individual macromolecules provide insights to their biological functions. For example, structural studies have revealed that the protein hemoglobin is made up of four interacting subunits, two a subunits and two ft subunits. Furthermore, each subunit has two distinct conformational states, called the R state and the T state, and the energy of interaction between two neighboring subunits in different states is different from that of two subunits in the same state. This phenomenon is the structural basis of the observed allosteric... 

This DFG-in/out phenomenon was first observed for the Abelson kinase where the ligand gleevec (78, 79) was found to bind both the ATP binding site and the allosteric binding pocket in the DFG-loop. This mechanism is observed not only for the Abelson and p38 kinases (74, 80, 81) but also for Raf (82) and KDR (83). 

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