Allosteric effectors/modifiers

Allosteric enzymes are regulated by molecules called effectors (also modifiers) that bind noncovalently at a site other than the active site. These enzymes are composed of multiple subunits, and the regula tory site that binds the effector may be located on a subunit that is not itself catalytic. The presence of an allosteric effector can alter the affinity of the enzyme for its substrate, or modify the maximal cat alytic activity of the enzyme, or both. Effectors that inhibit enzyme activity are termed negative effectors, whereas those that increase enzyme activity are called positive effectors. Allosteric enzymes usually contain multiple subunits, and frequently catalyze the commit ted step early in a pathway. 

Phosphorylation also can modify an enzyme s sensi-tivity to allosteric effectors. Phosphorylation of glycogen phosphorylase reduces its sensitivity to the allosteric activator adenosine monophosphate (AMP). Thus, a covalent modification triggered by an extracellular signal can override the influence of intracellular allosteric regulators. In other cases, variations in the concentrations of intracellular effectors can modify the response to the covalent modification, depending on the metabolic state of affairs in the cell. 

The enzyme pyruvate kinase (PK), one of the sites of ADP phosphorylation in glycolysis, provides a good example of adaptation via alteration of enzyme properties. This is because it is modified by the binding of allosteric effectors, it is phosphorylated in the liver and it binds regulatory proteins in the muscle. The reaction catalyzed by PK is as follows ... 

Allosteric effectors may modify the substrate specificity of an enzyme, as well as the reaction rate. Ribonucleotide reductase is a good example ... 

The key to allosteric behavior, including cooperativity and modifications of cooperativity, is the existence of multiple forms for the quaternary structures of allosteric proteins. The word allosteric is, derived from alio, other, and stetic, shape, referring to the fact that the possible conformations affect the behavior of the protein. The binding of substrates, inhibitors, and activators changes the quaternary structure of allosteric proteins, and the changes in structure are reflected in the behavior of those proteins. A substance that modifies the quaternary structure, and thus the behavior, of an allosteric protein by binding to it is called an allosteric effector. The term effector can apply to substrates, inhibitors, or activators. Several models for the behavior of allosteric enzymes have been proposed, and it is worthwhile to compare them. 

Finally, the modifying enzymes are themselves subject to covalent modification and allosteric control. This feature complicates the process considerably but adds the possibility of an amplified response to small changes in conditions. A small change in the concentration of an allosteric effector of a modifying enzyme can cause a large change in the concentration of an active, modified target enzyme this amplification response is due to the fact that the substrate... 

The regulation of covalent phosphorylation of acetyl-CoA carboxylase by the allosteric effectors is especially interesting from the point of view that the cellular metabolites could be determinants of the substrate specificity of protein kinases. At present, very little is known as to how the specificity of protein kinase is determined beyond the required primary amino acid sequence. Such metabolite-regulated covalent phosphorylation was shown to exist in the liver pyruvate kinase system 100), and it could be interesting to examine whether such regulation is a general phenomenon of covalent modifiable systems. 

On the basis of these results, we proposed that the binding of Phe-tRNA and EF-Tu depends on intact GTP, whereas GTP cleavage is required for, and has to precede, the release of EF-Tu from the ribosome and peptide bond formation. Thus, GTP may serve as an allosteric effector that is inactivated, or at least whose action is modified by cleavage into GDP and Pi. 

AT ALL LEVELS, COMCEMTIIATIOM (AS A FUNCTION OF SYNTHESIS AND DEGRADATION RATES, OF INFLUX AND EFFLUX RATES, ETC.), ACCESSIBILITY (DEFENDING ON INTRACELLULAR LOCATION, ON MASKING AND UNMASKING, ETC.) AND ACTIVITY (AS MODIFIED BY ALLOSTERIC EFFECTORS IN PROTEINS. BY METHYLATION IN RIBOSOMAl NUCLEIC ACIDS, ETC.) OF BIOCHEMICAL COMPONENTS REGULATE THE RATES OF REACTIONS. 

Kallos and Shaw found that 1 mole of H-bromoacetyl diethylstil-bestrol would react covalently with glutamate dehydrogenase. Both DES and ADP afforded protection against this alkylation reaction. The modified enzyme was insensitive to the allosteric effectors ADP and GTP, and cleavage of the DES group with hydroxylamine failed to restore normal enzymatic activity. 

Allosterism is a property of an enzyme or any protein, of which the reactivity is modified by binding of an effector at a site other, (alio), than the site where the substrate or the reactant binds. This leads to a conformational change, altering positively or negatively the biologically-relevant activity of the protein. The concept of allosterism was introduced by Jacques Monod. 

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