Allosteric effectors/modifiers negative

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. 

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. 

This reaction is the initial step in production of deoxynucleoside triphosphates (dNTPs) for DNA synthesis. Four dNTPs are needed for DNA synthesisdATP, dCTP, dGTP, and TTP (TTP comes from dUDP). The proportions of these dNTPs need to be balanced for efficient synthesis. The feedback molecules, or effectors, are the final products of the pathway, the dNTPs, and they act on ribonucleotide reductase to modify its substrate specificity in order to balance the production of dNTPs. In addition to the specificity control site, an additional allosteric control site determines the overall rate of the reaction. At this site, ATP acts as a positive regulator and dATP as a negative regulator. 

The ribonucleoside triphosphate reductase of L. leichmannii is an allosteric enzyme, the activity of which is modified in a complex manner by deoxyribonucleoside triphosphates 28, 29). Reduction of each of the four substrates is maximally stimulated by a particular deoxyribonucleoside triphosphate, which Beck 29) terms a prime effector. The data of Table 16-III illustrate the specific nature of the effector stimulation prime effectors are indicated by the italicized data. The effector-induced stimulation of reductase activity appears to be countered in particular ways by deoxyribonucleoside triphosphates for example, dTTP inhibits the dATP-acti-vated reduction of CTP. It has been speculated that these complicated positive and negative allosteric effects produced by nucleotides may constitute a mechanism for ensuring that surpluses or shortages in the production of deoxyribonucleotides do not occur in the cell 29). 

The chart in Fig. 2 shows an alternate path for the formation of dUMP by direct deamination of dCMP. This may be how cytidine could be converted to thymidylate in the cases cited above [125,126]. However, this deaminase is not usually detected in E. coli but is induced by infection with T(even) phages [132,133]. It has also been purified from chick embryo and mammalian tissues, and its properties have been extensively analyzed [134-136]. It acts as a typical allosteric enzyme in both the phage-infected E. coli and animal systems. Homotropic substrate interaction is evident, and this is modified by dCTP as an activator, and by dTTP (sometimes dGMP) as an allosteric inhibitor. This type of control apparently functions to regulate the level of dTTP by feedback inhibition and by activation when the supply of dTTP is depleted. Cytidine deaminase (EC 3.5.4.5) isolated from sheep liver [137] appears to have the same allosteric properties, with the same positive and negative effectors, as those of dCMP deaminase. The latter enzyme is also induced by phage infection in B. subtiUs, and in contrast to the deaminase from all other sources it does not show allosteric inhibition or activation by any nucleotide [138]. 

While competitive inhibition depends on a close structural relationship between the inhibitor and the normal substrate, certain enzymes may have their activity modified by metabolites which bear no structural relationship to the substrate and which bind reversibly to a site on the enzyme surface which is quite distinct from the substrate-binding site. This is known as the allosteric site. It is believed that allosteric regulators act by modifying the conformation of the active site so that it binds the substrate either more positive effectors or activators) or less negative effectors or inhibitors) strongly. The allosteric site is not necessarily close to the active site and may even be situated on a different type of subunit from the active site. 

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