Allosteric interactions feedback

Physical modification by noncovalent interactions allosteric control (feedback inhibition, precursor activation). Enzyme activity... 

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. 

Most of the pathways of amino acid biosynthesis are regulated by feedback inhibition, in which the committed step is allosterically inhibited by the final product. Branched pathways require extensive interaction among the branches that includes both negative and positive regulation. The regulation of glutamine synthetase from if. coli is a striking demonstration of cumulative feedback inhibition and of control by a cascade of reversible covalent modifications. 

ACTIVE FIGURE 23.4 The allosteric regulation of glutamine synthetase activity by feedback inhibition. Sign in at www.thomsonedu.com/login to explore an interactive version of this figure. 

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]. 

Feedback inhibition can be limited by optimizing both upstream and downstream enzyme expression such that the inhibitor does not significantly accumulate. In instances where a metabolite inhibits an enzyme in the isoflavonoid pathway, enzyme mutagenesis can alter the structural interaction between the enzyme and its inhibitor to block the inhibition mechanism. Recently, allosteric feedback inhibition of a tomato peel 4CL by naringenin 23, a product several steps downstream, was significantly reduced through directed evolution in E. coli [181]. 

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