Feedback inhibition cooperative effect

Multiple feedback loops can provide additional fine control. For example, as shown in Figure 9—5, the presence of excess product B decteases the tequitement for substrate 3. Howevet, Sj is also tequited fot synthesis of A, C, and D. Excess B should thetefote also curtail synthesis of all font end products. To circumvent this potential difficulty, each end product typically only partially inhibits catalytic activity. The effect of an excess of two or more end products may be strictly additive or, alternatively, may be greater than their individual effect (cooperative feedback inhibition). 

A variety of patterns of end-product inhibition have been described [5,69] (1) In enzyme multiplicity inhibition balanced control of an early enzyme of the common part of a branched pathway is obtained because the enzyme is present in the form of several isoenzymes, each specifically inhibited by an end product of one of the branches. (2) In cumulative feedback inhibition an enzyme which mediates the formation of a product used in many pathways is partly inhibited by individual end products of the pathways. Each inhibitor adds its effect to the total inhibition, but the combined effect is less than the sum of the single inhibitions. (3) In concerted feedback inhibition two or more end products are required to act together before any significant inhibition is exhibited. (4) In cooperative feedback inhibition several end products can act as partial inhibitors of an enzyme, but a mixture of two different inhibitors results in greater inhibition than the sum of the individual inhibitions. (5) The term sequential feedback inhibition refers to inhibition of an early enzyme by an intermediate whose accumulation is controlled by inhibition of one or more late pathway enzymes by the end product [71 ]. 

Since allopurinol has a half-life of only about 1-1/2 hours in man, due to its rapid oxidation, the level of allopurinol ribonucleotide in human liver is probably < 0.0001 mM. If one uses, as a first approximation, the values reported for the pigeon liver PRPP-amidotransferase, = 0.6 mM, [16] the levels of allopurinol ribonucleotide in liver are far below the amount required to inhibit this enz5mie appreciably. On the other hand, the levels of the natural purine ribonucleotides [9] lie much closer to the values for the pigeon liver enz3nne [16,17] or to the [I]0,5 values in human l3miphoblasts [18]. Hypoxanthine and xanthine levels are increased by the inhibition of xanthine oxidase produced by allopurinol and oxipurinol. The reutilization of these oxypurines is very efficient under these conditions [19,20]. This could result in feedback inhibition of novo synthesis through temporary increases in IMP and XMP, and subsequently AMP and GMP levels. This effect would be enhanced by the cooperative effect of AMP and GMP in the inhibition of PRPP - amidotransferase [17]. 

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