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Regulation of Enzyme Activity

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Regulation of Enzyme Activity
Page 174
Escherichia coli (E. coli) for use in dissolving blood clots in patients suffering myocardial infarction (see p. 98). t­PA also functions by activating the patient's plasminogen.
Asparaginase therapy is used for some types of adult leukemia. Tumor cells have a requirement for asparagine and must scavenge it from the host's plasma. Intravenous (i.v.) administration of asparaginase lowers the host's plasma level of asparagine, which results in depressing the viability of the tumor.
Most enzymes have a short half­life in blood; consequently, unreasonably large amounts of enzyme are required to maintain therapeutic levels. Work is in progress to enhance enzyme stability by coupling enzymes to solid matrices and implanting these materials in areas that are well perfused. In the future, enzyme replacement in individuals that are genetically deficient in a particular enzyme may be feasible.
Enzymes Linked to Insoluble Matrices Are Used As Chemical Reactors
Specific enzymes linked to insoluble matrices are used in the pharmaceutical industry as highly specific chemical reactors. For example, immobilized b ­galactosidase is used to decrease the lactose content of milk for lactose­intolerant people. In production of prednisolone, immobilized steroid 11­ b ­hydroxylase and a d ­1,2­
dehydrogenase convert a cheap precursor to prednisolone in a rapid, stereospecific, and economical manner.
4.10— Regulation of Enzyme Activity
Our discussion up to this point has centered on the chemical and physical characteristics of individual enzymes, but we must be concerned with the physiological integration of many enzymes into a metabolic pathway and the interrelationship of the products of one pathway with the metabolic activity of other pathways. Control of a pathway occurs through modulation of the activity of one or more key enzymes in the pathway. One of the key enzymes is the rate­limiting enzyme, which is the enzyme with the lowest Vmax. It usually occurs early in the pathway. Another is that catalyzing the committed step of the pathway, the first irreversible reaction that is unique to a metabolic pathway. The rate­limiting enzyme is not necessarily the enzyme associated with the committed step. Specific examples of these regulatory enzymes will be pointed out in the sections on metabolism.
The activity of the enzyme associated with the committed step or with the rate­limiting step can be regulated in a number of ways. First, the absolute amount of the enzyme can be regulated by change in de novo synthesis of the enzyme. Second, the activity of the enzyme can be modulated by activators, by inhibitors, and by covalent modification through mechanisms previously discussed. Finally, the activity of a pathway can be regulated by physically partitioning the pathway from its initial substrate and by controlling access of the substrate to the enzymes of the pathway. This is referred to as compartmentation.
Anabolic and catabolic pathways are usually segregated into different organelles in order to maximize the cellular economy. There would be no point to oxidation of fatty acids occurring at the same time and in the same compartment as biosynthesis of fatty acids. If such occurred, a futile cycle would exist. By maintaining fatty acid biosynthesis in the cytoplasm and oxidation in the mitochondria, control can be exerted by regulating transport of common intermediates across the mitochondrial membrane. Table 1.6 (p. 15) contains a compilation of some of the metabolic pathways and their intracellular distribution.
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