![]() ![]() The H-values are larger than 1 for enzymes with positive cooperativity and less than 1 for those with negative cooperativity. Instead, it is characterized by substrate concentration giving a half-maximal rate, 0.5, and the Hill coefficient (H). Since the affinity of the enzyme changes with substrate concentration, it cannot be described by simple Michaelis-Menten kinetics. Negative cooperativity means that the reaction of a substrate with one active site makes it more difficult for a substrate to react at the other active site. Positive cooperativity indicates that the reaction of a substrate with one active site makes it easier for another substrate to react at another active site. The effect is essentially identical with that described for the binding of O 2 to hemoglobin ( Chapter 4), except that in the case of enzymes, substrate binding leads to an enzyme-catalyzed reaction. ![]() The interactionīetween subunits makes the binding of substrate cooperative and results in a sigmoidal curve in the plot of v versus. Homotropic effects are observed when the reaction of one substrate molecule with a multimeric enzyme affects the binding of a second substrate molecule at a different active site on the enzyme. If the allosteric effector is different from the substrate, it is referred to as a heterotropic effect. In some cases, the substrate exerts allosteric effects this is referred to as a homotropic effect. An allosteric effector molecule binds to the enzyme at a site that is distinct and physically separate from the substrate-binding site, but which affects the overall substrate binding and/or On the other hand, allosteric enzymes often show sigmoidal plots of reaction velocity versus substrate concentration ( Fig. The substrate saturation curve for an 'isosteric' (single shape) enzyme is hyperbolic (see Fig. Thus, virus-infected cells are prone to be arrested at specific cell cycle stage, G 2-M checkpoint ( Chapter 41), but uninfected cells are resistant to the nucleoside analogs. While viral TK has low substrate specificity and efficiently phosphorylates nucleoside analogs, cellular nucleoside kinases have high substrate specificity and barely phosphorylate the nucleoside analogs. Cellular kinases next add phosphates to form the active triphosphate compounds, which are competitive inhibitors of the viral DNA polymerase during DNA replication ( Chapter 29). The thymidine kinase (TK), more properly a nucleoside kinase, of the viruses phosphorylate these compounds to their monophosphate form. They are pro-drugs that are activated by phosphorylation and terminate viral DNA synthesis by inhibiting the viral DNA polymerase reaction. Nucleoside analogs such as acyclovir and ganciclovir have been used for treatment of herpes simplex virus (HSV), varicella-zoster (VZV), and cytomegalovirus (CMV). Hemophilia A, the major (85%) form of hemophilia, is caused by a defect of clotting Factor VIII (See Chapter 6). Hemophilia is a disorder of blood clotting caused by a defect in one of the sequence of clotting factors. This last step is catalyzed by the serine protease, thrombin (Factor IIa). In the final step, the blood clot is formed by conversion of a soluble protein, fibrinogen (Factor I), into an insoluble, fibrous product, fibrin, which forms the matrix of the clot. Over a dozen different proteins, known as blood-clotting factors, are involved. Formation of a blood clot results from a cascade of zymogen-activation reactions. Factor VIII was administered to the patient to restore blood-clotting activity.Ĭomment. Laboratory findings indicated a blood-clotting disorder, hemophilia A, resulting from deficiency of Factor VIII. HEMOPHILIA IS CAUSED BY A DEFECT IN ZYMOGEN ACTIVATIONĪ child was admitted to hospital with muscle bleeding affecting the femoral nerve. This enzyme is described in more detail in Chapter 29. CTP, an end product, heterotropically inhibits, but ATP, a precursor, heterotropically activates ATCase. Aspartate (substrate) homotropically regulates ATCase activity, providing sigmoidal kinetics. Aspartate transcarbamoylase (ATCase) is an example of an allosteric enzyme. Plot of velocity ( v) versus substrate concentration in the presence of an allosteric activator or allosteric inhibitor. Allosteric regulation of rate-limiting enzymes in metabolic pathwaysįigure 5.9 Allosteric regulation of ATCase. ![]()
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