Enzyme reactions signal transduction

Most of the signals conveyed by AC/cAMP are mediated through phosphorylation reactions catalyzed by the protein kinases. Figure 12.1 illustrates the involvement of adenylyl cyclase as the effector enzyme in signal transduction. 

Most biological reactions fall into the categories of first-order or second-order reactions, and we will discuss these in more detail below. In certain situations the rate of reaction is independent of reaction concentration hence the rate equation is simply v = k. Such reactions are said to be zero order. Systems for which the reaction rate can reach a maximum value under saturating reactant conditions become zero ordered at high reactant concentrations. Examples of such systems include enzyme-catalyzed reactions, receptor-ligand induced signal transduction, and cellular activated transport systems. Recall from Chapter 2, for example, that when [S] Ku for an enzyme-catalyzed reaction, the velocity is essentially constant and close to the value of Vmax. Under these substrate concentration conditions the enzyme reaction will appear to be zero order in the substrate. 

The classical example is blood clotting, where successive steps involving enzyme-catalyzed proteolysis converts an inactive (or weakly active) proenzyme into its highly active form. Although unknown at the time of Wald s classical report, kinase-type and nucleotidyltransferase-type reactions (See Enzyme Cascade Kinetics) are frequently the source of biological signal transduction and amplification. 

The extent and specificity of the reactions of protein kinases and protein phosphatases are extremely dependent on the degree to which substrate and enzyme are localized at the same place in the cell. Many substrates of protein kinases occur either as membrane associated or particle associated forms (see 7.6.1, enzymes of glycogen metabolism). For protein kinases or protein phosphatases to perform their physiological function in a signal transduction process, they must be transported to the location of then-substrate in many cases (review Hubbard and Cohen, 1992 Mochly-Rosen, 1995). This is vahd both for the Ser/Tbr-specific protein kinases as well as for many Tyr-speci-fic protein kinases. In the course of activation of signal transduction pathways, com-partmentahzation of protein kinases, redistributed to new subcellular locations, is often observed. 

The examples of phosphorylase kinase and protein phosphatase I illustrate some important principles of regulation of enzyme activity by phosphorylation and dephosphorylation events. They clearly indicate how different signal transduction paths can meet in key reactions of metabolism, how signals can be coordinated with one another and how common components of a regulation network can be activated by different signals. The following principles are highlighted ... 

Considered in isolation, the Ras protein is a very inefficient enzyme. On the one hand, the rate of GTP hydrolysis is very low on the other hand, the complex of Ras protein and GDP is very stable and only dissociates very slowly. The rate constants of both processes are in the region of 10 " sec Both reactions may be accelerated in the process of signal transduction, however, and have a decisive influence on signal transduction via the Ras protein. 

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