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A specific metabolic cycle

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The three dimensional structure of dihydrofolate reductase colored by its surface potential. Positive values are depicted in red, negative values in blue.

The three dimensional structure of dihydrofolate reductase colored by its surface potential. Positive values are depicted in red, negative values in blue.

nodes of the metabolic cycle are labeled with the respective organic molecules, and the edges point in the direction from the substrate of the reaction to the product. Metabolic reactions can take place spontaneously under physiological conditions (in aqueous solution, under room temperature and neutral pH). However, nature has equipped each reaction (each line in Figure 1.1) with a specific molecule that catalyzes that reaction. This molecule is called an enzyme and, most often, it is a protein. An enzyme is a tailor-made binding site for the transition state of the catalyzed chemical reaction. Thus the enzyme speeds up the rate of that reaction tremendously, by rates of as much as 107. Furthermore, the rate of a reaction that is catalyzed by an enzyme can be regulated by controlling the effectivity of the enzyme or the number of enzyme molecules that are available. Even the direction of a reaction can effectively be controlled with the help of several enzymes.

How does the enzyme do its formidable task? For an example, consider the reaction in Figure 1.2 that turns dihydrofolate into tetrahydrofolate. This reaction is catalyzed by an enzyme called dihydrofolate reductase (DHFR). The surface of this protein is depicted in Figure 1.3. One immediately recognizes a large and deep pocket that is colored blue (representing its negative charge). This pocket is a binding pocket or binding site of the enzyme, and it is ideally formed in terms of geometry and chemistry, such as to bind to the substrate molecule dihydrofolate and present it in a conformation that is conducive for the desired chemical reaction to take place. In this case, this pocket is also where the reaction is catalyzed. We call this place the active site. (There can be other binding pockets in a protein that are far removed from the active site.)

There is another aspect of metabolic reactions that is not depicted in Figure 1.1: Many reactions involve co-factors. A co-factor is an organic molecule, a metal ion, or - in some cases - a protein or peptide that has to be present in order for the reaction to take place. If the co-factor is itself modified during the reaction, we call it a co-substrate. In the case of our example reaction, we need the co-substrate NADPH for the reaction to happen. The reaction modifies dihydrofolate to tetrahydrofolate and NADPH to NADP+. Figure 1.4 shows the molecular complex of DHFR, dihydrofolate (DHF) and NADPH before the reaction happens. After the reaction has been completed, both organic molecules dissociate from DHFR and the original state of the enzyme is recovered.

Now that we have discussed some of the details of metabolic reactions let us move back to the global view of Figure 1.1. We have seen that each of the edges in that figure represents a reaction that is catalyzed by a specific pro-

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