Multienzyme Metabolic Pathways

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The sequence of enzyme-mediated reactions leading to the formation of a particular product is known as a metabolic pathway. For example, the 19 reactions that convert glucose to carbon dioxide and water constitute the metabolic pathway for glucose catabolism. Each reaction produces only a small change in the structure of the substrate (see, for example, Figures 4-19 and 422). By such a sequence of small steps, a complex chemical structure, such as glucose, can be transformed to the relatively simple molecular structures, carbon dioxide and water.

Consider a metabolic pathway containing four enzymes (ei, e2, e3, and e4) and leading from an initial substrate A to the end product E, through a series of intermediates, B, C, and D:

(The irreversibility of the last reaction is of no consequence for the moment.) By mass action, increasing the concentration of A will lead to an increase in the concentration of B (provided e1 is not already saturated with substrate), and so on until eventually there is an increase in the concentration of the end product E.

Since different enzymes have different concentrations and activities, it would be extremely unlikely that the reaction rates of all these steps would be exactly the same. Thus, one step is likely to be slower than all the others. This step is known as the rate-limiting reaction in a metabolic pathway. None of the reactions that occur later in the sequence, including the formation of end product, can proceed more rapidly than the rate-limiting reaction since their substrates are being supplied by the previous steps. By regulating the concentration or activity of the rate-limiting enzyme, the rate of flow through the whole pathway can be increased or decreased. Thus, it is not necessary to alter all the enzymes in a metabolic pathway to control the rate at which the end product is produced.

Rate-limiting enzymes are often the sites of allosteric or covalent regulation. For example, if enzyme e2 is rate limiting in the pathway described above, and if the end product E inhibits the activity of e2, end-product inhibition occurs (Figure 4-15). As the concentration of the product increases, the inhibition of product formation increases. Such inhibition is frequently found in synthetic pathways where the formation of end product is effectively shut down when it is not being utilized, preventing excessive accumulation of the end product.

Control of enzyme activity also can be critical for reversing a metabolic pathway. Consider the pathway we have been discussing, ignoring the presence of end-product inhibition of enzyme e2. The pathway consists of three reversible reactions mediated by e1, e2, and e3, e

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

Protein Activity and Cellular Metabolism CHAPTER FOUR

Protein Activity and Cellular Metabolism CHAPTER FOUR

Inhibition of e2

Inhibition of e2

Rate-limiting enzyme

FIGURE 4-15

End-product inhibition of the rate-limiting enzyme in a metabolic pathway. The end product E becomes the modulator molecule that produces inhibition of enzyme e2.

Rate-limiting enzyme

End product (modulator molecule)

FIGURE 4-15

End-product inhibition of the rate-limiting enzyme in a metabolic pathway. The end product E becomes the modulator molecule that produces inhibition of enzyme e2.

followed by an irreversible reaction mediated by enzyme e4. E can be converted into D, however, if the reaction is coupled to the simultaneous breakdown of a molecule that releases large quantities of energy. In other words, an irreversible step can be "reversed" by an alternative route, using a second enzyme and its substrate to provide the large amount of required energy. Two such high-energy irreversible reactions are indicated by bowed arrows to emphasize that two separate enzymes are involved in the two directions:

By controlling the concentration and/or activities of e4 and e5, the direction of flow through the pathway can be regulated. If e4 is activated and e5 inhibited, the flow will proceed from A to E, whereas inhibition of e4 and activation of e5 will produce flow from E to A.

Another situation involving the differential control of several enzymes arises when there is a branch in a metabolic pathway. A single metabolite, C, may be the substrate for more than one enzyme, as illustrated by the pathway

Altering the concentration and/or activities of e3 and e6 regulates the flow of metabolite C through the two branches of the pathway.

When one considers the thousands of reactions that occur in the body and the permutations and combinations of possible control points, the overall result is staggering. The details of regulating the many metabolic pathways at the enzymatic level are beyond the scope of this book. In the remainder of this chapter, we consider only (1) the overall characteristics of the pathways by which cells obtain energy, and (2) the major pathways by which carbohydrates, fats, and proteins are broken down and synthesized.

The functioning of a cell depends upon its ability to extract and use the chemical energy in organic molecules. For example, when, in the presence of oxygen, a cell breaks down 1 mol of glucose to carbon dioxide and water, 686 kcal of energy is released. Some of this energy appears as heat, but a cell cannot use heat energy to perform its functions. The remainder of the energy is transferred to another molecule that can in turn transfer it to yet another molecule or to energy-requiring processes. In all cells, from bacterial to human, the primary molecule to which energy from the breakdown of fuel molecules—carbohydrates, fats, and proteins—is transferred and which then transfers this energy to cell functions is the nucleotide adenosine triphosphate (ATP) (Figure 4-16). (As we shall see in subsequent chapters, other nucleotide triphosphates, such as GTP, are also used to transfer energy in special cases.) For the moment we will disregard how ATP is formed from fuel molecules and focus on its energy release.

The chemical reaction (referred to as ATP hydrolysis) that removes the terminal phosphate group from ATP is accompanied by the release of a large amount of energy, 7 kcal/mol:

The products of the reaction are adenosine diphos-phate (ADP), inorganic phosphate (Pj) and H+. Note that 7 kcal of energy is released when one mol 6 X 1023 molecules) of ATP is hydrolyzed, not just one molecule.

The energy derived from the hydrolysis of ATP is used by energy-requiring processes in cells for (1) the production of force and movement, as in muscle contraction (Chapter 11); (2) active transport across membranes (Chapter 6); and (3) synthesis of the organic molecules used in cell structures and functions.

We must emphasize that cells use ATP not to store energy but rather to transfer it. ATP is an energy-carrying molecule that transfers relatively small amounts of energy from fuel molecules to the cell e e

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

PART ONE Basic Cell Functions

Adenine h/Tc%n VC^CH

Ribose

OH OH

Energy

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Essentials of Human Physiology

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  • tim
    What is a ratelimiting reaction in a metabolic pathway?
    8 years ago

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