Principles of Biochemistry Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Metabolism: An Overview
Corresponding catabolic and anabolic pathways differ, and these differences are of great significance

The catabolic pathway and its corresponding but directionally opposite anabolic pathway between a given precursor and a given product usually do not coincide. Both intermediate products and individual steps of these pathways may differ. For example, The breakdown of glucose to Pyruvate in the Liver is a process consisting of 11 sequential steps catalyzed by specific Enzymes. One might expect the Synthesis of glucose from pyruvate to be a simple reversal of all these enzymatic degradation steps; at first glance, such a pathway appears both the most natural and the most economical. In reality, however, glucose Biosynthesis in the liver proceeds differently. It includes only 9 of the 11 enzymatic steps involved in its breakdown, while the two missing steps are replaced by a completely different set of enzyme-mediated reactions unique to the biosynthetic pathway. Similarly, the corresponding Catabolic and anabolic pathways linking, for example, Proteins with Amino Acids or Fatty acids with acetyl-CoA are not identical.

One might consider the existence of two separate metabolic pathways between two given points to be unnecessary waste. There are, however, important reasons why catabolic and anabolic pathways do not coincide. The first is that the pathway along which a particular biomolecule is degraded may be energetically unfavorable for its biosynthesis. The breakdown of a complex organic molecule can be compared to descending a mountain, whereas its biosynthesis is like climbing up; in the first case, Free energy is released, while In the second, it must be expended to conquer the ascent. Let us illustrate this with a simple analogy. If a boulder is pushed from a mountain peak, it will roll downward, losing energy in the process. Over particularly steep sections of the path, or during a sheer drop, large amounts of energy are lost all at once. Hauling the boulder back to the summit with a tractor along the exact path it rolled down is hardly feasible. The tractor would likely manage to climb via a more gentle route, bypassing the steep slopes (Fig. 13-8). This detour requires additional energy. The biosynthetic pathway likewise requires extra Energy Expenditure to overcome the steep sections of the energetic "hill."

The second reason why corresponding catabolic and anabolic pathways are not identical is that these reaction sequences must be regulated independently. If the same pathway were used for both degradation and biosynthesis—that is, if it were a simple Reversal of the reaction sequence—then, for example, the inhibition of a catabolic pathway due to the suppression of one of its enzymes would inevitably entail a slowdown of the corresponding biosynthetic pathway as well. For the Synthesis and Breakdown of a compound to be regulated independently of each other, these metabolic pathways must be entirely distinct, or, if they share certain enzymatic steps, The rate of the process must be controlled by those enzymes that do not participate in the reverse reaction sequence (Fig. 13-9).

Sometimes, oppositely directed catabolic and anabolic pathways differ in their cellular localization. For instance, the Oxidation of Fatty acids to the acetyl-CoA stage in the liver is catalyzed by a set of enzymes localized predominantly in Cell/35.html">Mitochondria, where conditions favor oxidation; conversely, the synthesis of fatty acids from acetyl-CoA, which requires hydrogen atoms—that is, reducing equivalents—is carried out by a different set of enzymes localized in the Cytosol, where conditions favor reduction reactions (Fig. 13-10).

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Fig. 13-8. An analogy illustrating the energetic aspects of Catabolism and anabolic processes using a boulder rolling down a mountain. Catabolism can be compared to descending a mountain because it is accompanied by a loss of free energy. A particularly large amount of energy is lost on steep, nearly vertical sections of the path (indicated by arrows). Anabolism resembles climbing a mountain; it requires the input of free energy, which can only be supplied in small, strictly regulated portions. A tractor, for example, could haul a boulder back to the mountain peak only by taking a different, more gradual route that avoids the steep sections, which would otherwise require excessive energy to overcome.

Fig. 13-9. Parallel catabolic and anabolic pathways must differ in at least one enzymatic step so that they can be regulated independently. Two variants of independent regulation for catabolic and anabolic pathways between A and P are shown. In the first variant, the pathways are entirely distinct, meaning they are catalyzed by different sets of enzymes. In the second, the anabolic and Catabolic pathways differ by only a single enzyme. The regulated steps in both variants are indicated by red arrows.

However, although the corresponding catabolic and anabolic pathways are not identical, they are linked by a common stage (Stage III in Fig. 13-6), which includes The Citric Acid Cycle and several auxiliary enzymatic reactions. This shared stage is sometimes called the amphibolic stage of METABOLISM (from the Greek "amphi" meaning both) because it serves a dual function. In catabolism, this stage completes the breakdown of relatively small molecules produced in Stage II, whereas in anabolism, its role is to supply small precursor molecules for the BIOSYNTHESIS OF AMINO Acids, fatty acids, and CARBOHYDRATES (as will be discussed further below).

Fig. 13-10. Spatial Separation of oppositely directed metabolic pathways. Fatty acid oxidation occurs primarily in mitochondria, whereas their synthesis, which requires reducing power, takes place in the cytosol.

Almost all metabolic reactions are ultimately interconnected, since the product of one enzymatic reaction serves as the substrate for another, which Functions as the next step in the process. Thus, we can visualize metabolism as an extraordinarily complex network of enzymatic reactions. If the flow of nutrients in one part of this network diminishes or is disrupted, compensatory changes may occur elsewhere in the network to balance or offset the initial disturbance. Along any central metabolic pathway—whether catabolic or anabolic—the rate can be adjusted to meet the immediate needs of The Cell. Furthermore, both catabolic and anabolic reactions are apparently tuned to proceed with maximum economy, that is, with the lowest possible expenditure of energy and matter. For example, The oxidation of nutrients within a cell occurs at a rate just sufficient to satisfy its energy demands at any given moment.