BIOCHEMISTRY - L. Stryer - 1984

VOLUME 2

PART III. BIOSYNTHESIS OF MACROMOLECULAR PRECURSORS

CHAPTER 23. INTEGRATION OF METABOLISM

How is the complex network of metabolic reactions coordinated to meet the needs of the entire Organism? In this chapter, we will explore some of the fundamental Principles of Metabolic integration in mammals. We will begin by briefly summarizing the strategy of METABOLISM and its key regulatory mechanisms. Next, the interrelationships of Various metabolic pathways will be examined by analyzing the flow of matter at three major junctions: glucose 6-phosphate, Pyruvate, and acetyl-CoA. Following this, we will discuss the differences in metabolic patterns across the Brain, Muscle, adipose tissue, and Liver. We will then turn to the major Hormonal regulators of Energy Metabolism—Insulin, Glucagon, epinephrine, and norepinephrine. Next, we will address the most critical aspect of metabolism: the Regulation of Blood glucose concentration. The final section of the chapter examines the remarkable phenomenon of metabolic adaptation to prolonged starvation.

23.1. Strategy of Metabolism: Key Concepts

As discussed in Chapter 11, the strategic goals of metabolism are to generate ATP, reducing power, and building blocks for biosynthetic reactions. Let us briefly review these aspects.

Class="center">Fig. 23.1. Electron micrograph of liver Cells. The liver plays a key role in the integration of metabolism

1. ATP is the universal energy currency. The high phosphate-group transfer potential of ATP allows it to serve

as an energy source for Muscle contraction, Active Transport, signal Amplification, and biosynthetic processes. The Hydrolysis of a single ATP molecule shifts the equilibrium ratio of reactants to products in a coupled reaction by a factor of approximately 10⁸. Thus, a thermodynamically unfavorable sequence of reactions can be made favorable by coupling it to the hydrolysis of a sufficient number of ATP molecules. For example, The conversion of mevalonate to isopentenyl pyrophosphate, an activated five-carbon precursor for Cholesterol synthesis, requires the consumption of three ATP molecules.

2. ATP is generated by The oxidation of fuel molecules, such as glucose, Fatty acids, and Amino Acids. The common intermediate of most oxidative reactions is acetyl-CoA. The acetyl group is completely oxidized to CO₂ in The Citric Acid Cycle, with the simultaneous generation of NADH and FADH₂. These carriers then donate their high-energy electrons to the Respiratory Chain. The electrons flow along the respiratory chain to O₂, which leads to the pumping of protons across The inner mitochondrial membrane. The resulting proton gradient is used to synthesize ATP. Another process that produces ATP is Glycolysis; however, it yields much less ATP than Oxidative Phosphorylation. The oxidation of glucose to pyruvate yields only two ATP molecules, whereas the Complete oxidation of glucose to CO₂ yields 36 ATP molecules. However, unlike oxidative phosphorylation, which requires a continuous supply of O₂, glycolysis can proceed at a high rate under anaerobic conditions for short periods.

3. NADPH is the major electron donor in reductive biosynthetic reactions. In most biosynthetic pathways, the products are more reduced than their precursors, meaning that reducing power is required In addition to ATP. The high-energy electrons needed to drive these reactions are typically supplied by NADPH. For example, in FATTY ACID Biosynthesis, the keto group of the added two-carbon unit is reduced to a methylene group by four electrons from two NADPH molecules. The activation of O₂ by mixed-function oxygenases, which catalyze hydroxylation reactions, also illustrates the universal role of NADPH as a reductant. Most of the required NADPH is supplied by the Pentose Phosphate Pathway. In addition, a significant amount of this electron carrier is generated by the malic enzyme (decarboxylating malate dehydrogenase) during The transport of acetyl-CoA from Cell/35.html">Mitochondria to the Cytoplasm for fatty acid synthesis.

4. Biomolecules are constructed from a relatively small number of building blocks. The vast diversity of cellular molecules is synthesized from a much smaller number of distinct precursors. Metabolic reactions that generate ATP and NADPH also serve another purpose: they provide the building blocks for the synthesis of more complex molecules. For example, dihydroxyacetone phosphate, formed during glycolysis, is converted into the glycerol backbone of phosphatidylcholine and other phosphoacylglycerols. Another glycolytic intermediate, phosphoenolpyruvate, contributes to the carbon Skeleton of aromatic amino acids. Acetyl-CoA, the common intermediate in The breakdown of most fuel molecules, provides two-carbon units for A wide variety of biosynthetic reactions. Succinyl-CoA, generated in The Citric Acid cycle, is a precursor of Porphyrins. Ribose 5-phosphate, which is produced along with NADPH in The pentose phosphate pathway, is the source of the sugar moiety in NUCLEOTIDES. In addition, many biosynthetic reactions require single-carbon units. Tetrahydrofolate is the carrier of these units at various oxidation states. The formation of these derivatives, as well as the primary methyl donor S-adenosylmethionine, is closely linked to Amino acid metabolism. Thus, the Major Metabolic Pathways serve both anabolic and catabolic Functions.

Fig. 23.2. This electron micrograph shows numerous mitochondria in the inner segment of retinal rods. These photoreceptor cells generate large amounts of ATP and are highly dependent on a continuous supply of O₂

Fig. 23.3. Electron micrograph of a portion of a liver cell. The upper arrow points to a Glycogen granule, and the lower arrow points to the smooth Endoplasmic reticulum. Hydroxylation Reactions Catalyzed by mixed-function oxygenases occur in the smooth endoplasmic reticulum

5. BIOSYNTHESIS AND DEGRADATION pathways are almost always distinct. For example, the pathway for fatty acid synthesis is different from the pathway for their degradation. Similarly, glycogen is synthesized and degraded through different sequences of reactions. This Separation ensures that both biosynthetic and degradative pathways are thermodynamically favorable at all times. For a biosynthetic pathway to be exergonic, it must be coupled to the hydrolysis of a sufficient number of ATP molecules. For example, the conversion of pyruvate to glucose during Gluconeogenesis consumes four more high-energy ~P bonds than are generated during the conversion of glucose to pyruvate in glycolysis. These four additional ~P bonds make gluconeogenesis exergonic under any physiological conditions in The Cell. A fundamental feature of metabolic pathways is that their rates are determined not by the law of mass action, but by The activity of Key Enzymes. The separation of biosynthetic and degradative pathways is of paramount importance for the effective REGULATION OF METABOLISM.