LEHNINGER PRINCIPLES OF BIOCHEMISTRY - VOLUME 2. BIOENERGETICS AND METABOLISM - 2014

PART II. BIOENERGETICS AND METABOLISM

METABOLISM is the highly coordinated cellular activity in which many multienzyme systems (metabolic pathways) cooperate to: (1) obtain chemical energy from the environment (either by capturing solar energy or by degrading energy-rich nutrients); (2) convert nutrient molecules into The Cell's own characteristic molecules, including macromolecular precursors; (3) polymerize monomeric precursors into macromolecules: Proteins, Nucleic Acids, and Polysaccharides; and (4) carry out the synthesis and degrada

tion of Biomolecules required for specialized cellular Functions, such as Membrane Lipids, intracellular messengers, and pigments.

Metabolism consists of hundreds of different enzyme-catalyzed reactions. In this part of the book (Part II), we will examine the central metabolic pathways, which are far less numerous and remarkably similar in all life forms. Living organisms can be divided into two large groups based on the chemical form in which they obtain carbon from the environment. Autotrophs (such as photosynthetic Bacteria and vascular plants) can use atmospheric carbon dioxide as their sole carbon source, from which they construct all their carbon-containing biomolecules (see Fig. 1-5). Some autotrophic organisms, such as cyanobacteria, can also use atmospheric nitrogen to produce all their nitrogen-containing molecules. Heterotrophs cannot use atmospheric carbon dioxide and must obtain carbon from their environment in the form of relatively complex organic molecules, such as glucose. Multicellular animals and most microorganisms are heterotrophs. Autotrophic Cells and organisms are relatively self-sufficient, whereas heterotrophic cells and organisms require more complex organic molecules to satisfy their carbon needs and must therefore feed on the products of other organisms.

Many autotrophic organisms utilize Photosynthesis, in which sunlight serves as the energy source. Heterotrophic organisms obtain energy by degrading organic nutrients produced by autotrophs. In the biosphere, autotrophs and heterotrophs coexist in a giant, interdependent cycle. Autotrophic organisms use atmospheric carbon dioxide to build their organic biomolecules. In this process, some autotrophs generate oxygen from Water. Heterotrophs use the organic products made by autotrophs as nutrients and release carbon dioxide back into the atmosphere. Some oxidative reactions that produce carbon dioxide require oxygen, which is converted to water during oxidation. Thus, carbon, oxygen, and water are constantly cycled between heterotrophic and autotrophic natural ecosystems. This global process is driven by solar energy (Fig. 1).

Class="center">Fig. 1. Cycling of carbon dioxide and oxygen between the autotrophic (photosynthetic) and heterotrophic domains (ecosystems) of the biosphere. Huge masses of matter are involved in this cycle; the biospheric turnover is estimated at ~4 • 10¹¹ tons of carbon per year.

All living organisms also require a source of nitrogen, which is essential for the synthesis of Amino Acids, NUCLEOTIDES, and Other Compounds. Plants use mainly ammonia or nitrates as their nitrogen source. Vertebrate animals must obtain nitrogen in the form of amino acids or other Organic compounds. Only a few organisms—cyanobacteria and many species of soil bacteria living as symbionts on the roots of certain plants—are capable of converting (fixing) atmospheric nitrogen N₂ into ammonia. Other bacteria (nitrifying bacteria) oxidize ammonia to nitrites and nitrates, while still others convert nitrates back into free nitrogen N₂. Thus, In addition to the global Carbon and Oxygen cycles, a nitrogen cycle occurs in the biosphere, involving enormous amounts of this element (Fig. 2). The oxygen, carbon, and nitrogen cycles, in which all species are ultimately involved, depend on the natural balance between the activities of producers (autotrophs) and consumers (heterotrophs) in our biosphere.

Fig. 2. The Nitrogen Cycle in the biosphere. Gaseous nitrogen N₂ makes up 80% of the Earth's atmosphere.

The cycling of these elements is driven by a massive flow of energy entering the biosphere from the outside, which is then transformed within it; it all begins with the absorption of solar energy by photosynthetic organisms, followed by The Use of this energy to synthesize energy-rich CARBOHYDRATES and other organic compounds. These nutrients serve as the energy source for heterotrophic organisms. In metabolic processes and during any energy transformation, some Free energy is lost as heat released into the environment and as an increase in the system's Entropy. Thus, while matter cycles continuously in the biosphere, energy is utilized—organisms cannot regenerate energy that has dissipated as heat and entropy. The cycling of carbon, oxygen, and nitrogen is continuous, whereas energy is constantly converted into a form that can no longer be used—thermal energy.

Metabolism is the sum of all chemical transformations taking place in a cell or Organism, occurring through a series of consecutive enzyme-catalyzed reactions called metabolic pathways. The reactions (steps) of a metabolic pathway follow one another in a specific order, and at each step, a small, specific change is made to the Chemical Structure of the system. Typically, this involves the removal, transfer, or addition of a single atom or functional group. The conversion of a precursor into a final product proceeds through a series of metabolic intermediates called metabolites. The term Intermediary Metabolism is often applied to the combined ENZYMATIC REACTIONS OF all metabolic pathways that interconvert precursors, metabolites, and low molecular weight substances (typically with Mr <1000).

Catabolism is the degradative phase of metabolism, in which organic nutrient molecules (carbohydrates, fats, and proteins) are converted into smaller, simpler end products (such as lactic acid, CO₂, NH₃). Catabolism is accompanied by the release of energy, which is conserved in the form of ATP and reduced electron carriers (NADH, NADPH, FADH₂). The remaining energy is dissipated as heat. Anabolism, also called Biosynthesis, involves processes in which larger and more complex molecules, including lipids, polysaccharides, proteins, and nucleic acids, are synthesized from small, simple precursors. Anabolic reactions require an input of energy, generally provided by the Cleavage of phosphate bonds in ATP and the reduced NADH, NADPH, and FADH₂ (Fig. 3).

Fig. 3. Energy coupling between Catabolic and anabolic pathways. Catabolic pathways deliver chemical energy in the form of ATP, NADH, NADPH, and FADH₂. These energy carriers 'work' in anabolic pathways to convert small precursor molecules into macromolecules.

Some Metabolic pathways are linear chains of consecutive transformations. Other metabolic pathways are branched, meaning that a single precursor can yield multiple useful end products, or several starting Materials can lead to a single product. In general, catabolic pathways are convergent, whereas anabolic pathways are divergent (Fig. 4). Some pathways are cyclic, in which a starting molecule is regenerated through a series of reactions, while other molecules derived from the starting reactant are converted back into the starting material as a product. In the following

chapters, Examples of Various metabolic pathways are discussed.

Fig. 4. Three types of nonlinear metabolic pathways: (a) a convergent catabolic pathway; (b) a divergent anabolic pathway; (c) a cyclic pathway in which one of the starting materials (in this case, oxaloacetate) is regenerated, and the cycle begins anew. Acetate—a key metabolic intermediate—arises from The breakdown of a variety of energy-rich molecules (a); it serves as a precursor for many products (b) and is consumed in the catabolic pathway known as The Citric Acid Cycle (c).

Most cells contain Enzymes to carry out both the degradation and synthesis of important classes of biomolecules, such as Fatty acids. However, the simultaneous occurrence of fatty acid Synthesis and degradation would be wasteful; this is prevented by the Reciprocal Regulation of anabolic and catabolic pathways—when one pathway is active, the other is suppressed. Such regulation would be impossible if anabolic and catabolic pathways were catalyzed by the exact same set of enzymes operating in one direction for anabolism and in the opposite direction for catabolism. Inhibition of an enzyme involved in catabolism would also inhibit the pathway in the anabolic direction. Catabolic and anabolic pathways that have the same endpoints (for example, glucose —>—> Pyruvate and pyruvate —>—> glucose) may share many of the same enzymes. However, it is essential that at least one step in the catabolic and anabolic pathways is catalyzed by different enzymes and has different regulatory mechanisms; these enzymes serve as sites of separate regulation. Furthermore, for anabolic and catabolic pathways to be irreversible, the reaction sequences unique to each direction must include at least one reaction that is thermodynamically highly favorable; in other words, the reverse reaction is thermodynamically unfavorable. The independence of catabolic and anabolic regulation is further enhanced by the fact that paired catabolic and anabolic pathways usually occur in different cellular compartments. For example, fatty acid catabolism occurs in Mitochondria, whereas synthesis takes place in the Cytoplasm. The concentrations of intermediates, enzymes, and regulators can be maintained at different levels in different cellular compartments. Because metabolic pathways are kinetically controlled by Substrate Concentration, individual intermediates of anabolism and catabolism also control The rate of metabolic processes. We will pay special attention to the mechanisms of these anabolic and catabolic processes.

Metabolic pathways are regulated at several levels, both intracellularly and extracellularly. The most rapid response of metabolic processes is to substrate availability. In general, the intracellular substrate concentration is below the K_m; thus, the reaction rate is determined by substrate concentration (see Fig. 6-11). A second way to intracellularly control the rate of metabolic processes involves Allosteric Regulation (Vol. 1, p. 220) by a metabolic intermediate or coenzyme, such as an amino acid or ATP, which signals the metabolic state within the cell. When a cell contains a sufficient amount of, say, aspartate for its immediate needs, or when the cellular ATP level is such that further energy consumption is currently unnecessary, these signals allosterically inhibit The activity of one or more enzymes in the corresponding reaction sequence. In Multicellular Organisms, the METABOLIC ACTIVITY OF different Tissues is regulated and integrated by growth factors and Hormones acting from outside the cell. In some cases, this regulation occurs almost instantaneously (sometimes in less than a millisecond) through Changes in the levels of intracellular messengers, which alter enzyme activity via allosteric regulation or covalent modification, such as phosphorylation. In other cases, an extracellular signal leads to A change in the cellular concentration of an enzyme by affecting its rate of synthesis or degradation. Such an effect becomes apparent only after minutes or hours.

We begin Part II with a Description of the basic energetic Principles of Metabolism (Chapter 13). We then discuss the major catabolic pathways by which cells obtain energy by oxidizing various substances (Chapters 14-19). The energetic aspects of metabolism are examined in detail in Chapter 19, which is devoted to chemiosmotic energy coupling—a universal mechanism in which ATP synthesis is driven by a transmembrane Electrochemical Potential generated either during substrate oxidation or during solar energy absorption.

Chapters 20-22 cover the major anabolic pathways, where carbohydrates, lipids, amino acids, and nucleotides are synthesized from simpler precursor molecules at the expense of ATP energy. In Chapter 23, we will move on to a detailed Discussion of Metabolic Pathways in various organisms, from Escherichia coli to humans, and the hormonal mechanisms of their regulation and integration in mammals.

And with that, we will finally proceed to The Study of intermediary metabolism. As you study cellular metabolism, remember that the numerous reactions described in this book actually occur and play a crucial role in living organisms. Always try to understand The Role of a given chemical process (a reaction or an entire metabolic pathway) in the organism. How are the reactions under study connected to other reactions continuously occurring in the same cell to obtain the energy and substances necessary to maintain cell viability? How do multilevel regulatory mechanisms balance the intake and output of matter and energy, thereby achieving a steady-state dynamic condition for the entire organism? By studying metabolism from this perspective, you will experience an exciting and highly instructive journey into the very foundations of life, and the deep knowledge you acquire will undoubtedly find numerous Applications in medicine, agriculture, and biotechnology.

The total energy of the universe remains constant; the total entropy continuously increases.

Rudolf Clausius, The Mechanical Theory of Heat with Its Applications to the Steam-Engine and to the Physical Properties of Bodies, 1865

Thanks to the isomorphism of entropy and information, relations are established between two forms of energy: energy to do and energy to direct what is done.

François Jacob, La logique du vivant: une histoire de l'hérédité (The Logic of Life: A History of Heredity), 1970