Metabolism is the sum of all the chemical reactions in the living \Tcell\t that are used for the production of useful work and the synthesis of cell constituents. Almost all cellular reactions are catalyzed by complex \Tprotein\t molecules called \Lenzyme\ls, which are capable of speeding reaction rates by a factor of hundreds to millions. Many structures in the living cell are of great complexity and periodically must be replaced. This process of building new molecules is called anabolism. Structures that are worn out or no longer needed are broken down into smaller molecules and either reused or excreted; this process is called catabolism. Great quantities of energy are required not only to produce the work needed for the pumping of the heart, for muscular contraction, and for nerve conduction, but also to provide the chemical work needed to make the large molecules characteristic of living cells. Anabolism and catabolism are aspects of overall metabolism, and they occur interdependently and continuously. BASAL METABOLISM In the combustion of food, oxygen is used and carbon dioxide is given off. The rate of oxygen consumption indicates the energy expenditure of an organism, or its metabolic rate. The metabolic rate of any given animal at any given time is highly variable and is influenced by many diverse factors, including amount of muscular activity; quality of diet; presence or absence of digestion, lactation, or pregnancy; time of day or year; period of the menstrual cycle; and emotional state. In order to fix a point of reference, a convention has been adopted to serve as the standard metabolic rate. The ideal standard established is the metabolism of an animal under the least physiologically demanding conditions. In the case of humans, other mammals, and birds, this minimal-rate-of-energy metabolism is usually termed the basal metabolic rate (BMR): the rate of metabolism of a fasting animal at rest and under no thermal stress. For humans the BMR is defined as the rate of oxygen consumed while the subject rests quietly, after a sleep of at least 8 hours; the last meal should have been at least 12 hours earlier; no exercise should have been performed for at least 30 minutes; and the environmental temperature should be between 16.7 deg and 30.6 deg C (62 deg and 87 deg F). By definition, then, the BMR represents the minimal amount of energy required by the body per unit time merely to keep the individual alive--that is, the energy required to support muscle contraction for breathing, heartbeat, and muscle tone; the maintenance of such continuous synthetic processes as occur in various cells; and the electrical activity of the brain. Cold-blooded animals have no metabolic state to which the term basal can be applied because their body temperature depends on the environmental temperature, and the rate of metabolism varies with the body temperature. For these animals the minimum metabolism of fasting individuals at a given environmental temperature is referred to as the standard metabolic rate (SMR). Whichever term is used, BMR or SMR, what defines minimal stress varies from species to species; and so the precise conditions for measuring the minimum metabolic state can be determined only by an investigator who knows the species well. BIOENERGETICS All organisms require a continuous supply of energy for (1) maintenance, including the repair and replacement of worn-out parts and the carrying out of specific cell functions, (2) growth, and (3) reproduction. The energy that cells need comes from chemical reactions. Any chemical reaction that can go on spontaneously must do so by going from a more-energy-rich state to a less-energy-rich state, just as a ball on a hillside can roll to the bottom spontaneously but will never go up the hill unless it is pushed or carried. The difference in energy between the two states is released into the environment as work and heat. Of the energy released by a chemical reaction, only a certain percentage of the energy can be used to do work, no matter how efficient the process. The energy that can be used to do work is called the free energy (see \Tthermodynamics\t). Coupled Reactions "Uphill" reactions--that is, reactions whose products are at a higher energy level than the starting materials--cannot take place unless energy is supplied. The cell supplies it by first making a high-energy compound that, when broken down, will release more energy than is needed for the "uphill" reaction. The most frequently used of these high-energy compounds is adenosine triphosphate, or \TATP\t (see \TATP\t). Synthesis of the desired material and the breakdown of \TATP\t are linked together so that the overall reaction is "downhill" and is thus energetically possible. This linkage can take place by many mechanisms. Suppose, for example, the reaction of two substances, A and B, to form two products, C and D. If the products are at a higher energy level than the reactants, the reaction cannot go on spontaneously. If, however, D can react with a substance E to produce substances F and G at a much lower energy level--that is, a reaction that goes on readily--then, if the energy production by the second reaction exceeds the energy requirement of the first reaction, the two coupled reactions will proceed. Components of Living Organisms All organisms capable of independent life (in other words, all except the viruses) are made principally of fats, see \Tfats and oils\t, proteins, \Lcarbohydrate\ls, and \Lnucleic acid\ls. Proteins are polymers of smaller molecules--the amino acids--and nucleic acids are made up of mononucleotides. These polymers are suspended in a watery solution containing salts and small quantities of other materials. Carbohydrates also can form polymers--the \Tstarch\t of plants and the \Tglycogen\t of animals--and fat can be broken down into smaller molecules of fatty acids and glycerol. All these compounds form the structure of the cell, including the membranes and the organelles, or smaller distinct structures, within the cell such as the nucleus, nucleolus, mitochondria, robosomes, and lysosomes. Fats and carbohydrates can be broken down to simpler compounds--fatty acids, glycerol, and simple sugars--which may be used for immediate energy production. Fatty acids in excess of immediate needs can be rebuilt into fat and stored in special cells making up adipose tissue. Sugars in excess of current needs are either converted to fatty acids and stored as fat, or formed into a giant polymer--in plants, a starch granule; in animals, a glycogen molecule. Protein is degraded to amino acids, which, if not used to make new protein, can be converted to derivatives of fatty acids or sugars (depending on which amino acids are involved) and utilized accordingly. Because carbohydrates form many weak bonds to water, carbohydrates are always surrounded by water molecules; sugars and starches, as a result, weigh a great deal per calorie of energy, being the weight of the carbohydrate plus the weight of a considerable amount of water surrounding it. Fats, on the other hand, repel water and, per calorie of energy, weigh much less than carbohydrates. For this reason, organisms that move, primarily animals, have the bulk of their reserve energy stored as fat, with a small amount of stored sugar for rapid energy production; nonmoving organisms, such as the higher plants (trees, shrubs, and grasses), principally store sugars and starches. Seeds, the only portion of such plants that must move, typically store fat. Krebs Cycle The major source of energy in the cell is obtained from the oxidation of hydrogen obtained from food by respired oxygen to form water. The greatest single source of hydrogen molecules for oxidation is the Krebs cycle, named for its discoverer, Sir Hans Adolf \TKrebs\t. It is also called the tricarboxylic acid (TCA) cycle, or \Tcitric acid\t cycle. In animal cells, the entire cycle is found within the mitochondrion, an organelle of the cytoplasm; it is found in a more distributed fashion in bacterial cells. Plants can make high-energy compounds and carbohydrates by capturing the energy of light, a very different process (see \Tphotosynthesis\t). The cycle consists of nine compounds, each convertible into the next; the last of the nine, oxaloacetic acid, is converted to the first, citric acid, by the addition of an activated two-carbon compound, acetyl coenzyme A, completing one turn of the cycle and simultaneously beginning the next. Each of the steps in the cycle is catalyzed by a specific enzyme. On each turn of the cycle an acetyl molecule is oxidized, converting the carbons to carbon dioxide and removing the hydrogens, which are bound to a vitamin-derived carrier compound, nicotinamide adenine dinucleotide (NAD), involved in the electron transport system discussed below. The Krebs cycle intermediates--the individual members of the cycle--can be made from glucose as well as from a number of amino acids. The acetyl groups, which must be supplied in a steady stream, can be obtained from fatty acids or from glucose and are activated by the addition of coenzyme A, a derivative of the vitamin called pantothenic acid. Thus all three major foodstuffs can be used to produce high-energy compounds in reactions beginning in the Krebs cycle. The two-carbon acetyl group of acetyl coenzyme A is attached to the last member of the cycle, four-carbon oxaloacetate, to form six-carbon citric acid. This is converted to five-carbon ketoglutaric acid, which in turn becomes four-carbon succinic acid, eventually being converted to oxaloacetic acid. Each time, the lost carbon becomes carbon dioxide, eventually appearing in expired air. A steady state is preserved, with acetyl groups entering, and carbon dioxide and hydrogens attached to NAD leaving. Because the intermediates are readily interconverted to glucose or amino acids, the cell has little difficulty in maintaining their concentration. The Krebs cycle can be looked on as a machine for removing hydrogens from foodstuffs; the hydrogens are sent to the electron transport system, where they are combusted to water, and the free energy obtained is used to form the crucial high-energy compound, \TATP\t. Electron Transport Within and on the inner membrane of the mitochondrion are large molecules capable of rapidly alternating oxidation and reduction reactions. These make up the electron transport system (ETS). Each molecule of the hydrogen carrier mentioned above, NAD, delivers two electrons and one proton of a hydrogen molecule to the ETS. The system passes the electrons along the entire sequence of reactions; the protons go into the solution after the first few compounds, including a derivative of the vitamin riboflavin, several iron-sulfur complexes, and a quinone called coenzyme Q. The electrons are then passed through a series of cytochromes (close relatives of hemoglobin), the last of which catalyzes the formation of water from the electrons, protons, and oxygen derived from respired air. Each member of this series has an increasingly greater affinity for electrons, so that the entire series runs "downhill" and energy is produced. If the energy is not used for chemical work, it is dissipated as heat. Oxidative Phosphorylation The energy produced by the ETS is used to form a chemical bond between adenosine diphosphate (ADP) and inorganic phosphate to form \TATP\t. In fact, as a pair of electrons passes down the ETS from beginning to end, where it is captured by oxygen, enough energy is trapped to synthesize three \TATP\t molecules. In fully functional cells, electron transport is tightly coupled to oxidative phosphorylation. That is, if \TATP\t synthesis is prevented (which would happen if there were a lack of inorganic phosphate, ADP, or oxygen), electron transport will not take place. The \TATP\t generated is used throughout the cell to drive most of the otherwise energetically unfavorable reactions. In certain vertebrate tissues, notably skeletal muscle and the brain, an extra store of energy is maintained by using excess \TATP\t to convert creatine to creatine phosphate, which is also a high-energy compound. Creatine phosphate can quickly transfer the phosphate group to ADP to reform \TATP\t when the latter is needed. Invertebrates use phosphoarginine in a similar fashion. Anaerobic Reactions All cells can synthesize some \TATP\t in the absence of oxygen by means of anaerobic reactions. Usually glucose, the most important sugar in the cell, is broken down to pyruvic acid, which is then converted to lactic acid and excreted from the cell. As an example, bacteria present in milk absorb milk sugar and convert it to lactic acid in a metabolic process that produces enough \TATP\t to meet the bacteria's needs. The lactic acid is excreted and sours the milk. Similarly, in animals, muscles can continue to function for short periods of time without oxygen; the lactic acid is excreted into the bloodstream. If the muscle cell is deprived of oxygen for a longer period, the acidity prevents further metabolism and the cell begins to die. Glycolysis When oxygen is present the pyruvic acid obtained from glucose does not become lactic acid but is instead converted either to oxaloacetic acid or to acetyl coenzyme A, depending on the cell's needs at the time. In either case it enters the TCA cycle. The steps from glucose to pyruvic acid may be called glycolysis, the anaerobic pathway (anaerobic meaning not requiring oxygen), or, in honor of two of its discoverers, the Embden-Myerhof pathway. It must be stressed that the TCA cycle is a much more efficient producer of \TATP\t than glycolysis. In fact, the complete combustion of a molecule of glucose to carbon dioxide and water results in the production of 36 molecules of \TATP\t, of which 34 are produced from the TCA cycle and only 2 from glycolysis in the absence of oxygen. The TCA cycle is often called the final common pathway of energy production because acetyl coenzyme A originates from sugars, fats, and proteins. Polymerization and Hydrogenation In order to build new cell constituents, one or more of the following processes must take place. One process, polymerization, can involve the production of proteins by joining together large numbers of amino acids in specific arrangements; it can also involve the production of \TRNA\t or \TDNA\t from mononucleotides. Polymerization requires the presence of either \TATP\t or certain other high-energy compounds, many of which are derived from \TATP\t. Another process, hydrogenation, also called reduction, is the addition of hydrogen to a molecule. This process usually requires a carrier molecule, such as a pyridine nucleotide, and a hydrogen source, usually from the degradation of glucose. Most large molecules are built by chemical linkage of small molecules, a process whose immediate source of energy usually is \TATP\t. PLANT METABOLISM Unlike animals--which typically obtain both energy and nutrients by eating plants or other animals--plants, especially the higher plants, obtain the atoms for synthesis from atmospheric carbon dioxide and absorb water and simple salts of potassium, nitrogen, and phosphorus from the soil. The energy of sunlight is captured in a process called photosynthesis by the chloroplast, an organelle in leaf cells that contains chlorophyll. The chloroplast synthesizes sugar, which is used as the basic raw material for all the compounds found in the plant cell. Energy for metabolism is obtained in catabolism of this sugar. The chemical reactions by which plant constituents are formed, interconverted, and degraded constitute the complex of plant metabolism. Knowledge of plant metabolism is probably less complete than that of metabolism in animals or bacteria. New plant compounds are reported almost yearly, and each new compound requires long study to determine its function or mode of synthesis in the plant. Indeed, several thousand species of plants make substances that, despite years of investigation by plant physiologists and biochemists, have no discernible role in metabolism. The substances include rubber; such \Lterpene\ls as turpentine and menthol; such \Lalkaloid\ls as morphine, caffeine, and nicotine; tannin (used in tanning leather); and many other substances useful to industry and medicine. Nevertheless, careful investigations have shown that both the overall pattern of metabolism and the enzymes that catalyze individual chemical reactions are basically similar in plants, animals, and microorganisms. Basically similar, too, are the mechanisms that regulate plant and animal metabolism by means of plant hormones and animal hormones. The Role of Photosynthesis Unlike animals and many microorganisms, green plants are able to use photosynthesis to make all their basic foodstuff. In photosynthesis plants combine carbon dioxide, water, and the energy in sunlight to build carbohydrate, which then becomes the chief internal source of building materials and the energy to drive metabolic processes. The ability to make organic molecules from inorganic nutrients makes photosynthesizers the major link between the inorganic and organic worlds. Photosynthesis is also exhibited by certain bacteria, some protozoa, and the blue-green algae. A few chemosynthetic bacteria also make their own organic food from carbon dioxide, water, and nitrate or ammonia in their surroundings; however, they derive the energy not from light but by oxidizing simple substances such as iron or sulfur. Photosynthesis may be the single most important process for all living things. First, it is the ultimate source of organic carbon compounds. Second, the energy in the carbon-carbon bonds of these compounds--the energy in sunlight--is the ultimate source of metabolic energy in all living cells. Finally, photosynthesis maintains a continual supply of oxygen in the atmosphere. Biochemical Activity Plant nitrogen commonly originates from nitrates absorbed through the roots. Nitrates must be converted to ammonia before the nitrogen can be used in protein synthesis, and the reactions necessary for this conversion are initiated by oxidative processes of respiration. Hence, the application of nitrate boosts the demand for respiration--and overall respiration increases. Almost all of the different plant compounds originate, one way or another, from sugar produced in photosynthesis. The bulk of the plant consists of modified sugars or their polymers, the polysaccharides: cellulose; noncellulose polysaccharides such as xylans and mannans; hemicellulose; pectins; and, in woody plants, lignin. Energy Reserves Many plants store sugar as sucrose, but most deposit reserve sugar as starch--a larger and more insoluble molecule than sucrose and therefore more stable. Starch is also stored in many seeds, where it serves as food during germination; in woody twigs, where it provides energy for the growth of buds; and in many tubers and roots, where it serves as food for new growth. Starch is made by a series of reactions similar to those for its counterpart in animals, glycogen. When the demand for energy is sufficient, the process of converting plant starch back to glucose (which is then catabolized in respiration) is a simple one. Fat is also accumulated as long-term reserve material. It is most concentrated in fruits and seeds, and thus edible plant fats are usually extracted from, for example, corn, cottonseed, coconuts, and soybeans. ANIMAL METABOLISM Animal metabolism consists of the utilization of nutrients absorbed from the digestive tract and their catabolism as fuel for energy or their conversion into substances of the body. Metabolism is a continuous process because the molecules and even most cells of the body have brief lifetimes and are constantly replaced, while tissue as a whole maintains its characteristic structure. This constant rebuilding process without a net change in the amount of a cell constituent is known as dynamic equilibrium. The basic building blocks of metabolism are glucose (sugar) derived from the digestion of dietary \Tcarbohydrate\t, amino acids (from dietary \Tprotein\t), and fatty acids and glycerol (from fats). Glucose is preferentially used by most cells if it is available, such as shortly after meals, but fat takes over as the major source a few hours later, and body tissues may be sacrificed for their protein content as fasting continues. Energy Reserves Excess nutrients not immediately used to meet energy needs are stored in a carbohydrate reserve called glycogen (mostly in the liver and skeletal muscle) and in a fat reserve called triglyceride, deposited in adipose tissue. Vertebrates can quickly convert excess carbohydrate to fat but not vice versa. In mammals, about 50% of glucose is normally oxidized completely to carbon dioxide and water; 5% is converted to glycogen; and 30 to 40% is converted to fat. The carbohydrate stored as glycogen is sufficient for energy needs for only a few hours, whereas the adult human has sufficient fat stored for several weeks of starvation. Neither glycogen nor the fat deposits are comparable, however, to food cellars where reserves are kept only for emergencies. Instead they are in almost constant use as energy "buffers"; that is, during food absorption they take up excess nutrients, and, conversely, after feeding they supply glucose (from glycogen breakdown) and fatty acids and glycerol (from triglyceride breakdown) to make up ongoing energy deficits. The dynamic quality of fat reserves is strikingly illustrated by the so-called fat body of flying insects, the major energy source during flight. In mammals, free fatty acids in the bloodstream are a major energy source for muscle and heart tissue, and their half-lives are only a few minutes. Regulation of Metabolism In order for an animal to function, cell metabolism must be integrated; equally important, the metabolism of the component cells must be coordinated. This latter task requires the exchange of information between cells, even in widely separated parts of the body. Most higher animals possess two major modalities for such communication: the nervous system, and many kinds of messenger substances. Of the latter the best known are the \Lhormone\ls, secretions of the endocrine glands that enter the bloodstream and are carried throughout the body. Each hormone affects the metabolism of cells that have receptors for that hormone. Sometimes the target cells may even be another endocrine gland, which in turn secretes another hormone affecting still other cells. Secretions of these glands cause metabolic changes in many areas of the body. Another group of messenger chemicals characteristically acts quite locally. These chemicals include the \Tprostaglandins\t, which are found throughout the body but tend to affect only those cells within the area from which they are released. Other such local messengers affect nervous tissue, and some chemicals are so localized that they are formed within a cell and affect enzymes contained there. Hormones regulate cell metabolism either by changing the cell membrane's permeability to extracellular substances or by altering the activity of intracellular enzymes. Groups of enzymes are linked together in so-called metabolic pathways (chains of reactions), and hormones often act by increasing or decreasing the activity of "pacemaker" enzymes that control major pathways. Thus, for example, glucose uptake by muscle cells is controlled by the permeability of the cell membrane to glucose and by the enzyme hexokinase (which catalyzes the phosphorylation of glucose to glucose-6-phosphate); glycogen synthesis is controlled by the enzyme glycogen synthetase; glycogen breakdown to glucose, by the enzyme phosphorylase; and fat mobilization from fat deposits, by the enzyme lipoprotein lipase. The hormone insulin, for instance, increases glucose uptake by muscle cells and increases the storage of glycogen and triglyceride, and roughly matches protein synthesis to protein losses. The importance of insulin to overall coordination is dramatically shown by the disorders seen in persons with uncontrolled \Tdiabetes\t MELLITUS. The basic disturbance in the diabetes mellitus found in young people is insulin deficiency, which depresses glucose uptake by certain cells and increases glycogen breakdown, thereby causing hyperglycemia (an abnormally high level of glucose in the bloodstream). Hyperglycemia increases the osmotic pressure of the blood, thus removing tissue water and causing cellular dehydration and electrolyte loss. In the face of glucose starvation, cells obtain fuel by the abnormally rapid breakdown of triglyceride (lipolysis) and the conversion of body protein to glucose (gluconeogenesis). The result is protein deficiency and weight loss, while the gluconeogenesis increases hyperglycemia and sets up a vicious cycle. Finally, in this example, excessive lipolysis leads to an excess of free fatty acids in the bloodstream; this in turn leads to ketoacidosis--the formation of an acidic ketone, which raises the acidity of the blood, interferes with oxygen uptake by cells and may depress consciousness to the point of coma. The animal responds to low blood glucose, on the other hand, by secreting epinephrine (adrenalin) from the adrenal gland and glucagon from the pancreas. On reaching the liver these hormones boost the activity of phosphorylase, thereby increasing the conversion of glycogen to glucose. Glucagon and insulin normally work against each other to establish the level of the various fuels in the circulation and to prevent violent departures from normal values. Reviewed by Aaron D. Freeman, M.D. Bibliography: Alberts, Bruce, et al., Molecular Biology of the Cell (1983); Bidwell, R. G. S., Plant Physiology, 2d ed. (1979); Kirk, David, Biology Today, 3d ed. (1980); Levine, Louis, Biology for a Modern Society (1977); Smith, E. L., et al., Principles of Biochemistry, 7th ed. (1983); Stryer, Lubert, Biochemistry, 2d ed. (1981).