Dictionary:
me·tab·o·lism (mĭ-tăb'ə-lĭz'əm)  |
[From Greek metabolē, change, from metaballein, to change : meta-, meta- + ballein, to throw.]
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| Science of Everyday Things: Metabolism |
Concept
The term metabolism refers to all of the chemical reactions by which complex molecules taken into an organism are broken down to produce energy and by which energy is used to build up complex molecules. All metabolic reactions fall into one of two general categories: catabolic and anabolic reactions, or the processes of breaking down and building up, respectively. The best example of metabolism from daily life occurs in the process of taking in and digesting nutrients, but sometimes these processes become altered, either through a person's choice or through outside factors, and metabolic disorders follow. Such disorders range from anorexia and bulimia to obesity. These are all examples of an unhealthy, unnatural alteration to the ordinary course of metabolism; on the other hand, hibernation allows animals to slow down their metabolic rates dramatically as a means of conserving energy during times when food is scarce.
How It Works
The Body's Furnace
The term metabolism, strangely enough, is related closely to devil, with which it shares the Greek root ballein, meaning "to throw." By adding dia ("through" or "across"), one arrives at devil and many related words, such as diabolical ; on the other hand, the replacement of that prefix with meta ("after" or "beyond") yields the word metabolism. The connection between the two words has been obscured over time, but it might be helpful to picture metabolism in terms of an image that goes with that of a devil: a furnace.
Metabolism is indeed like a furnace, in that it burns energy, and that is the aspect most commonly associated with this concept. But metabolism also involves a function that a furnace does not: building new material. All metabolic reactions can be divided into either catabolic or anabolic reactions. Catabolism is the process by which large molecules are broken down into smaller ones with the release of energy, whereas anabolism is the process by which energy is used to build up complex molecules needed by the body to maintain itself and develop new tissue.
Digestion
One way to understand the metabolic process is to follow the path of a typical nutrient as it passes through the body. The digestive process is discussed in Digestion, while nutrients are examined in Nutrients and Nutrition as well as in Proteins, Amino Acids, Enzymes, Carbohydrates, and Vitamins. Here we touch on the process only in general terms, as it relates to metabolism.
The term digestion is not defined in the essay on that subject, because it is an everyday word whose meaning is widely known. For the present purposes, however, it is important to identify it as the process of breaking down food into simpler chemical compounds as a means of making nutrients absorbable by the body. This is a catabolic process, because the molecules of which foods are made are much too large to pass through the lining of the digestive system and directly into the bloodstream. Thanks to the digestive process, smaller molecules are formed and enter the bloodstream, from whence they are carried to individual cells throughout a person's body.
The smaller molecules into which nutrients are broken down make up the metabolic pool, which consists of simpler substances. The metabolic pool includes simple sugars, made by the breakdown of complex carbohydrates; glycerol and fatty acids, which come from the conversion of lipids, or fats; and amino acids, formed by the breakdown of proteins. Substances in the metabolic pool provide material from which new tissue is constructed—an anabolic process.
The chemical breakdown of substances in the cells is a complex and wondrous process. For instance, a cell converts a sugar molecule into carbon dioxide and water over the course of about two dozen separate chemical reactions. This is what cell biologists call a metabolic pathway: an orderly sequence of reactions, with particular enzymes (a type of protein that speeds up chemical reactions) acting at each step along the way. In this instance, each chemical reaction makes a relatively modest change in the sugar molecule—for example, the removal of a single oxygen atom or a single hydrogen atom—and each is accompanied by the release of energy, a result of the breaking of chemical bonds between atoms.
Atpand Adp
Cells capture and store the energy released in catabolic reactions through the use of chemical compounds known as energy carriers. The most significant example of an energy carrier is adenosine triphosphate, or ATP, which is formed when a simpler compound, adenosine diphosphate (ADP), combines with a phosphate group. (A phosphate is a chemical compound that contains oxygen bonded to phosphorus, and the term group in chemistry refers to a combination of atoms from two or more elements that tend to bond with other elements or compounds in certain characteristic ways.)
ADP will combine with a phosphate group only if energy is added to it. In cells, that energy comes from the catabolism of compounds in the metabolic pool, including sugars, glycerol (related to fats), and fatty acids. The ATP molecule formed in this manner has taken up the energy previously stored in the sugar molecule, and thereafter, whenever a cell needs energy for some process, it can obtain it from an ATP molecule. The reverse of this process also takes place inside cells. That is, energy from an ATP molecule can be used to put simpler molecules together to make more complex molecules. For example, suppose that a cell needs to repair a rupture in its cell membrane. To do so, it will need to produce new protein molecules, which are made from hundreds or thousands of amino-acid molecules. These molecules can be obtained from the metabolic pool.
The reactions by which a compound is metabolized differ for various nutrients. Also, energy carriers other than ATP may play a part. For example, the compound known as nicotinamide adenine dinucleotide phosphate (NADPH) also has a role in the catabolism and anabolism of various substances. The general outline described here, however, applies to all metabolic reactions.
Catabolism and Anabolism
Energy released from organic nutrients (those containing carbon and hydrogen) during catabolism is stored within ATP, in the form of the high-energy chemical bonds between the second and third molecules of phosphate. The cell uses ATP for synthesizing cell components from simple precursors, for the mechanical work of contraction and motion, and for transport of substances across its membrane. ATP's energy is released when this bond is broken, turning ATP into ADP. The cell uses the energy derived from catabolism to fuel anabolic reactions that synthesize cell components. Although anabolism and catabolism occur simultaneously in the cell, their rates are controlled independently. Cells separate these pathways because catabolism is a "downhill" process, or one in which energy is released, while anabolism is an "uphill" process requiring the input of energy.
Catabolism and anabolism share an important common sequence of reactions known collectively as the citric acid cycle, the tricarboxylic acid cycle, or the Krebs cycle. Named after the German-born British biochemist Sir Hans Adolf Krebs (1900-1981), the Krebs cycle is a series of chemical reactions in which tissues use carbohydrates, fats, and proteins to produce energy; it is part of a larger series of enzymatic reactions known as oxidative phosphorylation. In the latter reaction, glucose is broken down to release energy, which is stored in the form of ATP—a catabolic sequence. At the same time, other molecules produced by the Krebs cycle are used as precursor molecules for reactions that build proteins, fats, and carbohydrates—an anabolic sequence. (A precursor is a substance, cellular component, or cell from which another substance, cellular component, or cell—different in kind from the precursor—is formed.)
Introduction to Lipids
As noted earlier, many practical aspects of metabolism are discussed elsewhere, particularly in the essays Digestion and Nutrients and Nutrition. Also, two types of chemical compound, proteins and carbohydrates, are so important to a variety of metabolic processes that they are examined in detail within entries of their own. In the present context, let us focus on the third major kind of nutrient, lipids or fats.
Lipids are soluble in nonpolar solvents, which is the reason why a gravy stain or other grease stain is difficult to remove from clothing without a powerful detergent or spot remover. Water molecules are polar, because the opposing electric charges tend to occupy opposite sides or ends of the molecule. In a molecule of oil, whether derived from petroleum or from animal or vegetable fat, electric charges are very small, and are distributed evenly throughout the molecule.
Whereas water molecules tend to bond relatively well, like a bunch of bar magnets attaching to one another at their opposing poles, oil and fat molecules tend not to bond. (The "bond" referred to here is the fairly weak one between molecules. Much stronger is the chemical bond within molecules—a bond that, when broken, brings about a release of energy, as noted earlier.) Their functions are as varied as their structures, but because they are all fat-soluble, lipids share in the ability to approach and even to enter cells. The latter have membranes that, while highly complex in structure, can be identified in simple terms as containing lipids or lipoproteins (lipids attached to proteins). The behavior of lipids and lipid-like molecules, therefore, becomes very important in understanding how a substance may or may not enter a cell. Such a substance may be toxic, as in the case of some pesticides, but if they are lipid-like, they are able to penetrate the cell's membrane. (See Food Webs for more about the biomagnification of DDT.)
In addition to lipoproteins, there are glycolipids, or lipids attached to sugars, as well as lipids attached to alcohols and some to phosphoric acids. The attachment with other compounds greatly alters the behavior of a lipid, often making them bipolar—that is, one end of the molecule is water-soluble. This is important, because it allows lipids to move out of the intestines and into the bloodstream. In the digestive process, lipids are made water-soluble either by being broken down into smaller parts or through association with another substance. The breaking down usually is done via two different processes: hydrolysis, or chemical reaction with water, and saponification. The latter, a reaction in which certain kinds of organic compounds are hydrolyzed to produce an alcohol and a salt, is used in making soap.
Real-Life Applications
Putting Lipids to Use
Derived from living systems of plants, animals, or humans, lipids are essential to good health, not only for humans but also for other animals and even plants. Seeds, for example, contain lipids for the storage of energy. Because fat is a poor conductor of heat, lipids also can function as effective insulators, and for this reason, people living in Arctic zones seek fatty foods such as blubber. Some lipids function as chemical messengers in the body, while others serve as storage areas for chemical energy. There is a good reason why babies are born with "baby fat" and why children entering puberty often tend to become chubby: in both cases, they are building up energy reserves for the great metabolic hurdles that lie ahead, and within a few years, they will have used up those excessive fat stores.
Fats and Oils
Fats and oils are both energy-rich compounds that are basic components of the normal diet. Both have essentially the same chemical structure—a mixture of fatty acids combined with glycerol—and are insoluble (do not dissolve) in water. While fats remain solid or at least semisolid at room temperature, however, most oils very quickly become liquid at increased temperatures. Animal fats and oils include butter, lard, tallow, and fish oil. Numerous other oils, such as cottonseed, peanut, and corn oils, are derived from plants.
Fats have two main functions: they provide some of the raw material for synthesizing (creating) and repairing tissues, and they serve as a concentrated source of fuel energy. Fats, in fact, provide humans with roughly twice as much energy, per unit weight, as carbohydrates and proteins. Fats are not only an important source of day-to-day energy, but they also can be stored indefinitely as adipose (fat) tissue in case of future need. Fats also help by transporting fat-soluble vitamins, such as A and D (see Vitamins), throughout the system. They cushion and form protective pads around delicate organs, such as the heart, liver and kidneys, and the layer of fat under the skin helps insulate the body against too much heat loss. They even add to the flavor of foods that might otherwise be inedible.
Not All Fat Is Created Equal
Although normal amounts of certain kinds of fat in the diet are essential to good health, unnecessarily high amounts (especially of unhealthy fats) can lead to various problems. Healthy fats include those from fatty fish, such as salmon, mackerel, or tuna, or from fat-containing vegetables, such as the avocado. In addition, many vegetable oils, particularly olive oil, can be beneficial.
Bad fats, on the other hand, are usually ones that have been tampered with through a process known as hydrogenation. This is a term describing any chemical reaction in which hydrogen atoms are added to fill in chemical bonds between carbon and other atoms, but in the case of fatty foods, hydrogenation involves the saturation of hydrocarbons, organic chemical compounds whose molecules are made up of nothing but carbon and hydrogen atoms. When they are treated with hydrogen gas, they become "saturated" with hydrogen atoms. Saturated fats, as they are called, are harder and more stable and stand up better to the heat of frying, which makes them more desirable for use in commercial products. For this reason, many foods contain hydrogenated vegetable oil; however, saturated fats have been linked to a rise in blood cholesterol levels—and to an increased risk of heart disease.
Cholesterol is a variety of lipid, and, like other lipids, some of it is essential—but only some and only of the right kind. Most cholesterol is transported through the blood in low-density lipoproteins, or LDLs, which have been nicknamed bad cholesterol. These lipoproteins are received by LDL receptors on the cell membranes, but if there are more LDLs than LDL receptors, the excess LDLs will be deposited in the arteries. Thus, LDLs are not really "bad" unless there are too many of them. On the other hand, "good" cholesterol (HDLs, or high-density lipoproteins) help protect against damage to the artery walls by carrying excess LDLs back to the liver.
How Much Is Too Much?
A certain amount of excess adipose tissue can be valuable during periods of illness, overactivity, or food shortages. Too much, however, can be unsightly and also can overwork the heart and put added stress on other parts of the body. High levels of certain circulating fats may lead to atherosclerosis, which is a thickening of the artery walls, and they have been linked to various illnesses, including cancer.
With fat, as with many things where the body is concerned, if a little is a good, this does not mean that a lot is better. In the past, nutritionists considered a diet that obtained 40% of its calories from fats a reasonable one; today, however, they recommend that no more than 30% of all calories (and preferably an even smaller percentage) come from fat. Agreement on this point, however, is far from universal. Some physicians and scientists maintain that dietary fat does not contribute as much to body fat as do carbohydrates. Carbohydrates are good for someone who needs a boost of energy that can be consumed easily by the body, such as an athlete going into competition. But for in active people—and this includes a large portion of Americans—carbohydrates simply are stored as fat.
Experts do not even agree on the answer to a question much simpler than "How much is too much fat in the diet?"—the question "How much is too much fat on the body?" Some doctors classify a person as obese whose weight is at least 20% more than the recommended weight for his or her height, but others say that standard height-and-weight charts are misleading. After all, muscle weighs more than fat, and it is conceivable that a very muscular athlete with very little body fat might qualify as "overweight" compared with the recommended weight for his or her height.
Body Fat, the Sexes, and Nature
Because of the complexity of the issue, many experts contend that the proportion of fat to muscle, measured by the skinfold "pinch" test, is a better measure of obesity. (Being obese is not the same as being overweight: the muscular athlete described in the last paragraph is overweight but not obese, a term that implies an excess of body fat.) In healthy adults, fat typically should account for about 18-25% of the body weight in females and 15-20% in males.
The reason for the difference between men and women is that fat naturally accumulates in a woman's buttocks and thighs, because nature "assumes" that she will bear children, in which case such excess fat will be useful. This is why women over the age of about 25 often complain that when they and their husbands or boyfriends embark on a fitness program together, the men usually see results faster. The reason is that there is no genetic or evolutionary benefit to be gained from a man having fat around his waist, which is where men usually gain. If anything—since our genetic codes and makeup have changed little since prehistory—the well-being and propagation of the human species are best served by a lean, muscular male capable of killing animals to feed and protect his family. All of this means, of course, that men should not gloat if they see better results from a regular workout program; instead, they should just recognize that nature is at work in their wives' or girlfriends' bodies as in their own.
Metabolic Disorders
Enzymes, as we noted earlier, are critical participants in metabolic reactions. They are like relay runners in a race, in this case a race along the metabolic pathways whereby nutrients are turned into energy or new bodily material. Therefore, if an enzyme is missing or does not function as it should, it can create a serious metabolic disorder. An example is phenylketonuria (PKU), caused by the lack of an enzyme known as phenylalanine hydroxylase. This enzyme is responsible for converting the amino acid phenylalanine to a second amino acid, tyrosine; when this does not happen, phenylalanine builds up in the body. It is converted to a compound called phenylpyruvate, which impairs normal brain development, resulting in severe mental retardation.
Other examples of metabolic disorders include alkaptonuria, thalassemia, porphyria, Tay-Sachs disease, Hurler syndrome, Gaucher disease, galactosemia, Cushing syndrome, diabetes mellitus, hyperthyroidism, and hypothyroidism. Most of these conditions affect a small population; however, diabetes mellitus (discussed in Noninfectious Diseases) is one of the leading killers in America. At present, no cures for metabolic disorders exist. The best approach is to diagnose such conditions as early as possible and then arrange a person's diet to deal as effectively as possible with that disorder.
Eating Disorders
Eating disorders are a different matter, because they are psychological rather than physiological conditions. No one is sure what causes eating disorders, but researchers think that family dynamics, biochemical abnormalities, and modern American society's preoccupation with thinness all may contribute. Eating disorders are virtually unknown in parts of the world where food is scarce, but in wealthy lands, such as the United States, problems of overeating, self-induced starvation, or forced purging have gained considerable attention.
Anorexia nervosa, bulimia, and obesity are the most well known types of eating disorder. The word anorexia comes from the Greek for "lack of appetite," but the problem for people with anorexia is not that they are not hungry. On the contrary, they are starving, but unlike poor people in the Third World, they are not starving as the result of a shortage of food but because they are denying themselves nutrition. They do this because they fear gaining weight, even when they are so severely underweight that they look like skeletons.
The name of a related condition, bulimia, literally means "hungry as an ox." People with this problem go on eating binges, often gorging on junk food. Then they force their bodies to get rid of the food, either by vomiting or by taking large amounts of laxatives. A third type of eating disorder, obesity, also is characterized by uncontrollable overeating, but in this case the person does not force the body to eject the food that has been consumed. That, at least, makes obesity more healthy than bulimia, but there is nothing healthy about accumulating vast amounts of body fat, as severely obese people do.
Anorexia and Bulimia
Young people are more likely than older people to suffer anorexia or bulimia, conditions that typically become apparent at about the age of 20 years. Although both men and women can experience the problem, in fact, only about 5% of people with these eating disorders are male. And though anorexia and bulimia are closely related—particularly inasmuch as they are psychological in origin but can exact a heavy biological toll—there are several important differences.
People who have anorexia or bulemia often come from families with overprotective parents who have unrealistically high expectations of their children. Frequently, high expectations go hand in hand with a wealthy background, and certainly anorexia and bulimia are not conditions that typically affect the poor. Anorexia and bulimia often seem to develop after some stressful experience, such as moving to a new town, changing schools, or going through puberty. Low self-esteem, fear of losing control, and fear of growing up are common characteristics of people with these conditions. Their need for approval manifests in a quest to meet or exceed our culture's idealized concept of extreme thinness. This quest is a part of our popular culture, promoted by waiflike models whose sunken eyes stare out of fashion magazines.
Like anorexia, bulimia results in starvation, but there are behavioral, physical, and psychological differences between the two. Bulimia is both less and more dangerous: on the one hand, people who have it tend to be of normal weight or are overweight, and unlike those with anorexia, they are aware of the fact that they have a problem. On the other hand, because the effects of their behavior are not so readily apparent, it is easier for a person with bulimia to persist in the pattern of bingeing and purging for much longer.
Approximately one in five persons with bulimia has a problem with drug or alcohol use, and they pursue their binges in a way not unlike that of a guilty addict or alcoholic hiding the spent needles or empty bottles from family members. They may go from restaurant to restaurant to avoid being seen eating too much in any one place, or they may pretend to be shopping for a large dinner party when, in fact, they intend to eat all the food themselves. Because of the expense of consuming so much food, some resort to shoplifting.
During a binge, people suffering from bulimia favor high-carbohydrate foods, such as doughnuts, candy, ice cream, soft drinks, cookies, cereal, cake, popcorn, and bread, and they consume many times the number of calories they would normally consume in one day. No matter what their normal eating habits, they tend to eat quickly and messily during a binge, stuffing the food into their mouths and gulping it down, sometimes without even tasting it. Some say they get a feeling of euphoria during binges, similar to the "runner's high" that some people get from exercise. Then, when they have gorged themselves, they force the food back out, either by causing themselves to vomit or by taking large quantities of laxatives.
Regular self-induced vomiting can cause all sorts of physical problems, such as damage to the stomach and esophagus, chronic heartburn, burst blood vessels in the eyes, throat irritation, and erosion of tooth enamel from the acid in vomit. Excessive use of laxatives can induce muscle cramps, stomach pains, digestive problems, dehydration, and even poisoning, while bulimia, in general, brings about vitamin deficiencies and imbalances of critical body fluids, which, in turn, can lead to seizures and kidney failure.
The self-imposed starvation of people with anorexia likewise takes a heavy toll on the body. The skin becomes dry and flaky, muscles begin to waste away, bones stop growing and may become brittle, and the heart weakens. Seeking to protect itself in the absence of proper insulation from fat, the body sprouts downy hair on the face, back, and arms in response to lower body temperature. In women, menstruation stops, and permanent infertility may result. Muscle cramps, dizziness, fatigue, and even brain damage as well as kidney and heart failure are possible. An estimated 10% to 20% of people with anorexia die either as a direct result of starvation or by suicide.
To save people with anorexia, force-feeding may be necessary. Some 70% of anorexia patients who are treated for about six months return to normal body weight, but about 15-20% can be expected to relapse. Bulimia is not as likely as anorexia to reach life-threatening stages, so hospitalization typically is not necessary. Treatment generally calls for psychotherapy and sometimes the administration of antidepressant drugs. Unlike people with anorexia, those with bulimia usually admit they have a problem and want help overcoming it.
Obesity
Unlike anorexia or bulimia, obesity is more of a problem among people from lower-income backgrounds. This probably relates to a lack of education concerning nutrition, combined with the fact that healthier food is more expensive; by contrast, unhealthy items, such as white sugar, corn meal, and fatty cuts of pork and other meats can fill or overfill a person's stomach inexpensively. In addition, though men and women both tend to gain weight as they age, women are almost twice as likely as men to be obese.
Some cases of obesity relate to metabolic problems, while others stem from compulsive eating, which is psychologically motivated. Some studies suggest that obese people are much more likely than others to eat in response to stress, loneliness, or depression. And just as emotional pain can lead to obesity, obesity can lead to psychological scars. From childhood on, obese people are taunted and shunned, and throughout life they may face discrimination in school and on the job.
Physically, obesity is a killer, especially for those who are morbidly obese—that is, people whose obesity endangers their health. Obesity is a risk factor for diabetes, high blood pressure, arteriosclerosis, angina pectoralis (chest pains due to inadequate blood flow to the heart), varicose veins, cirrhosis of the liver, and kidney disease. Obese people are about 1.5 times more likely to have heart attacks than are other people, and the overall death rate among people ages 20-64 is 50% higher for the obese than for people of ordinary weight.
Hibernation
Having looked at several unnatural ways in which people alter their metabolisms, let us close with an example of a very natural way that animals sometimes temporarily change theirs. This is hibernation, a state of inactivity in which an animal's heart rate, body temperature, and breathing rate are decreased as a way to conserve energy through the cold months of winter. A similar state, known as estivation, is adopted by some desert animals during the dry months of summer.
Hibernation is a technique that animals have developed, as a result of natural selection over the generations (see Evolution), to adapt to harsh environmental conditions. When food is scarce, a nonhibernating animal would be like a business operating at a loss—that is, using more energy maintaining its body temperature and searching for food than it would receive from consuming the food. Hibernating animals use 70-100 times less energy than when they are active, allowing them to survive until food is once again plentiful.
Contrast With Sleep
Many animals sleep more often when food is scarce, but only a few truly hibernate. Bears, which many people think of as the classic hibernating animal, are actually just deep sleepers. By contrast, true hibernation occurs only in small mammals, such as bats and woodchucks and a few birds, among them nighthawks. Some insects also practice a form of hibernation. Hibernation differs from sleep, in that a hibernating animal shows a drastic reduction in metabolism and then awakes relatively slowly, whereas a sleeping animal decreases its metabolism only slightly and can wake up almost instantly if disturbed. Also, hibernating animals do not show periods of rapid eye movement (REM), the stage of sleep associated with dreaming in humans.
The Process of Hibernation
Animals prepare for hibernation in the fall by storing food; usually this storage is internal, in the form of fat reserves. A woodchuck in early summer may have only about 5% body fat, but as fall approaches, changes in the animal's brain chemistry cause it to feel hungry and to eat constantly. As a result, the woodchuck's body fat increases to about 15% of its total weight. In other animals, such as the dormouse, fat may constitute as much as 50% of the animal's weight by the time hibernation begins. A short period of fasting follows the feeding frenzy, to ensure that the digestive tract is emptied completely before hibernation begins.
Going into hibernation is a gradual process. Over a period of days, an animal's heart rate and breathing rate drop slowly, eventually reaching rates of just a few beats or breaths per minute. Their body temperatures also drop from levels of about 100°F (38°C) to about 60°F (15°C). The lowered body temperature makes fewer demands on metabolism and food stores. Electric activity in the brain ceases almost completely during hibernation, although some areas—those that respond to external stimuli, such as light, temperature, and noise—remain active. Thus, the hibernating animal can be aroused under extreme conditions.
Periodically—perhaps every two weeks or so—the hibernating animal awakes and takes a few deep breaths to refresh its air supply. If the weather is particularly mild, some animals may venture from their lairs. An increase in heart rate signals that the time for arousal, or ending hibernation, is near. Blood vessels dilate, particularly around the heart, lungs, and brain, and this leads to an increased breathing rate. Eventually, the increase in circulation and metabolic activity spreads throughout the body, and the animal resumes a normal waking state.
Where to Learn More
Bouchard, Claude. Physical Activity and Obesity. Champaign, IL: Human Kinetics, 2000.
"KEGG Metabolic Pathways ." KEGG: Kyoto Encyclopedia of Genes and Genomes—GenomeNet, Bioinformatics Center, Institute for Chemical Research, Kyoto University (Web site). <http://www.genome.ad.jp/kegg/metabolism.html>.
Medline Plus: Food, Nutrition, and Metabolism Topics. Medline, National Library of Medicine, National Insti tutes of Health (Web site). <http://www.nlm.nih.gov/medlineplus/foodnutritionandmetabolism.html>.
Metabolic Pathways of Biochemistry. George Washington University (Web site). <http://www.gwu.edu/~mpb/>.
Metabolism (Web site). <http://www.ultranet.com/~jkimball/BiologyPages/M/Metabolism.html>.
Michal, Gerhard. Biochemical Pathways: An Atlas of Bio chemistry and Molecular Biology. New York: Wiley, 1999.
Pasternak, Charles A. The Molecules Within Us: Our Body in Health and Disease. New York: Plenum, 1998.
Pathophysiology of the Digestive System (Web site). <http://arbl.cvmbs.colostate.edu/hbooks/pathphys/digestion/>.
Spallholz, Julian E. Nutrition, Chemistry, and Biology. Englewood Cliffs, NJ: Prentice-Hall, 1989.
Wolinsky, Ira. Nutrition in Exercise and Sport. 3d ed. Boca Raton, FL: CRC Press, 1998.
| Sci-Tech Encyclopedia: Metabolism |
All the physical and chemical processes by which living, organized substance is produced and maintained and the transformations by which energy is made available for use by an organism.
In defining metabolism, it is customary to distinguish between energy metabolism and intermediary metabolism, although the two are, in fact, inseparable. Energy metabolism is primarily concerned with overall heat production in an organism, while intermediary metabolism deals with chemical reactions within cells and tissues. In general, the term metabolism is interpreted to mean intermediary metabolism. See also Energy metabolism.
Metabolism thus includes all biochemical processes within cells and tissues which are concerned with their building up, breaking down, and functioning. The synthesis and maintenance of tissue structure generally involves the union of smaller into larger molecules. This part of metabolism, the building of tissues, is termed anabolism. The process of breaking down tissue, of splitting larger protoplasmic molecules into smaller ones, is termed catabolism. Growth or weight gain occurs when anabolism exceeds catabolism. On the other hand, weight loss results if catabolism proceeds more rapidly than anabolism, as in periods of starvation, serious injury, or disease. When the two processes are balanced, tissue mass remains the same.
The metabolism of the three major foodstuffs, carbohydrates, fats, and proteins, is intimately interrelated, so any clearcut division of the three is arbitrary and inaccurate. Thus the metabolism of protoplasm is concerned with all three of these foodstuffs. The metabolic pathways of carbohydrates, fats, and proteins cross at many points; thus certain pathways of metabolism are shared in common by fragments of these different classes of foodstuffs.
Some of the metabolic processes of the protoplasm of both plant and animal cells occur alongcommon pathways; carbohydrate metabolism in plants is similar in many details to carbohydrate metabolism in animals. Therefore the study of metabolism in any organism is, in a sense, the study of metabolism in all protoplasm. See also Carbohydrate metabolism; Lipid metabolism; Protein metabolism.
| World of the Body: metabolism |
According to the Shorter Oxford English Dictionary, the term metabolism is defined as ‘the chemical processes by which nutritive material is built up into living matter, or by which complex molecules are broken down into simpler substances during the performance of special functions’. The various reactions which involve the synthesis of complex molecules can be grouped under the heading of anabolism, whereas the breakdown of complex molecules is known as catabolism. As might be expected, both anabolic and catabolic processes include a vast number of different chemical reactions, but there are a number of common features. Most of the metabolic processes occur inside the cells of the body, mainly in the cytoplasm, but also inside intracellular organelles such as the mitochondria. Anabolic and catabolic reactions involve the action of enzymes and the utilization of energy. In some cases the metabolic processes are regulated locally, i.e. by the cell itself, but often the metabolism of the whole body is controlled in an integrated fashion by the action of hormones and/or the nervous system.
Anabolic processes
These mainly involve the use of the carbohydrates, fats, proteins, and minerals consumed in the diet to synthesize complex molecules — such as the structural material of the skeleton, connective tissue, and cell membranes; nutrient stores for later use; and hormones and proteins which are secreted from cells into the blood or into the digestive tract. In order for these anabolic processes to proceed efficiently, it is essential that the cells are provided with the correct raw materials (and are able to extract them from the blood) and that the appropriate enzymes are present within the cells. Obviously, these enzymes will have been synthesized within the cells, as a result of activation of the appropriate genes in the cell nucleus.
Catabolic processes
These can be classified into a variety of categories, including the breakdown of energy-containing components of the diet (or their storage forms) to make energy available for the cells; the removal and breakdown of potentially toxic substances in the bloodstream; and the breakdown of damaged cells and tissues with the re-use of many of the components. These catabolic processes require the presence of the appropriate enzymes; many also require oxygen to be available, and the waste products to be removed from the tissues by the blood.
In many cases the processes of anabolism and catabolism occur coincidentally. A good example relates to the protein in the body, which is in a constant state of flux. Every day some of the body protein undergoes catabolism and is replaced by new material. Thus, there is a constant turnover of protein in the body, which requires a continuous supply of protein in the diet, and which also uses a substantial amount of energy.
Control of metabolism
For the body to function efficiently, there has to be an effective means of controlling and integrating the metabolic processes occurring in all the cells, tissues, and organs. This integration and control is mainly achieved by circulating hormones, with their release being regulated in turn partly by the nervous system and partly by direct effects of substances in the blood on the endocrine glands. An example of this integrated control of metabolism is the way in which blood glucose concentration is regulated to ensure an adequate supply of glucose to the brain. After meals, the hormone insulin acts to promote storage of glucose in the form of glycogen in the liver. The brain continuously extracts glucose from the blood to use as a fuel for its metabolic processes. In the periods between meals, this continued use of blood glucose causes the concentration to fall, which could impair brain function. However, a fall in blood glucose is detected in the pancreas and leads to the release of the hormone glucagon, which acts on the liver to cause breakdown of glycogen and release of glucose into the blood. In addition, if blood glucose falls sufficiently to affect brain metabolism, the sympathetic nervous system is activated, causing the adrenal gland to release adrenaline, which also stimulates the release of glucose from the liver; also the individual feels hungry and is prompted to eat.
Energy metabolism
A fundamental feature of both anabolic and catabolic processes is the utilization of energy. Almost all of the chemical reactions in the body require the expenditure of energy, which is made available mainly by the catabolism of the ‘macronutrients’: fats and carbohydrates (particularly glucose), and (to a small extent) proteins. This utilization of energy can be compared with the use of fuel for cooking or for generating electricity. In these two cases, the combustion of a fuel (coal, gas, or oil) produces carbon dioxide and water and releases heat which is used to warm the food (often causing chemical changes in it) or to generate steam to drive turbines. In the body's metabolism, the energy released from the oxidation of the macronutrients is used for a series of chemical reactions, instead of being released only as heat.
The main way in which the energy contained in the macronutrients is used in metabolism is via the substance adenosine triphosphate (ATP). Cells require energy for their metabolic processes, so they contain the enzymes and organelles needed to produce ATP from the catabolism of fats, carbohydrates, and/or proteins. In most cases, the production of ATP occurs in association with the oxidation, so that the final products are ATP, carbon dioxide, and water, as illustrated below for the oxidation of glucose (C6H12O6):
C6H12O6 + 6O2 = 6CO2 + 6H2O + ATPThis is an example of aerobic metabolism, requiring the supply of oxygen and the removal of carbon dioxide from the cells by the circulating blood. Thus, in order for this predominant type of metabolism to proceed effectively in the whole body, there needs to be integration of the respiration, circulation, and supply of nutrients.
— I. A. Macdonald
See also blood sugar; exercise; hunger.
| Food and Nutrition: metabolism |
The processes of interconversion of chemical compounds in the body. Anabolism is the process of forming larger and more complex compounds, commonly linked to the utilization of metabolic energy. Catabolism is the process of breaking down larger molecules to smaller ones, commonly oxidation reactions linked to release of energy. There is approximately a 30% variation in the underlying metabolic rate (basal metabolic rate) between different individuals, determined in part by the activity of the thyroid gland. See also energy.
| Food and Fitness: metabolism |
The sum total of all the chemical reactions that take place in the body. Metabolism includes anabolic reactions which manufacture substances needed for growth and repair, and catabolic reactions which break down substances to release energy. See also basal metabolic rate.
| Architecture and Landscaping: Metabolism |
Japanese architectural movement founded in 1960 by Tange. With members including Kikutake, Kurokawa, and Maki, it was concerned with the nature and expression of private and public spaces, with flexibility, and changeable use. Prefabrication, advanced technology, and industrialization were employed to create small capsules or living-units for private spaces, connected to service-towers and circulation-areas, as in Kurokawa's Nagakin Capsule Tower, Tokyo (1972).
Bibliography
The full bibliography for this book is available to download as a pdf file.
Download the bibliography for A Dictionary of Architecture and Landscape Architecture (PDF: 1.2MB)
| Columbia Encyclopedia: metabolism |
| Wikipedia: Metabolism |
Metabolism is the set of chemical reactions that occur in living organisms to maintain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories. Catabolism breaks down organic matter, for example to harvest energy in cellular respiration. Anabolism, uses energy to construct components of cells such as proteins and nucleic acids.
The chemical reactions of metabolism are organized into metabolic pathways, in which one chemical is transformed through a series of steps into another chemical, by a sequence of enzymes. Enzymes are crucial to metabolism because they allow organisms to drive desirable reactions that require energy and will not occur by themselves, by coupling them to spontaneous reactions that release energy. As enzymes act as catalysts they allow these reactions to proceed quickly and efficiently. Enzymes also allow the regulation of metabolic pathways in response to changes in the cell's environment or signals from other cells.
The metabolism of an organism determines which substances it will find nutritious and which it will find poisonous. For example, some prokaryotes use hydrogen sulfide as a nutrient, yet this gas is poisonous to animals.[1] The speed of metabolism, the metabolic rate, also influences how much food an organism will require.
A striking feature of metabolism is the similarity of the basic metabolic pathways between even vastly different species. For example, the set of carboxylic acids that are best known as the intermediates in the citric acid cycle are present in all organisms, being found in species as diverse as the unicellular bacteria Escherichia coli and huge multicellular organisms like elephants.[2] These striking similarities in metabolism are probably due to the high efficiency of these pathways, and their early appearance in evolutionary history.[3][4]
Contents |
Most of the structures that make up animals, plants and microbes are made from three basic classes of molecule: amino acids, carbohydrates and lipids (often called fats). As these molecules are vital for life, metabolic reactions focus on making these molecules during the construction of cells and tissues, or breaking them down and using them as a source of energy, in the digestion and use of food. Many important biochemicals can be joined together to make polymers such as DNA and proteins. These macromolecules are essential parts of all living organisms. Some of the most common biological polymers are listed in the table below.
| Type of molecule | Name of monomer forms | Name of polymer forms | Examples of polymer forms |
|---|---|---|---|
| Amino acids | Amino acids | Proteins (also called polypeptides) | Fibrous proteins and globular proteins |
| Carbohydrates | Monosaccharides | Polysaccharides | Starch, glycogen and cellulose |
| Nucleic acids | Nucleotides | Polynucleotides | DNA and RNA |
Proteins are made of amino acids arranged in a linear chain and joined together by peptide bonds. Many proteins are the enzymes that catalyze the chemical reactions in metabolism. Other proteins have structural or mechanical functions, such as the proteins that form the cytoskeleton, a system of scaffolding that maintains the cell shape.[5] Proteins are also important in cell signaling, immune responses, cell adhesion, active transport across membranes, and the cell cycle.[6]
Lipids are the most diverse group of biochemicals. Their main structural uses are as part of biological membranes such as the cell membrane, or as a source of energy.[6] Lipids are usually defined as hydrophobic or amphipathic biological molecules that will dissolve in organic solvents such as benzene or chloroform.[7] The fats are a large group of compounds that contain fatty acids and glycerol; a glycerol molecule attached to three fatty acid esters is a triacylglyceride.[8] Several variations on this basic structure exist, including alternate backbones such as sphingosine in the sphingolipids, and hydrophilic groups such as phosphate in phospholipids. Steroids such as cholesterol are another major class of lipids that are made in cells.[9]
Carbohydrates are straight-chain aldehydes or ketones with many hydroxyl groups that can exist as straight chains or rings. Carbohydrates are the most abundant biological molecules, and fill numerous roles, such as the storage and transport of energy (starch, glycogen) and structural components (cellulose in plants, chitin in animals).[6] The basic carbohydrate units are called monosaccharides and include galactose, fructose, and most importantly glucose. Monosaccharides can be linked together to form polysaccharides in almost limitless ways.[10]
The polymers DNA and RNA are long chains of nucleotides. These molecules are critical for the storage and use of genetic information, through the processes of transcription and protein biosynthesis.[6] This information is protected by DNA repair mechanisms and propagated through DNA replication. A few viruses have an RNA genome, for example HIV, which uses reverse transcription to create a DNA template from its viral RNA genome.[11] RNA in ribozymes such as spliceosomes and ribosomes is similar to enzymes as it can catalyze chemical reactions. Individual nucleosides are made by attaching a nucleobase to a ribose sugar. These bases are heterocyclic rings containing nitrogen, classified as purines or pyrimidines. Nucleotides also act as coenzymes in metabolic group transfer reactions.[12]
Metabolism involves a vast array of chemical reactions, but most fall under a few basic types of reactions that involve the transfer of functional groups.[13] This common chemistry allows cells to use a small set of metabolic intermediates to carry chemical groups between different reactions.[12] These group-transfer intermediates are called coenzymes. Each class of group-transfer reaction is carried out by a particular coenzyme, which is the substrate for a set of enzymes that produce it, and a set of enzymes that consume it. These coenzymes are therefore continuously being made, consumed and then recycled.[14]
One central coenzyme is adenosine triphosphate (ATP), the universal energy currency of cells. This nucleotide is used to transfer chemical energy between different chemical reactions. There is only a small amount of ATP in cells, but as it is continuously regenerated, the human body can use about its own weight in ATP per day.[14] ATP acts as a bridge between catabolism and anabolism, with catabolic reactions generating ATP and anabolic reactions consuming it. It also serves as a carrier of phosphate groups in phosphorylation reactions.
A vitamin is an organic compound needed in small quantities that cannot be made in the cells. In human nutrition, most vitamins function as coenzymes after modification; for example, all water-soluble vitamins are phosphorylated or are coupled to nucleotides when they are used in cells.[15] Nicotinamide adenine dinucleotide (NADH), a derivative of vitamin B3 (niacin), is an important coenzyme that acts as a hydrogen acceptor. Hundreds of separate types of dehydrogenases remove electrons from their substrates and reduce NAD+ into NADH. This reduced form of the coenzyme is then a substrate for any of the reductases in the cell that need to reduce their substrates.[16] Nicotinamide adenine dinucleotide exists in two related forms in the cell, NADH and NADPH. The NAD+/NADH form is more important in catabolic reactions, while NADP+/NADPH is used in anabolic reactions.
Inorganic elements play critical roles in metabolism; some are abundant (e.g. sodium and potassium) while others function at minute concentrations. About 99% of mammals' mass are the elements carbon, nitrogen, calcium, sodium, chlorine, potassium, hydrogen, phosphorus, oxygen and sulfur.[17] The organic compounds (proteins, lipids and carbohydrates) contain the majority of the carbon and nitrogen and most of the oxygen and hydrogen is present as water.[17]
The abundant inorganic elements act as ionic electrolytes. The most important ions are sodium, potassium, calcium, magnesium, chloride, phosphate, and the organic ion bicarbonate. The maintenance of precise gradients across cell membranes maintains osmotic pressure and pH.[18] Ions are also critical for nerves and muscles, as action potentials in these tissues are produced by the exchange of electrolytes between the extracellular fluid and the cytosol.[19] Electrolytes enter and leave cells through proteins in the cell membrane called ion channels. For example, muscle contraction depends upon the movement of calcium, sodium and potassium through ion channels in the cell membrane and T-tubules.[20]
The transition metals are usually present as trace elements in organisms, with zinc and iron being most abundant.[21][22] These metals are used in some proteins as cofactors and are essential for the activity of enzymes such as catalase and oxygen-carrier proteins such as hemoglobin.[23] These cofactors are bound tightly to a specific protein; although enzyme cofactors can be modified during catalysis, cofactors always return to their original state after catalysis has taken place. The metal micronutrients are taken up into organisms by specific transporters and bound to storage proteins such as ferritin or metallothionein when not being used.[24][25]
Catabolism is the set of metabolic processes that break down large molecules. These include breaking down and oxidising food molecules. The purpose of the catabolic reactions is to provide the energy and components needed by anabolic reactions. The exact nature of these catabolic reactions differ from organism to organism and organisms can be classified based on their sources of energy and carbon (their primary nutritional groups), as shown in the table below. Organic molecules being used as a source of energy in organotrophs, while lithotrophs use inorganic substrates and phototrophs capture sunlight as chemical energy. However, all these different forms of metabolism depend on redox reactions that involve the transfer of electrons from reduced donor molecules such as organic molecules, water, ammonia, hydrogen sulfide or ferrous ions to acceptor molecules such as oxygen, nitrate or sulfate.[26] In animals these reactions involve complex organic molecules being broken down to simpler molecules, such as carbon dioxide and water. In photosynthetic organisms such as plants and cyanobacteria, these electron-transfer reactions do not release energy, but are used as a way of storing energy absorbed from sunlight.[6]
| energy source | sunlight | photo- | -troph | ||
| preformed molecules | chemo- | ||||
| electron donor | organic compound | organo- | |||
| inorganic compound | litho- | ||||
| carbon source | organic compound | hetero- | |||
| inorganic compound | auto- | ||||
The most common set of catabolic reactions in animals can be separated into three main stages. In the first, large organic molecules such as proteins, polysaccharides or lipids are digested into their smaller components outside cells. Next, these smaller molecules are taken up by cells and converted to yet smaller molecules, usually acetyl coenzyme A (acetyl-CoA), which releases some energy. Finally, the acetyl group on the CoA is oxidised to water and carbon dioxide in the citric acid cycle and electron transport chain, releasing the energy that is stored by reducing the coenzyme nicotinamide adenine dinucleotide (NAD+) into NADH.
Macromolecules such as starch, cellulose or proteins cannot be rapidly taken up by cells and need to be broken into their smaller units before they can be used in cell metabolism. Several common classes of enzymes digest these polymers. These digestive enzymes include proteases that digest proteins into amino acids, as well as glycoside hydrolases that digest polysaccharides into monosaccharides.
Microbes simply secrete digestive enzymes into their surroundings,[27][28] while animals only secrete these enzymes from specialized cells in their guts.[29] The amino acids or sugars released by these extracellular enzymes are then pumped into cells by specific active transport proteins.[30][31]
Carbohydrate catabolism is the breakdown of carbohydrates into smaller units. Carbohydrates are usually taken into cells once they have been digested into monosaccharides.[32] Once inside, the major route of breakdown is glycolysis, where sugars such as glucose and fructose are converted into pyruvate and some ATP is generated.[33] Pyruvate is an intermediate in several metabolic pathways, but the majority is converted to acetyl-CoA and fed into the citric acid cycle. Although some more ATP is generated in the citric acid cycle, the most important product is NADH, which is made from NAD+ as the acetyl-CoA is oxidized. This oxidation releases carbon dioxide as a waste product. In anaerobic conditions, glycolysis produces lactate, through the enzyme lactate dehydrogenase re-oxidizing NADH to NAD+ for re-use in glycolysis. An alternative route for glucose breakdown is the pentose phosphate pathway, which reduces the coenzyme NADPH and produces pentose sugars such as ribose, the sugar component of nucleic acids.
Fats are catabolised by hydrolysis to free fatty acids and glycerol. The glycerol enters glycolysis and the fatty acids are broken down by beta oxidation to release acetyl-CoA, which then is fed into the citric acid cycle. Fatty acids release more energy upon oxidation than carbohydrates because carbohydrates contain more oxygen in their structures.
Amino acids are either used to synthesize proteins and other biomolecules, or oxidized to urea and carbon dioxide as a source of energy.[34] The oxidation pathway starts with the removal of the amino group by a transaminase. The amino group is fed into the urea cycle, leaving a deaminated carbon skeleton in the form of a keto acid. Several of these keto acids are intermediates in the citric acid cycle, for example the deamination of glutamate forms α-ketoglutarate.[35] The glucogenic amino acids can also be converted into glucose, through gluconeogenesis (discussed below).[36]
In oxidative phosphorylation, the electrons removed from food molecules in pathways such as the citric acid cycle are transferred to oxygen and the energy released is used to make ATP. This is done in eukaryotes by a series of proteins in the membranes of mitochondria called the electron transport chain. In prokaryotes, these proteins are found in the cell's inner membrane.[37] These proteins use the energy released from passing electrons from reduced molecules like NADH onto oxygen to pump protons across a membrane.[38]
Pumping protons out of the mitochondria creates a proton concentration difference across the membrane and generates an electrochemical gradient.[39] This force drives protons back into the mitochondrion through the base of an enzyme called ATP synthase. The flow of protons makes the stalk subunit rotate, causing the active site of the synthase domain to change shape and phosphorylate adenosine diphosphate - turning it into ATP.[14]
Chemolithotrophy is a type of metabolism found in prokaryotes where energy is obtained from the oxidation of inorganic compounds. These organisms can use hydrogen,[40] reduced sulfur compounds (such as sulfide, hydrogen sulfide and thiosulfate),[1] ferrous iron (FeII)[41] or ammonia[42] as sources of reducing power and they gain energy from the oxidation of these compounds with electron acceptors such as oxygen or nitrite.[43] These microbial processes are important in global biogeochemical cycles such as acetogenesis, nitrification and denitrification and are critical for soil fertility.[44][45]
The energy in sunlight is captured by plants, cyanobacteria, purple bacteria, green sulfur bacteria and some protists. This process is often coupled to the conversion of carbon dioxide into organic compounds, as part of photosynthesis, which is discussed below. The energy capture and carbon fixation systems can however operate separately in prokaryotes, as purple bacteria and green sulfur bacteria can use sunlight as a source of energy, while switching between carbon fixation and the fermentation of organic compounds.[46][47]
In many organisms the capture of solar energy is similar in principle to oxidative phosphorylation, as it involves energy being stored as a proton concentration gradient and this proton motive force then driving ATP synthesis.[14] The electrons needed to drive this electron transport chain come from light-gathering proteins called photosynthetic reaction centres or rhodopsins. Reaction centers are classed into two types depending on the type of photosynthetic pigment present, with most photosynthetic bacteria only having one type, while plants and cyanobacteria have two.[48]
In plants, algae, and cyanobateria, photosystem II uses light energy to remove electrons from water, releasing oxygen as a waste product. The electrons then flow to the cytochrome b6f complex, which uses their energy to pump protons across the thylakoid membrane in the chloroplast.[6] These protons move back through the membrane as they drive the ATP synthase, as before. The electrons then flow through photosystem I and can then either be used to reduce the coenzyme NADP+, for use in the Calvin cycle which is discussed below, or recycled for further ATP generation.[49]
Anabolism is the set of constructive metabolic processes where the energy released by catabolism is used to synthesize complex molecules. In general, the complex molecules that make up cellular structures are constructed step-by-step from small and simple precursors. Anabolism involves three basic stages. Firstly, the production of precursors such as amino acids, monosaccharides, isoprenoids and nucleotides, secondly, their activation into reactive forms using energy from ATP, and thirdly, the assembly of these precursors into complex molecules such as proteins, polysaccharides, lipids and nucleic acids.
Organisms differ in how many of the molecules in their cells they can construct for themselves. Autotrophs such as plants can construct the complex organic molecules in cells such as polysaccharides and proteins from simple molecules like carbon dioxide and water. Heterotrophs, on the other hand, require a source of more complex substances, such as monosaccharides and amino acids, to produce these complex molecules. Organisms can be further classified by ultimate source of their energy: photoautotrophs and photoheterotrophs obtain energy from light, whereas chemoautotrophs and chemoheterotrophs obtain energy from inorganic oxidation reactions.
Photosynthesis is the synthesis of carbohydrates from sunlight and carbon dioxide (CO2). In plants, cyanobacteria and algae, oxygenic photosynthesis splits water, with oxygen produced as a waste product. This process uses the ATP and NADPH produced by the photosynthetic reaction centres, as described above, to convert CO2 into glycerate 3-phosphate, which can then be converted into glucose. This carbon-fixation reaction is carried out by the enzyme RuBisCO as part of the Calvin – Benson cycle.[50] Three types of photosynthesis occur in plants, C3 carbon fixation, C4 carbon fixation and CAM photosynthesis. These differ by the route that carbon dioxide takes to the Calvin cycle, with C3 plants fixing CO2 directly, while C4 and CAM photosynthesis incorporate the CO2 into other compounds first, as adaptations to deal with intense sunlight and dry conditions.[51]
In photosynthetic prokaryotes the mechanisms of carbon fixation are more diverse. Here, carbon dioxide can be fixed by the Calvin – Benson cycle, a reversed citric acid cycle,[52] or the carboxylation of acetyl-CoA.[53][54] Prokaryotic chemoautotrophs also fix CO2 through the Calvin – Benson cycle, but use energy from inorganic compounds to drive the reaction.[55]
In carbohydrate anabolism, simple organic acids can be converted into monosaccharides such as glucose and then used to assemble polysaccharides such as starch. The generation of glucose from compounds like pyruvate, lactate, glycerol, glycerate 3-phosphate and amino acids is called gluconeogenesis. Gluconeogenesis converts pyruvate to glucose-6-phosphate through a series of intermediates, many of which are shared with glycolysis.[33] However, this pathway is not simply glycolysis run in reverse, as several steps are catalyzed by non-glycolytic enzymes. This is important as it allows the formation and breakdown of glucose to be regulated separately and prevents both pathways from running simultaneously in a futile cycle.[56][57]
Although fat is a common way of storing energy, in vertebrates such as humans the fatty acids in these stores cannot be converted to glucose through gluconeogenesis as these organisms cannot convert acetyl-CoA into pyruvate; plants do, but animals do not, have the necessary enzymatic machinery.[58] As a result, after long-term starvation, vertebrates need to produce ketone bodies from fatty acids to replace glucose in tissues such as the brain that cannot metabolize fatty acids.[59] In other organisms such as plants and bacteria, this metabolic problem is solved using the glyoxylate cycle, which bypasses the decarboxylation step in the citric acid cycle and allows the transformation of acetyl-CoA to oxaloacetate, where it can be used for the production of glucose.[58][60]
Polysaccharides and glycans are made by the sequential addition of monosaccharides by glycosyltransferase from a reactive sugar-phosphate donor such as uridine diphosphate glucose (UDP-glucose) to an acceptor hydroxyl group on the growing polysaccharide. As any of the hydroxyl groups on the ring of the substrate can be acceptors, the polysaccharides produced can have straight or branched structures.[61] The polysaccharides produced can have structural or metabolic functions themselves, or be transferred to lipids and proteins by enzymes called oligosaccharyltransferases.[62][63]
Fatty acids are made by fatty acid synthases that polymerize and then reduce acetyl-CoA units. The acyl chains in the fatty acids are extended by a cycle of reactions that add the actyl group, reduce it to an alcohol, dehydrate it to an alkene group and then reduce it again to an alkane group. The enzymes of fatty acid biosynthesis are divided into two groups, in animals and fungi all these fatty acid synthase reactions are carried out by a single multifunctional type I protein,[64] while in plant plastids and bacteria separate type II enzymes perform each step in the pathway.[65][66]
Terpenes and isoprenoids are a large class of lipids that include the carotenoids and form the largest class of plant natural products.[67] These compounds are made by the assembly and modification of isoprene units donated from the reactive precursors isopentenyl pyrophosphate and dimethylallyl pyrophosphate.[68] These precursors can be made in different ways. In animals and archaea, the mevalonate pathway produces these compounds from acetyl-CoA,[69] while in plants and bacteria the non-mevalonate pathway uses pyruvate and glyceraldehyde 3-phosphate as substrates.[68][70] One important reaction that uses these activated isoprene donors is steroid biosynthesis. Here, the isoprene units are joined together to make squalene and then folded up and formed into a set of rings to make lanosterol.[71] Lanosterol can then be converted into other steroids such as cholesterol and ergosterol.[71][72]
Organisms vary in their ability to synthesize the 20 common amino acids. Most bacteria and plants can synthesize all twenty, but mammals can synthesize only the ten nonessential amino acids.[6] Thus, the essential amino acids must be obtained from food. All amino acids are synthesized from intermediates in glycolysis, the citric acid cycle, or the pentose phosphate pathway. Nitrogen is provided by glutamate and glutamine. Amino acid synthesis depends on the formation of the appropriate alpha-keto acid, which is then transaminated to form an amino acid.[73]
Amino acids are made into proteins by being joined together in a chain by peptide bonds. Each different protein has a unique sequence of amino acid residues: this is its primary structure. Just as the letters of the alphabet can be combined to form an almost endless variety of words, amino acids can be linked in varying sequences to form a huge variety of proteins. Proteins are made from amino acids that have been activated by attachment to a transfer RNA molecule through an ester bond. This aminoacyl-tRNA precursor is produced in an ATP-dependent reaction carried out by an aminoacyl tRNA synthetase.[74] This aminoacyl-tRNA is then a substrate for the ribosome, which joins the amino acid onto the elongating protein chain, using the sequence information in a messenger RNA.[75]
Nucleotides are made from amino acids, carbon dioxide and formic acid in pathways that require large amounts of metabolic energy.[76] Consequently, most organisms have efficient systems to salvage preformed nucleotides.[76][77] Purines are synthesized as nucleosides (bases attached to ribose). Both adenine and guanine are made from the precursor nucleoside inosine monophosphate, which is synthesized using atoms from the amino acids glycine, glutamine, and aspartic acid, as well as formate transferred from the coenzyme tetrahydrofolate. Pyrimidines, on the other hand, are synthesized from the base orotate, which is formed from glutamine and aspartate.[78]
All organisms are constantly exposed to compounds that they cannot use as foods and would be harmful if they accumulated in cells, as they have no metabolic function. These potentially damaging compounds are called xenobiotics.[79] Xenobiotics such as synthetic drugs, natural poisons and antibiotics are detoxified by a set of xenobiotic-metabolizing enzymes. In humans, these include cytochrome P450 oxidases,[80] UDP-glucuronosyltransferases,[81] and glutathione S-transferases.[82] This system of enzymes acts in three stages to firstly oxidize the xenobiotic (phase I) and then conjugate water-soluble groups onto the molecule (phase II). The modified water-soluble xenobiotic can then be pumped out of cells and in multicellular organisms may be further metabolized before being excreted (phase III). In ecology, these reactions are particularly important in microbial biodegradation of pollutants and the bioremediation of contaminated land and oil spills.[83] Many of these microbial reactions are shared with multicellular organisms, but due to the incredible diversity of types of microbes these organisms are able to deal with a far wider range of xenobiotics than multicellular organisms, and can degrade even persistent organic pollutants such as organochloride compounds.[84]
A related problem for aerobic organisms is oxidative stress.[85] Here, processes including oxidative phosphorylation and the formation of disulfide bonds during protein folding produce reactive oxygen species such as hydrogen peroxide.[86] These damaging oxidants are removed by antioxidant metabolites such as glutathione and enzymes such as catalases and peroxidases.[87][88]
Living organisms must obey the laws of thermodynamics, which describe the transfer of heat and work. The second law of thermodynamics states that in any closed system, the amount of entropy (disorder) will tend to increase. Although living organisms' amazing complexity appears to contradict this law, life is possible as all organisms are open systems that exchange matter and energy with their surroundings. Thus living systems are not in equilibrium, but instead are dissipative systems that maintain their state of high complexity by causing a larger increase in the entropy of their environments.[89] The metabolism of a cell achieves this by coupling the spontaneous processes of catabolism to the non-spontaneous processes of anabolism. In thermodynamic terms, metabolism maintains order by creating disorder.[90]
As the environments of most organisms are constantly changing, the reactions of metabolism must be finely regulated to maintain a constant set of conditions within cells, a condition called homeostasis.[91][92] Metabolic regulation also allows organisms to respond to signals and interact actively with their environments.[93] Two closely linked concepts are important for understanding how metabolic pathways are controlled. Firstly, the regulation of an enzyme in a pathway is how its activity is increased and decreased in response to signals. Secondly, the control exerted by this enzyme is the effect that these changes in its activity have on the overall rate of the pathway (the flux through the pathway).[94] For example, an enzyme may show large changes in activity (i.e. it is highly regulated) but if these changes have little effect on the flux of a metabolic pathway, then this enzyme is not involved in the control of the pathway.[95]
There are multiple levels of metabolic regulation. In intrinsic regulation, the metabolic pathway self-regulates to respond to changes in the levels of substrates or products; for example, a decrease in the amount of product can increase the flux through the pathway to compensate.[94] This type of regulation often involves allosteric regulation of the activities of multiple enzymes in the pathway.[96] Extrinsic control involves a cell in a multicellular organism changing its metabolism in response to signals from other cells. These signals are usually in the form of soluble messengers such as hormones and growth factors and are detected by specific receptors on the cell surface.[97] These signals are then transmitted inside the cell by second messenger systems that often involved the phosphorylation of proteins.[98]
A very well understood example of extrinsic control is the regulation of glucose metabolism by the hormone insulin.[99] Insulin is produced in response to rises in blood glucose levels. Binding of the hormone to insulin receptors on cells then activates a cascade of protein kinases that cause the cells to take up glucose and convert it into storage molecules such as fatty acids and glycogen.[100] The metabolism of glycogen is controlled by activity of phosphorylase, the enzyme that breaks down glycogen, and glycogen synthase, the enzyme that makes it. These enzymes are regulated in a reciprocal fashion, with phosphorylation inhibiting glycogen synthase, but activating phosphorylase. Insulin causes glycogen synthesis by activating protein phosphatases and producing a decrease in the phosphorylation of these enzymes.[101]
The central pathways of metabolism described above, such as glycolysis and the citric acid cycle, are present in all three domains of living things and were present in the last universal ancestor.[2][102] This universal ancestral cell was prokaryotic and probably a methanogen that had extensive amino acid, nucleotide, carbohydrate and lipid metabolism.[103][104] The retention of these ancient pathways during later evolution may be the result of these reactions being an optimal solution to their particular metabolic problems, with pathways such as glycolysis and the citric acid cycle producing their end products highly efficiently and in a minimal number of steps.[3][4] The first pathways of enzyme-based metabolism may have been parts of purine nucleotide metabolism, with previous metabolic pathways being part of the ancient RNA world.[105]
Many models have been proposed to describe the mechanisms by which novel metabolic pathways evolve. These include the sequential addition of novel enzymes to a short ancestral pathway, the duplication and then divergence of entire pathways as well as the recruitment of pre-existing enzymes and their assembly into a novel reaction pathway.[106] The relative importance of these mechanisms is unclear, but genomic studies have shown that enzymes in a pathway are likely to have a shared ancestry, suggesting that many pathways have evolved in a step-by-step fashion with novel functions being created from pre-existing steps in the pathway.[107] An alternative model comes from studies that trace the evolution of proteins' structures in metabolic networks, this has suggested that enzymes are pervasively recruited, borrowing enzymes to perform similar functions in different metabolic pathways (evident in the MANET database)[108] These recruitment processes result in an evolutionary enzymatic mosaic.[109] A third possibility is that some parts of metabolism might exist as "modules" that can be reused in different pathways and perform similar functions on different molecules.[110]
As well as the evolution of new metabolic pathways, evolution can also cause the loss of metabolic functions. For example, in some parasites metabolic processes that are not essential for survival are lost and preformed amino acids, nucleotides and carbohydrates may instead be scavenged from the host.[111] Similar reduced metabolic capabilities are seen in endosymbiotic organisms.[112]
Classically, metabolism is studied by a reductionist approach that focuses on a single metabolic pathway. Particularly valuable is the use of radioactive tracers at the whole-organism, tissue and cellular levels, which define the paths from precursors to final products by identifying radioactively labelled intermediates and products.[113] The enzymes that catalyze these chemical reactions can then be purified and their kinetics and responses to inhibitors investigated. A parallel approach is to identify the small molecules in a cell or tissue; the complete set of these molecules is called the metabolome. Overall, these studies give a good view of the structure and function of simple metabolic pathways, but are inadequate when applied to more complex systems such as the metabolism of a complete cell.[114]
An idea of the complexity of the metabolic networks in cells that contain thousands of different enzymes is given by the figure showing the interactions between just 43 proteins and 40 metabolites to the right: the sequences of genomes provide lists containing anything up to 45,000 genes.[115] However, it is now possible to use this genomic data to reconstruct complete networks of biochemical reactions and produce more holistic mathematical models that may explain and predict their behavior.[116] These models are especially powerful when used to integrate the pathway and metabolite data obtained through classical methods with data on gene expression from proteomic and DNA microarray studies.[117] Using these techniques, a model of human metabolism has now been produced, which will guide future drug discovery and biochemical research.[118] These models are now being used in network analysis, to classify human diseases into groups that share common proteins or metabolites.[119][120]
A major technological application of this information is metabolic engineering. Here, organisms such as yeast, plants or bacteria are genetically modified to make them more useful in biotechnology and aid the production of drugs such as antibiotics or industrial chemicals such as 1,3-propanediol and shikimic acid.[121] These genetic modifications usually aim to reduce the amount of energy used to produce the product, increase yields and reduce the production of wastes.[122]
The term metabolism is derived from the Greek Μεταβολισμός – "Metabolismos" for "change", or "overthrow".[123] The history of the scientific study of metabolism spans several centuries and has moved from examining whole animals in early studies, to examining individual metabolic reactions in modern biochemistry. The concept of metabolism dates back to Ibn al-Nafis (1213-1288), who stated that "the body and its parts are in a continuous state of dissolution and nourishment, so they are inevitably undergoing permanent change."[124] The first controlled experiments in human metabolism were published by Santorio Santorio in 1614 in his book Ars de statica medecina.[125] He described how he weighed himself before and after eating, sleep, working, sex, fasting, drinking, and excreting. He found that most of the food he took in was lost through what he called "insensible perspiration".
In these early studies, the mechanisms of these metabolic processes had not been identified and a vital force was thought to animate living tissue.[126] In the 19th century, when studying the fermentation of sugar to alcohol by yeast, Louis Pasteur concluded that fermentation was catalyzed by substances within the yeast cells he called "ferments". He wrote that "alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells."[127] This discovery, along with the publication by Friedrich Wöhler in 1828 of the chemical synthesis of urea,[128] proved that the organic compounds and chemical reactions found in cells were no different in principle than any other part of chemistry.
It was the discovery of enzymes at the beginning of the 20th century by Eduard Buchner that separated the study of the chemical reactions of metabolism from the biological study of cells, and marked the beginnings of biochemistry.[129] The mass of biochemical knowledge grew rapidly throughout the early 20th century. One of the most prolific of these modern biochemists was Hans Krebs who made huge contributions to the study of metabolism.[130] He discovered the urea cycle and later, working with Hans Kornberg, the citric acid cycle and the glyoxylate cycle.[131][60] Modern biochemical research has been greatly aided by the development of new techniques such as chromatography, X-ray diffraction, NMR spectroscopy, radioisotopic labelling, electron microscopy and molecular dynamics simulations. These techniques have allowed the discovery and detailed analysis of the many molecules and metabolic pathways in cells.
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Major families of biochemicals
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