For many years it was the custom to classify enzymes solely by the reactions which they catalyzed. As already noted there is within living systems an amazing variety of chemical reactions and these many diverse reactions are specifically catalyzed by individual enzymes. However, as the chemical composition of enzymes becomes better understood, there is an increasing tendency to classify enzymes not merely in terms of what they do but also in terms of their true chemical composition.
In the first place it is possible to characterize a large group of enzymes as hydrolyzing enzymes or hydrolases. The hydrolases are concerned primarily with the breaking down and the building up of proteins, carbohydrates and lipids. It is a characteristic of these essential organic materials that their large molecules are built up by a progressive subtraction of water molecules. When amino acids unite, the acid group of one amino acid combines with the basic amino group of a second, and as in typical acid-base reactions, water is split off. In this way protein molecules are built up, and if they are to be broken down to amino acids again, water molecules must be added. Similarly, when an alcohol unites with an organic acid to form an ester, water is split off; and in the reverse process by the addition of water an ester may be converted into an acid and an alcohol. Thus by the addition of water, a fat may be hydrolyzed to fatty acid and the trivalent alcohol glycerol. When two molecules of a simple sugar such as dextrose unite to form a disaccharide, then also water is split off, and with the addition of water the double sugar may be broken into simple sugars again. Similarly starch is formed from sugar by a series of reactions in which water is removed. All of these reactions in which water is removed or added are catalyzed by the hydrolases. Proteolytic enzymes break down proteins to polypeptids and amino acids (or build up proteins from such compounds), lipases split fats into fatty acids and glycerol (or synthesize the fats from the fatty acids and glycerol), amylase acts on starch, sucrase (often called invertase) acts on sucrose, and there are other specific enzymes which act on the various isomers of sucrose. The hydrolases also include the lecithinases which split off fatty acids from the rest of the lecithin molecule, and the phosphatases. The latter split off phosphate from organic combination. Thus one phosphatase breaks glycerol phosphate into glycerol and phosphate; another group of phosphatase enzymes, the nucleotidases, break nucleotides into nucleosides and phosphoric acid. Most hydrolases are concerned primarily with the breakdown of large molecules as it occurs in digestion and with the synthesis of the breakdown products to form large molecules again in the cells. Such reactions are of primary importance in nutrition, but they yield little energy.
In addition to the hydrolases concerned primarily with nutrition, there are some hydrolases which play a part in other vital phenomena. Thus the enzyme cholinesterase, which hydrolyzes acetylcholine into choline and acetic acid, is believed to have great importance for nervous function. Another hydrolase enzyme which has excited great interest is hyaluronidase. This breaks down hyaluronic acid, a polysaccharide that tends to hold cells together. The enzyme is found in various bacteria; also in testis extracts. When skin is treated with hyaluronidase, the cells separate sufficiently to permit the spreading between them of substances like India ink. Heparin, like hyaluronic acid, is a mucopolysaccharide. There is apparently a heparinase which breaks up heparin or at least destroys its activity. Mention has already been made of the enzymes which specifically attack ribonucleic acid and desoxyribonucleic acid. These likewise are hydrolases.
The enzymes which cause coagulation or clotting, thrombin and rennin, may also be hydrolases. Thrombin causes clotting of vertebrate blood and rennin clots milk. They may both produce this effect as a result of proteolytic action.
Similar to the hydrolases are the phosphorylases. These enzymes, which should not be confused with the phosphatases, add phosphoric acid instead of water. They are very important in carbohydrate metabolism and will be discussed later in this connection.
Enzymes which act on inorganic pyrophosphates and hydrolyze them to orthophosphates are called pyrophosphatases. (This is a reaction which occurs even without the aid of enzymes.) Pyrophosphatases are found in many different types of living material.
In addition to the hydrolases there are various other categories of enzymes. There are enzymes which transfer a radical or group from one substance, the donor, to another, the acceptor. These have been called transferases, and they include the transaminases, which transfer amino groups; and the phosphokinases, which transfer phosphate groups.
An interesting enzyme found especially in the red blood cells of higher animals, is carbonic anhydrase. This catalyzes the reaction in which carbonic acid is split into carbon dioxide and water. Actually, the reaction is speeded in both directions, so that carbonic acid can be formed more rapidly as well as broken down. The reaction needs to be speeded in order to hasten the gain or loss of carbon dioxide from the blood.
Wednesday, December 5, 2007
Definition of Enzymes
The living machine is essentially a chemical engine, dependent for its growth, maintenance and energy on chemical reactions. These reactions are controlled by catalysts. One of the most striking achievements of modern biology and biological chemistry is the isolation of more and more of these catalysts so important for the vital process. Once isolated, it is possible to study their behavior in test tubes or other suitable containers. In other words, one can detach from the living material certain non-living substances capable of causing or promoting the complex chemical transformations which constitute a major part of the mystery of protoplasm.
Originally, enzymes were defined as "catalytic substances produced by living cells." With increase in knowledge and understanding, it has become necessary to restrict this definition. The original concept was that enzymes were not only produced by living things but were peculiar to them. There are some rather simple substances in protoplasm which can act catalytically; so for example, ascorbic acid, glutathione or as a matter of fact, even the hydrogen ion. The term enzyme was never meant to apply to these. Hence in modern usage an enzyme is defined as a "catalyst of biological origin, possessing a high molecular weight." In the light of what we now know, it is generally believed that all enzymes are proteins.
In as much as enzymes are catalysts, it is important to remember that they hasten rather than initiate reactions, and that when they act on reversible reactions they accelerate the progress of the reaction in either direction. Thus the same enzyme may synthesize as well as break down a complex chemical compound, and the very enzyme which digests proteins or fats or carbohydrates also serves, under the proper conditions, to build up these compounds from their breakdown products.
Originally, enzymes were defined as "catalytic substances produced by living cells." With increase in knowledge and understanding, it has become necessary to restrict this definition. The original concept was that enzymes were not only produced by living things but were peculiar to them. There are some rather simple substances in protoplasm which can act catalytically; so for example, ascorbic acid, glutathione or as a matter of fact, even the hydrogen ion. The term enzyme was never meant to apply to these. Hence in modern usage an enzyme is defined as a "catalyst of biological origin, possessing a high molecular weight." In the light of what we now know, it is generally believed that all enzymes are proteins.
In as much as enzymes are catalysts, it is important to remember that they hasten rather than initiate reactions, and that when they act on reversible reactions they accelerate the progress of the reaction in either direction. Thus the same enzyme may synthesize as well as break down a complex chemical compound, and the very enzyme which digests proteins or fats or carbohydrates also serves, under the proper conditions, to build up these compounds from their breakdown products.
Digestion--Enzymes
Whenever an organism consumes food in the solid state, this must be brought into solution before it can be utilized. It is necessary, therefore, that such solid food be digested. In some organisms, as pointed out in the last chapter, digestion may occur outside of the body, and this may constitute an important adaptation for those animals which are in the habit of eating animals larger than themselves. Ordinarily, however, food is taken into the body and digested there. Digestion may occur in cavities of special organs such as the stomach or intestine, or it may occur within the protoplasm of cells. The latter type of digestion obviously takes place in protozoa. In organisms such as paramecium or ameba the ingested food is enclosed in a food vacuole, which serves the same purpose as the stomach or intestine of a complicated metazoan. Within the food vacuole the solid food particle is brought into solution. It must not be thought, however, that intracellular digestion is confined to protozoa. In sponges, coelenterates, and flatworms, much of the solid food taken into the body is ingested by ameboid cells lining the walls of the digestive tract, and digestion takes place within the protoplasm of these cells rather than in the lumen of the digestive tube or cavity. Moreover, in some animals rather higher in the evolutionary scale, there is also a certain amount of intracellular digestion. In spiders and in arachnids generally, the digestion of protein, begun either outside the animal or in the digestive tract, is finally completed within the cells lining the tract. In clams and other lamellibranchs, the digestion of protein and fat has been thought to occur exclusively within cells. Both in lamellibranchs and echinoderms, amebocyte cells play an important role. These phagocytic cells even enter into the lumen of the stomach or intestine, ingest particles of food there and then carry these food particles back into the tissues and digest them there. Such intracellular digestion, however, is a primitive character and it does not occur to any extent in higher animals such as the insects and vertebrates.
In the conversion of solid food to a state of solution, enzymes play the leading role. It will be necessary, therefore, to consider the subject of enzymes and the nature of enzyme action. It should be strongly emphasized, however, that enzymes are not concerned only with digestion, but that they are essential factors in all of the chemical activities of the organism. Our discussion at this point will be somewhat parenthetical. It will also be brief; indeed, it would scarcely be possible to present an up to date summary of enzyme chemistry in the space of a single chapter. The subject has grown so rapidly that it has become a science by itself (enzymology), and the modern books on enzymes are heavy with information.
In the conversion of solid food to a state of solution, enzymes play the leading role. It will be necessary, therefore, to consider the subject of enzymes and the nature of enzyme action. It should be strongly emphasized, however, that enzymes are not concerned only with digestion, but that they are essential factors in all of the chemical activities of the organism. Our discussion at this point will be somewhat parenthetical. It will also be brief; indeed, it would scarcely be possible to present an up to date summary of enzyme chemistry in the space of a single chapter. The subject has grown so rapidly that it has become a science by itself (enzymology), and the modern books on enzymes are heavy with information.
Metazoa
Most many-celled animals take solid food into some cavity within their bodies, in which it is dissolved or digested. This is not always the case, however. There are quite a few organisms which are able to digest their food outside of their bodies. Thus a starfish or sea urchin may pour digestive juices out over some fish or other large animal which it has captured. It is sometimes possible for an animal to eat other animals larger than itself. When a spider captures a fly, it pours digestive juices into the body of its prey and then sucks out the dissolved interior. Many parasitic animals require no digestive apparatus. In the case of animals such as tapeworms, there is no need for the ingestion of solid food, and the dissolved food substances in the alimentary canal of the host pass directly through the body wall of the animal. Other worms derive food in the same manner from the blood of their hosts.
Some authors have tried to classify animals on the basis of their methods of ingestion. Thus there have been distinctions between whirlers (ciliary feeders), snarers, scrapers and suckers. Small particles are often pulled into the body by ciliary action. This occurs not only in the protozoa, but also in practically every other phylum, except the arthropoda. Ciliary mechanisms for feeding are most highly developed in the mollusca. Tentacles and setae are also used in obtaining small particles. The animals that feed on large particles or masses have mechanisms for swallowing inactive food, for seizing prey, or for scraping and boring.
The usual form of ingestion in metazoa involves some sort of passage into the mouth. Jaws and teeth of various types may aid in the capture and in the subdivision of the food. The earthworm has a pharynx which is pulled on by muscles attached to its outer wall so that it can behave as a suction pump. Marine (polychaete) worms also may have sucking pumps. Thus in Autolytus the proventriculus, by its pulsations (120 per minute), produces a strong inward current of water and food. Sucking pumps also occur in insects of various orders, and these pumps may have a rather complicated structure. Even in the case of those animals which ingest food through the mouth there is sometimes a possibility that food may be taken in through the body wall.
Some authors have tried to classify animals on the basis of their methods of ingestion. Thus there have been distinctions between whirlers (ciliary feeders), snarers, scrapers and suckers. Small particles are often pulled into the body by ciliary action. This occurs not only in the protozoa, but also in practically every other phylum, except the arthropoda. Ciliary mechanisms for feeding are most highly developed in the mollusca. Tentacles and setae are also used in obtaining small particles. The animals that feed on large particles or masses have mechanisms for swallowing inactive food, for seizing prey, or for scraping and boring.
The usual form of ingestion in metazoa involves some sort of passage into the mouth. Jaws and teeth of various types may aid in the capture and in the subdivision of the food. The earthworm has a pharynx which is pulled on by muscles attached to its outer wall so that it can behave as a suction pump. Marine (polychaete) worms also may have sucking pumps. Thus in Autolytus the proventriculus, by its pulsations (120 per minute), produces a strong inward current of water and food. Sucking pumps also occur in insects of various orders, and these pumps may have a rather complicated structure. Even in the case of those animals which ingest food through the mouth there is sometimes a possibility that food may be taken in through the body wall.
Feeding habits of protozoa
Feeding habits of protozoa vary widely. Some contain chlorophyll and behave essentially like plants. Thus the various species of Euglena are able to manufacture starch from simple inorganic materials. These forms and also ciliates without mouths, such as the Opalinidae, are able to absorb food materials through their surfaces. In all of the sporozoa, moreover, food enters the organism through the body wall. These forms are parasites and live on the organic materials provided by their hosts.
Most ciliates and flagellates have definite mouths, but it does not follow that all of the food taken up by these organisms passes through the mouth opening. In flagellates, especially, it seems probable that much of the food enters the cell by diffusion through the body wall. Ciliates like paramecium sweep food particles into their gullet by the beat of their cilia. Although various useless materials may enter the gullet and pass into the cell, there is apparently some power of discrimination.
The ingestion of food by ameba is essentially the same process as that which occurs when leukocytes or other ameboid cells take up foreign particles. Such phagocytosis occurs in practically all metazoa, and is of great importance both in the normal life of animals and in the resistance of animals to disease. Phagocytosis plays an essential role in metamorphosis and, both in insects and in amphibia, larval organs are destroyed bit by bit by the ameboid cells which ingest them. Because of its importance as a protection against disease, phagocytosis has been very widely studied by bacteriologists, pathologists, and students of medical sciences generally. Just as amebae select their food, so do leukocytes exercise a selection of the particles they ingest. The rate of ingestion of bacteria by leukocytes has often been studied under a variety of conditions. Bacteriologists have tried to obtain quantitative data by determining either the number of bacilli taken up per leukocyte or the percentage of leukocytes participating. Important factors (not always properly considered) are the absolute and relative concentrations of bacteria and leukocytes. Phagocytosis increases with increase in the number of bacteria, but the rate of ingestion does not keep pace with the increasing possibilities for collision between bacteria and leukocytes. Various authors have studied the effect of temperature on phagocytosis; curves are obtained like those found for ingestion of food by ameba. Any explanation of the mechanism of phagocytosis could at the same time serve as an explanation of the ingestion of food by ameba. At the present time, however, none of the theories of phagocytosis seems very satisfactory.
In higher animals, phagocytosis is not restricted to leukocytes. Scattered through various tissues and organs of the animal are numerous cells capable of ingesting solid objects. Of these, the macrophages move somewhat more freely than the histiocytes, and there are also morphological differences between the two types of cells. Together, they constitute the reticuloendothelial system.
Most ciliates and flagellates have definite mouths, but it does not follow that all of the food taken up by these organisms passes through the mouth opening. In flagellates, especially, it seems probable that much of the food enters the cell by diffusion through the body wall. Ciliates like paramecium sweep food particles into their gullet by the beat of their cilia. Although various useless materials may enter the gullet and pass into the cell, there is apparently some power of discrimination.
The ingestion of food by ameba is essentially the same process as that which occurs when leukocytes or other ameboid cells take up foreign particles. Such phagocytosis occurs in practically all metazoa, and is of great importance both in the normal life of animals and in the resistance of animals to disease. Phagocytosis plays an essential role in metamorphosis and, both in insects and in amphibia, larval organs are destroyed bit by bit by the ameboid cells which ingest them. Because of its importance as a protection against disease, phagocytosis has been very widely studied by bacteriologists, pathologists, and students of medical sciences generally. Just as amebae select their food, so do leukocytes exercise a selection of the particles they ingest. The rate of ingestion of bacteria by leukocytes has often been studied under a variety of conditions. Bacteriologists have tried to obtain quantitative data by determining either the number of bacilli taken up per leukocyte or the percentage of leukocytes participating. Important factors (not always properly considered) are the absolute and relative concentrations of bacteria and leukocytes. Phagocytosis increases with increase in the number of bacteria, but the rate of ingestion does not keep pace with the increasing possibilities for collision between bacteria and leukocytes. Various authors have studied the effect of temperature on phagocytosis; curves are obtained like those found for ingestion of food by ameba. Any explanation of the mechanism of phagocytosis could at the same time serve as an explanation of the ingestion of food by ameba. At the present time, however, none of the theories of phagocytosis seems very satisfactory.
In higher animals, phagocytosis is not restricted to leukocytes. Scattered through various tissues and organs of the animal are numerous cells capable of ingesting solid objects. Of these, the macrophages move somewhat more freely than the histiocytes, and there are also morphological differences between the two types of cells. Together, they constitute the reticuloendothelial system.
Vitamins of the B Complex
B 13 has been described as a growth factor for rats and for pigs. There is also a description of a vitamin B 14, extracted from urine.
Over the years, there has been a large and controversial literature about what has been called vitamin P. Substances with vitamin P activity are supposed to maintain proper permeability of the blood capillaries of higher animals and to prevent excessive loss of fluid from them. (The letter P is due to this permeability action.) There is now general agreement that substances with P activity are not to be considered as vitamins. At least this is the judicial opinion of the American Society of Biological Chemists.
Para-aminobenzoic acid (often called paba). This relatively simple compound is an important growth factor for many bacteria. As previously noted, it forms part of the folic acid molecule. Para-aminobenzoic acid and sulfanilamide are very close chemically, as is apparent from their structural formulae:
Thus sulfanilamide is an antagonistic analogue of para-aminobenzoic acid, and its antibacterial action is due to this similarity in structure. Choline. This substance, the basic constituent of lecithin, is believed by many to be a vitamin. Rats deprived of choline develop fatty livers and other types of hepatic injury. They may also show degenerative changes in the kidney. Choline deficiency is also a factor in the development of a leg deficiency (perosis) in chicks and turkeys.
It should be remembered that choline is a constituent not only of lecithin, but also of the important humoral substance, acetylcholine. Inositol. Inositol is a derivative of benzene. It can be prepared from hexahydroxy-benzene by reduction, in the course of which 6 hydrogen atoms are added. Thus inositol is hexahydroxy-hexahydro-benzene. It is an optically active substance found in yeast, muscle, and in various other types of animal and plant tissue.
Inositol is important for the growth of yeasts, and is indispensable for some types of yeast. It also promotes the growth of some fungi. In the presence of inositol, chicks grow more rapidly than when it is absent. However, rats may be bred for three generations without inositol, and György was led to conclude that "the facts presented do not, at the present time, warrant the identification of inositol as a primary and really essential vitamin; they rather favor the assumption that it is a supporting and at least not always specific vitamin." a-Lipoic Acid. This substance, also called protogen, is probably to be included among the vitamins of the B group, for it is water soluble. It is important for the growth of some bacteria and for the protozoan Tetrahymena, and it is involved in the oxidation of the important keto acid, pyruvic acid (for this reason it was formerly called pyruvate oxidase factor). Many types of living material contain a-lipoic acid. It is now known to be a derivative of octanoic (caprylic) acid and it contains sulfur in the form of an S-S group.
Throughout the course of vitamin study, there have indeed been many extravagant claims and many false leads. The vast literature is often contradictory and confused. But in spite of this, in the course of time the truth has gradually emerged and the main outlines of the picture are now clear. All sorts of organisms, from bacteria to man, require certain specific types of organic molecules. These can be synthesized by green plants and by many lower organisms. Higher forms have frequently lost the power for such synthesis, and unless, like the ruminants, they provide themselves with huge storehouses for bacteria, they must depend for their existence on obtaining the vitamins with their food.
From the knowledge of the nature of the vitamins, we can begin to develop a chemical anatomy of living systems. The vitamins represent indispensable organic molecules and apparently the same molecules are almost universally needed. Moreover, we are beginning to discover why the vitamins are needed and what work they do in the living cell.
Much of our information is still fragmentary. The vitamin requirements for the lower vertebrates and for the hosts of invertebrate animals have scarcely been investigated at all. Moreover, in some instances we are completely at a loss to account for the fundamental necessity for a given vitamin. Such superficial disturbances as a reddening of the eye or a scaliness of the skin give no direct indication of the part a vitamin may play in protoplasmic activity.
Over the years, there has been a large and controversial literature about what has been called vitamin P. Substances with vitamin P activity are supposed to maintain proper permeability of the blood capillaries of higher animals and to prevent excessive loss of fluid from them. (The letter P is due to this permeability action.) There is now general agreement that substances with P activity are not to be considered as vitamins. At least this is the judicial opinion of the American Society of Biological Chemists.
Para-aminobenzoic acid (often called paba). This relatively simple compound is an important growth factor for many bacteria. As previously noted, it forms part of the folic acid molecule. Para-aminobenzoic acid and sulfanilamide are very close chemically, as is apparent from their structural formulae:
Thus sulfanilamide is an antagonistic analogue of para-aminobenzoic acid, and its antibacterial action is due to this similarity in structure. Choline. This substance, the basic constituent of lecithin, is believed by many to be a vitamin. Rats deprived of choline develop fatty livers and other types of hepatic injury. They may also show degenerative changes in the kidney. Choline deficiency is also a factor in the development of a leg deficiency (perosis) in chicks and turkeys.
It should be remembered that choline is a constituent not only of lecithin, but also of the important humoral substance, acetylcholine. Inositol. Inositol is a derivative of benzene. It can be prepared from hexahydroxy-benzene by reduction, in the course of which 6 hydrogen atoms are added. Thus inositol is hexahydroxy-hexahydro-benzene. It is an optically active substance found in yeast, muscle, and in various other types of animal and plant tissue.
Inositol is important for the growth of yeasts, and is indispensable for some types of yeast. It also promotes the growth of some fungi. In the presence of inositol, chicks grow more rapidly than when it is absent. However, rats may be bred for three generations without inositol, and György was led to conclude that "the facts presented do not, at the present time, warrant the identification of inositol as a primary and really essential vitamin; they rather favor the assumption that it is a supporting and at least not always specific vitamin." a-Lipoic Acid. This substance, also called protogen, is probably to be included among the vitamins of the B group, for it is water soluble. It is important for the growth of some bacteria and for the protozoan Tetrahymena, and it is involved in the oxidation of the important keto acid, pyruvic acid (for this reason it was formerly called pyruvate oxidase factor). Many types of living material contain a-lipoic acid. It is now known to be a derivative of octanoic (caprylic) acid and it contains sulfur in the form of an S-S group.
Throughout the course of vitamin study, there have indeed been many extravagant claims and many false leads. The vast literature is often contradictory and confused. But in spite of this, in the course of time the truth has gradually emerged and the main outlines of the picture are now clear. All sorts of organisms, from bacteria to man, require certain specific types of organic molecules. These can be synthesized by green plants and by many lower organisms. Higher forms have frequently lost the power for such synthesis, and unless, like the ruminants, they provide themselves with huge storehouses for bacteria, they must depend for their existence on obtaining the vitamins with their food.
From the knowledge of the nature of the vitamins, we can begin to develop a chemical anatomy of living systems. The vitamins represent indispensable organic molecules and apparently the same molecules are almost universally needed. Moreover, we are beginning to discover why the vitamins are needed and what work they do in the living cell.
Much of our information is still fragmentary. The vitamin requirements for the lower vertebrates and for the hosts of invertebrate animals have scarcely been investigated at all. Moreover, in some instances we are completely at a loss to account for the fundamental necessity for a given vitamin. Such superficial disturbances as a reddening of the eye or a scaliness of the skin give no direct indication of the part a vitamin may play in protoplasmic activity.
Vitamin B 12
Year by year, the number of B vitamins increases. B 10 and B 11 are required by chicks, the former for proper feathering, the latter for growth. From liver it has been possible to isolate a pink crystalline substance which can be used to cure pernicious anemia. Folic acid is useful in this disease, for it has a hematopoietic effect (that is to say, it favors increased production of blood cells), but it does not correct the nervous symptoms of the disease. These depend on degenerative changes in the nervous system. Vitamin B 12 in tiny amounts has been thought to correct diseases of both blood and nervous systems, but apparently if the nervous system is badly affected, it can not be cured. The vitamin has been crystallized. It contains 4-4.5 per cent cobalt and also phosphorus; the molecular weight is approximately 1500. (Estimates vary from 1300 to 1600.) In liver extracts there are really two active substances with slightly different absorption spectra. One of these is the definitive B 12, the other is B 12b. (B 12a is another similar substance derived from B 12 by hydrogenation.)
Vitamin B 12 is apparently identical with what has been called "animal protein factor." This was originally obtained from such diverse sources as milk, muscle, liver and cow manure. Although called animal protein factor, it can likewise be obtained from plant sources. Both animal protein factor and vitamin B 12 promote growth in some bacteria, in chickens, rats and mice. The effect on growth may be due to the fact that the vitamin seems to increase the utilization of amino acids. At any rate, this has been reported for chicks.
Vitamin B 12 is apparently identical with what has been called "animal protein factor." This was originally obtained from such diverse sources as milk, muscle, liver and cow manure. Although called animal protein factor, it can likewise be obtained from plant sources. Both animal protein factor and vitamin B 12 promote growth in some bacteria, in chickens, rats and mice. The effect on growth may be due to the fact that the vitamin seems to increase the utilization of amino acids. At any rate, this has been reported for chicks.
Folic acid
This vitamin occurs in green leaves; hence the name, which is taken from the Latin word for leaf. Folic acid also occurs in mushrooms and yeast; and in animal tissues, such as liver and kidney. The vitamin has been called by many different names, and it exists in various forms. These have different potencies for different types of organisms.
Chemically, folic acid consists of pteroic acid combined with the common amino acid, glutamic acid. Pteroic acid itself is a combination of para-aminobenzoic acid and a pteridine base. Pteridine bases are pyrimidine derivatives related to the pyrimidine bases thymine and uracil found in the nucleic acids. The formula of folic acid is given below:
The compound shown above is pteroylglutamic acid, sometimes called PGA. Pteroic acid may also combine with 3 glutamic acid groups to form pteroyltriglutarnic acid (P3GA) or with 7 molecules of glutamic acid to form pteroylheptaglutamic acid (P7GA). All of these compounds are found naturally and all have vitamin activity for certain types of living materials.
Folic acid is required by some bacteria, by certain ciliate protozoal, by some insects and by various birds and mammals. The bacteria in the rat intestine normally manufacture a sufficient quantity of the vitamin, and treatment with antibiotics such as sulfa drugs is necessary to cause folic acid deficiency. Folic acid is commonly an essential growth factor, not only for bacteria but for higher organisms as well. Lack of the vitamin in mammals results in various ailments, but especially in a type of anemia characterized by a small number of red blood cells of large size. This type of anemia, called macrocytic anemia, occurs in the tropical disease sprue, and sprue can be cured either by liver extract (which contains folic acid) or by folic acid itself. Folic acid is apparently important both for growth and cell division. When chick embryos are in contact with antagonistic analogues such as 4amino folic acid, their growth is greatly retarded. Similar results have been obtained in numerous other studies with folic acid antagonists. Thus 4-amino folic acid has a retarding effect on tumor growth.
A substance related to folic acid is the so-called "citrovorum factor," 45 which is apparently identical with "folinic acid." This factor favors growth of the bacterium, Leuconostoc citrovorum. The citrovorum factor may be obtained from liver extracts; also it is excreted into the urine of rats or men fed folic acid.
Chemically, folic acid consists of pteroic acid combined with the common amino acid, glutamic acid. Pteroic acid itself is a combination of para-aminobenzoic acid and a pteridine base. Pteridine bases are pyrimidine derivatives related to the pyrimidine bases thymine and uracil found in the nucleic acids. The formula of folic acid is given below:
The compound shown above is pteroylglutamic acid, sometimes called PGA. Pteroic acid may also combine with 3 glutamic acid groups to form pteroyltriglutarnic acid (P3GA) or with 7 molecules of glutamic acid to form pteroylheptaglutamic acid (P7GA). All of these compounds are found naturally and all have vitamin activity for certain types of living materials.
Folic acid is required by some bacteria, by certain ciliate protozoal, by some insects and by various birds and mammals. The bacteria in the rat intestine normally manufacture a sufficient quantity of the vitamin, and treatment with antibiotics such as sulfa drugs is necessary to cause folic acid deficiency. Folic acid is commonly an essential growth factor, not only for bacteria but for higher organisms as well. Lack of the vitamin in mammals results in various ailments, but especially in a type of anemia characterized by a small number of red blood cells of large size. This type of anemia, called macrocytic anemia, occurs in the tropical disease sprue, and sprue can be cured either by liver extract (which contains folic acid) or by folic acid itself. Folic acid is apparently important both for growth and cell division. When chick embryos are in contact with antagonistic analogues such as 4amino folic acid, their growth is greatly retarded. Similar results have been obtained in numerous other studies with folic acid antagonists. Thus 4-amino folic acid has a retarding effect on tumor growth.
A substance related to folic acid is the so-called "citrovorum factor," 45 which is apparently identical with "folinic acid." This factor favors growth of the bacterium, Leuconostoc citrovorum. The citrovorum factor may be obtained from liver extracts; also it is excreted into the urine of rats or men fed folic acid.
Biotin
As long ago as 1898 it was shown that if dogs were fed raw egg white, diarrhea resulted. Following this it was shown that other mammals also suffered from egg white feeding, and that in addition to the diarrhea, skin ailments and nervous symptoms appeared. The phenomenon became known as egg white injury. Cooking the egg white prevented the injury. György proposed the term vitamin H for a factor which prevented egg white injury. Later, it was shown that this factor is identical with biotin, a vitamin known to be important for yeasts and microorganisms. The raw egg white unites with the biotin and prevents its utilization by mammals or birds.
Chemically, biotin is rather complicated. It has in its molecule a urea ring containing one sulfur atom; the ring is combined with a valeric acid group. The presence of sulfur in the molecule is not important for the vitamin activity, for if the sulfur is replaced by oxygen, the vitamin activity is retained. The formula of biotin is given below:
Biotin acts in extremely low concentration, and it is thus one of the most potent of the vitamins. Many organisms do not grow unless biotin is available for them. Usually in higher organisms it is synthesized in sufficient quantity, but biotin deficiency can occur naturally in birds and in insects. Lack of sufficient biotin has the same effect as egg white injury--diarrhea, disturbances in the skin and nervous system, in rats loss of hair about the eyes. It can also prevent the birth of young in rats. The protein in egg white which binds biotin is called avidin; it is a basic, carbohydrate-containing protein and it occurs not only in the eggs of birds but also in frog eggs.
There is now strong evidence that biotin is important in a process which is known as carbon dioxide fixation. Many bacteria, and higher organisms also, are able to utilize carbon dioxide and form organic compounds from it. This process is interfered with if biotin is lacking.
Chemically, biotin is rather complicated. It has in its molecule a urea ring containing one sulfur atom; the ring is combined with a valeric acid group. The presence of sulfur in the molecule is not important for the vitamin activity, for if the sulfur is replaced by oxygen, the vitamin activity is retained. The formula of biotin is given below:
Biotin acts in extremely low concentration, and it is thus one of the most potent of the vitamins. Many organisms do not grow unless biotin is available for them. Usually in higher organisms it is synthesized in sufficient quantity, but biotin deficiency can occur naturally in birds and in insects. Lack of sufficient biotin has the same effect as egg white injury--diarrhea, disturbances in the skin and nervous system, in rats loss of hair about the eyes. It can also prevent the birth of young in rats. The protein in egg white which binds biotin is called avidin; it is a basic, carbohydrate-containing protein and it occurs not only in the eggs of birds but also in frog eggs.
There is now strong evidence that biotin is important in a process which is known as carbon dioxide fixation. Many bacteria, and higher organisms also, are able to utilize carbon dioxide and form organic compounds from it. This process is interfered with if biotin is lacking.
Pantothenic acid
Pantothenic acid is found in many diverse types of living materials. Chemically, it consists of ß-alanine in a peptid linkage with a dihydroxy acid. (ß-alanine differs from ordinary alanine in being ß-aminopropionic acid instead of α-aminopropionic acid.) The formula of pantothenic acid is given below:
The acid is unstable and for this reason is sold as a calcium salt. This salt is a white powder, readily soluble in water but not in alcohol.
Many organisms from bacteria and protozoa to higher mammals require pantothenic acid. In its absence these organisms do not grow properly and they may show various ill effects. Symptoms of pantothenic acid deficiency include dermatitis (inflammation of the skin) in rats, deficient feathering in chicks, graying of hair in rats, degeneration of the nervous system in pigs, hemorrhages in the adrenal gland and general disturbance of function of this gland, etc.
The vitamin constitutes part of an enzyme system. Combined with various substances including phosphate, adenylic acid, and a sulfhydryl group, it is coenzyme A, and this in combination with a protein is an enzyme capable of acetylating various organic substances such as choline and sulfanilamide. The acetylation of choline may be very important physiologically. How the acetylation, or rather the lack of it, can produce all the pathological conditions noted above is not clear, although in the case of the nervous system, any alteration of acetylcholine metabolism would certainly be harmful.
The acid is unstable and for this reason is sold as a calcium salt. This salt is a white powder, readily soluble in water but not in alcohol.
Many organisms from bacteria and protozoa to higher mammals require pantothenic acid. In its absence these organisms do not grow properly and they may show various ill effects. Symptoms of pantothenic acid deficiency include dermatitis (inflammation of the skin) in rats, deficient feathering in chicks, graying of hair in rats, degeneration of the nervous system in pigs, hemorrhages in the adrenal gland and general disturbance of function of this gland, etc.
The vitamin constitutes part of an enzyme system. Combined with various substances including phosphate, adenylic acid, and a sulfhydryl group, it is coenzyme A, and this in combination with a protein is an enzyme capable of acetylating various organic substances such as choline and sulfanilamide. The acetylation of choline may be very important physiologically. How the acetylation, or rather the lack of it, can produce all the pathological conditions noted above is not clear, although in the case of the nervous system, any alteration of acetylcholine metabolism would certainly be harmful.
Vitamin B6: pyridoxine, pyridoxal, pyridoxamine
The term vitamin B6 is now properly used, according to a decision of the American Society of Biological Chemists, to designate three naturally occurring substances: pyridoxine, pyridoxal and pyridoxamine. The formulae of these substances are given below:
Pyridoxine is 2-methyl-3-hydroxy-4,5-dihydroxymethyl pyridine. Pyridoxal is the aldehyde derivative of pyridoxine and has a formyl group instead of a hydroxymethyl group at the 4 position. Pyridoxamine is an amino derivative and has an amino methyl instead of a hydroxymethyl group at the 4 position. The three forms of the vitamin are almost equally effective for higher animals, but some bacteria
have specific requirements for one form or the other. Vitamin B 6 is needed by many bacteria, by some protozoa, and by most of the insects whose vitamin requirements have been investigated.
When rats are deprived of vitamin B 6, they develop a painful inflammation of the skin. This is especially evident in the skin of the extremities--the paws, snout, and ears. The ailment is sometimes called rat acrodynia because of a supposed similarity to a human ailment in which the nerves and skin of the hands and feet are affected. The disease is not wholly specific for vitamin B 6 deficiency; it can be produced also in other ways, for example by a lack of unsaturated fatty acids. In various higher animals, convulsions may follow extreme vitamin B 6 deficiency. Sometimes lack of the vitamin causes muscular weakness; it can also cause anemia.
Vitamin B 6 deficiency can be induced by the addition of an antagonistic analogue, desoxypyridoxine. Thus if this compound is injected into hens' eggs, the embryos do not proceed very far in their development.
Vitamin B 6 is important for the proper metabolism of the amino acids. It forms part of an enzyme system which promotes the synthesis of amino acids by the addition of carboxyl groups. Acting as part of what is presumably the same enzyme system, the vitamin also favors the removal of carboxyl groups from amino acids. Another type of enzyme for which vitamin B 6 is an important constituent is transaminase. This enzyme catalyzes the transfer of an amino group from one amino acid to another; an important type of reaction in protein metabolism. Thus there is some important information as to how the vitamin functions with respect to the chemical reactions occurring during the metabolism of proteins and amino acids, but how this is related to the disturbances which occur in skin, nerves, muscle and blood when the vitamin is lacking has yet to be explained. It has been claimed, on the basis of isolation studies of mitochondria, that these granules contain especially large amounts of vitamin B 6. However, it is the nucleoprotein-containing granules of the cytoplasm that are believed to be especially important for protein metabolism.
Pyridoxine is 2-methyl-3-hydroxy-4,5-dihydroxymethyl pyridine. Pyridoxal is the aldehyde derivative of pyridoxine and has a formyl group instead of a hydroxymethyl group at the 4 position. Pyridoxamine is an amino derivative and has an amino methyl instead of a hydroxymethyl group at the 4 position. The three forms of the vitamin are almost equally effective for higher animals, but some bacteria
have specific requirements for one form or the other. Vitamin B 6 is needed by many bacteria, by some protozoa, and by most of the insects whose vitamin requirements have been investigated.
When rats are deprived of vitamin B 6, they develop a painful inflammation of the skin. This is especially evident in the skin of the extremities--the paws, snout, and ears. The ailment is sometimes called rat acrodynia because of a supposed similarity to a human ailment in which the nerves and skin of the hands and feet are affected. The disease is not wholly specific for vitamin B 6 deficiency; it can be produced also in other ways, for example by a lack of unsaturated fatty acids. In various higher animals, convulsions may follow extreme vitamin B 6 deficiency. Sometimes lack of the vitamin causes muscular weakness; it can also cause anemia.
Vitamin B 6 deficiency can be induced by the addition of an antagonistic analogue, desoxypyridoxine. Thus if this compound is injected into hens' eggs, the embryos do not proceed very far in their development.
Vitamin B 6 is important for the proper metabolism of the amino acids. It forms part of an enzyme system which promotes the synthesis of amino acids by the addition of carboxyl groups. Acting as part of what is presumably the same enzyme system, the vitamin also favors the removal of carboxyl groups from amino acids. Another type of enzyme for which vitamin B 6 is an important constituent is transaminase. This enzyme catalyzes the transfer of an amino group from one amino acid to another; an important type of reaction in protein metabolism. Thus there is some important information as to how the vitamin functions with respect to the chemical reactions occurring during the metabolism of proteins and amino acids, but how this is related to the disturbances which occur in skin, nerves, muscle and blood when the vitamin is lacking has yet to be explained. It has been claimed, on the basis of isolation studies of mitochondria, that these granules contain especially large amounts of vitamin B 6. However, it is the nucleoprotein-containing granules of the cytoplasm that are believed to be especially important for protein metabolism.
Nicotinic acid: Niacin
Nicotinic acid and pyridoxine are closely related substances. Both are derivatives of pyridine. This substance is a weak base, the molecule of which contains five CH-groups and a nitrogen atom arranged in a six-membered ring. As is customary with ring compounds, the various positions on the ring have numbers. In pyridine, nitrogen occupies the number 1 position. Nicotinic acid is 3-pyridine carboxylic acid. The structural formulas of the acid and its amide are given below:
The amide is more important than the acid itself, for some organisms require it and cannot manufacture it from the acid. Both acid and amide are white crystalline powders, without odor.
Nicotinic acid is one of the commonest growth factors needed by bacteria; in other words the ability to synthesize it is one most frequently lost. This may be due to its very wide distribution in soil and natural media. It is an essential requirement for those ciliate protozoa that have been studied (Colpoda and Tetrahymena) and also for most of the insects that have been investigated. Nicotinic acid is essential for the dog, the pig, and for man. However, if enough tryptophan is added to the diet, neither dog nor pig requites it. As noted previously, tryptophan is a precursor of nicotinic acid, and the tissues can synthesize the vitamin from tryptophan.
From a lack of nicotinic acid, dogs become afflicted with what is known as blacktongue disease. In man, nicotinic acid deficiency is the primary cause of pellagra. This serious disease, common enough in the United States, involves the lining of the digestive tract, the skin, and the nervous system.
Nicotinic acid amide enters into the composition of two substances of great importance for the oxidative metabolism of the cell. These are coenzyme I and coenzyme II. Presumably nicotinic acid deficiency is associated with a lack in the tissues of coenzymes I and II. But what connection there is between such a lack and the manifold disturbances present in a disease like pellagra is not at all clear.
The amide is more important than the acid itself, for some organisms require it and cannot manufacture it from the acid. Both acid and amide are white crystalline powders, without odor.
Nicotinic acid is one of the commonest growth factors needed by bacteria; in other words the ability to synthesize it is one most frequently lost. This may be due to its very wide distribution in soil and natural media. It is an essential requirement for those ciliate protozoa that have been studied (Colpoda and Tetrahymena) and also for most of the insects that have been investigated. Nicotinic acid is essential for the dog, the pig, and for man. However, if enough tryptophan is added to the diet, neither dog nor pig requites it. As noted previously, tryptophan is a precursor of nicotinic acid, and the tissues can synthesize the vitamin from tryptophan.
From a lack of nicotinic acid, dogs become afflicted with what is known as blacktongue disease. In man, nicotinic acid deficiency is the primary cause of pellagra. This serious disease, common enough in the United States, involves the lining of the digestive tract, the skin, and the nervous system.
Nicotinic acid amide enters into the composition of two substances of great importance for the oxidative metabolism of the cell. These are coenzyme I and coenzyme II. Presumably nicotinic acid deficiency is associated with a lack in the tissues of coenzymes I and II. But what connection there is between such a lack and the manifold disturbances present in a disease like pellagra is not at all clear.
Riboflavin Vitamin B2 Vitamin G
Riboflavin is an orange crystalline substance, sparingly soluble in water, and markedly sensitive to light. The riboflavin molecule is complex. The structural formula follows:
The three rings represent an isoalloxazine constituent and this is combined with ribose, the pentose sugar also present in ribonucleic acids.
Although riboflavin is apparently a constituent of all or almost all types of protoplasm, many lower organisms do not require it in their food. Yeasts and molds have no need for it. Bacteria, in general, can get along without it. However, riboflavin serves as a growth factor for the tetanus bacillus, for lactic acid and propionic acid bacteria, and it is a requirement for Erysipelothrix rhusiopathiae and Listerella monocytogenes. The protozoan ciliates that have been investigated require riboflavin. So, too, do almost all the insects that have been studied. Riboflavin is essential for the growth and normal health of the rat, mouse, dog, pig, man, chicken and turkey. In riboflavin deficiency, various symptoms of ill health may appear. These include redness and roughness of the cornea of the eye, soreness at the corners of the lips, redness and soreness of the tongue, etc. At one time, it was thought that "ariboflavinosis," the disease caused by riboflavin deficiency, was extremely common. But the symptoms mentioned above are not always due to lack of riboflavin.
The presence of riboflavin in cells may be detected by fluorescence microscopy. Riboflavin is important for cell respiration. It and other alloxazine compounds combine with phosphoric acid and protein to form enzyme systems known as flavoproteins.
The three rings represent an isoalloxazine constituent and this is combined with ribose, the pentose sugar also present in ribonucleic acids.
Although riboflavin is apparently a constituent of all or almost all types of protoplasm, many lower organisms do not require it in their food. Yeasts and molds have no need for it. Bacteria, in general, can get along without it. However, riboflavin serves as a growth factor for the tetanus bacillus, for lactic acid and propionic acid bacteria, and it is a requirement for Erysipelothrix rhusiopathiae and Listerella monocytogenes. The protozoan ciliates that have been investigated require riboflavin. So, too, do almost all the insects that have been studied. Riboflavin is essential for the growth and normal health of the rat, mouse, dog, pig, man, chicken and turkey. In riboflavin deficiency, various symptoms of ill health may appear. These include redness and roughness of the cornea of the eye, soreness at the corners of the lips, redness and soreness of the tongue, etc. At one time, it was thought that "ariboflavinosis," the disease caused by riboflavin deficiency, was extremely common. But the symptoms mentioned above are not always due to lack of riboflavin.
The presence of riboflavin in cells may be detected by fluorescence microscopy. Riboflavin is important for cell respiration. It and other alloxazine compounds combine with phosphoric acid and protein to form enzyme systems known as flavoproteins.
Thiamine: Vitamin B1
The formula for thiamine is C 12 H 18 N 4 OS. It is prepared synthetically as the chloride hydrochloride. This is a white crystalline compound readily soluble in water. Thiamine is a combination of a pyrimidine ring and a sulfur-containing thiazole ring. The structural formula of the chloride hydrochloride is as follows:
Apparently all sorts of protoplasm need thiamine. Some types of cells can synthesize it, others can not. Higher organisms generally require the intact thiamine molecule; on the other hand some lower organisms are able to synthesize thiamine provided they can obtain both parts of the molecule, pyrimidine and thiazole. Other organisms may require either the pyrimidine fraction or the thiazole fraction, but not both. Many bacteria require neither and can synthesize whatever thiamine they need.
Lack of thiamine in the diet produces beriberi, a paralytic disease of men rather common in Japan and in various other portions of the world. In birds, lack of thiamine produces polyneuritis, a disease similar to beriberi. In this disease the nerve fibers show degenerative changes.
Experimentally, it has been shown that a similar paralysis could be produced in chicks, cats, pigeons and rats. The effect is due to the fact that some species of fish contain in their tissues an enzyme, thiaminase, which destroys thiamine. Thiaminase is found not only in fish but also in clams. In addition to its effect on the nervous system, lack of thiamine may also cause retardation of growth. Thiamine is important for the utilization of carbohydrate. Combined with 2 phosphate groups as diphosphothiamine, it forms part of an enzyme system that acts on pyruvic acid, a keto acid of great importance in intermediary metabolism. When animals are deprived of thiamine, their tissues are unable to oxidize pyruvic acid. Thiamine is also important in the transmission of the nerve impulse. When isolated nerves are stimulated, they are believed to release thiamine to the surrounding solution.
Apparently all sorts of protoplasm need thiamine. Some types of cells can synthesize it, others can not. Higher organisms generally require the intact thiamine molecule; on the other hand some lower organisms are able to synthesize thiamine provided they can obtain both parts of the molecule, pyrimidine and thiazole. Other organisms may require either the pyrimidine fraction or the thiazole fraction, but not both. Many bacteria require neither and can synthesize whatever thiamine they need.
Lack of thiamine in the diet produces beriberi, a paralytic disease of men rather common in Japan and in various other portions of the world. In birds, lack of thiamine produces polyneuritis, a disease similar to beriberi. In this disease the nerve fibers show degenerative changes.
Experimentally, it has been shown that a similar paralysis could be produced in chicks, cats, pigeons and rats. The effect is due to the fact that some species of fish contain in their tissues an enzyme, thiaminase, which destroys thiamine. Thiaminase is found not only in fish but also in clams. In addition to its effect on the nervous system, lack of thiamine may also cause retardation of growth. Thiamine is important for the utilization of carbohydrate. Combined with 2 phosphate groups as diphosphothiamine, it forms part of an enzyme system that acts on pyruvic acid, a keto acid of great importance in intermediary metabolism. When animals are deprived of thiamine, their tissues are unable to oxidize pyruvic acid. Thiamine is also important in the transmission of the nerve impulse. When isolated nerves are stimulated, they are believed to release thiamine to the surrounding solution.
Ascorbic acid: Vitamin C
The fat-soluble vitamins are still generally referred to by their alphabetical names. On the other hand, the water-soluble vitamins are now for the most part usually given chemical names which have no relation to the alphabet. This became necessary when what was originally the B vitamin became a whole assortment of heterogeneous substances, distinguished by somewhat variable and uncertain subscripts of the letter B. At present the water-soluble vitamins include the clearly defined ascorbic acid (vitamin C) plus the vitamins of the B complex. Because of the fact that vitamin C is one substance, clearly defined and understood, we shall consider it first rather than in its alphabetical order.
Ascorbic acid is now well understood chemically and it can indeed be synthesized. The structural formula of the L-form is:
The L-form is much more potent than the D-form. Ascorbic acid is really an acid hexose sugar. Its acidity is due to the dissociation of an enolic hydrogen rather than to opening of the lactone ring.
Ascorbic acid is a strongly reducing substance, and because of this, it is easy to demonstrate its presence in cells and tissues. A standard method involves the reduction of silver nitrate. Because of its reducing power, there is doubtless a relation of ascorbic acid to the oxidative processes in cells, but there is still no clear understanding as to the exact function or functions of the vitamin in metabolism. In animals suffering from scurvy there is lack of intercellular material; presumably the cells enclosing the blood vessels are not held together as firmly as they should be and this is doubtless the cause of hemorrhage. Mucopolysaccharides are known to be important constituents of the cementing substances which hold cells together. In view of the fact that mucopolysaccharides are polymers of acid sugars, it is possible that ascorbic acid is involved in the synthesis of such substances. There is some indirect evidence for this. Normally in wound healing mucopolysaccharides are detectable in the healing tissues and may have considerable importance for the process. However, when the store of ascorbic acid is depleted, these substances do not appear.
Ascorbic acid is now well understood chemically and it can indeed be synthesized. The structural formula of the L-form is:
The L-form is much more potent than the D-form. Ascorbic acid is really an acid hexose sugar. Its acidity is due to the dissociation of an enolic hydrogen rather than to opening of the lactone ring.
Ascorbic acid is a strongly reducing substance, and because of this, it is easy to demonstrate its presence in cells and tissues. A standard method involves the reduction of silver nitrate. Because of its reducing power, there is doubtless a relation of ascorbic acid to the oxidative processes in cells, but there is still no clear understanding as to the exact function or functions of the vitamin in metabolism. In animals suffering from scurvy there is lack of intercellular material; presumably the cells enclosing the blood vessels are not held together as firmly as they should be and this is doubtless the cause of hemorrhage. Mucopolysaccharides are known to be important constituents of the cementing substances which hold cells together. In view of the fact that mucopolysaccharides are polymers of acid sugars, it is possible that ascorbic acid is involved in the synthesis of such substances. There is some indirect evidence for this. Normally in wound healing mucopolysaccharides are detectable in the healing tissues and may have considerable importance for the process. However, when the store of ascorbic acid is depleted, these substances do not appear.
Vitamins K: fat-soluble vitamins
Fourth and last of the commonly recognized fat-soluble vitamins are the vitamins K, so named because they are important for blood coagulation (coagulation is spelled with a K in German and in the Scandinavian languages). The K vitamins are close to the E vitamins chemically. Tocopherols are very similar to the naphthoquinones chemically; the K vitamins are actually naphthoquinones.
The basic structure of a naphthoquinone is shown below:
This is a 1,4 naphthoquinone. The most active form of vitamin K, a form which can be prepared synthetically, is 2-methyl-1,4-naphthoquinone. This is sometimes called menadione. It does not occur naturally nearly as abundantly as vitamin K1, which resembles menadione except that instead of having a methyl group in the 3 position, it has a phytol group. (Phytol is a 20 carbon mono-unsaturated primary alcohol which can be obtained from the saponification of chlorophyll.) Vitamin K 2 also resembles menadione except that in the 3 position it has a difarnesyl group. (Farnesol is similar to phytol; it is a 15 carbon primary alcohol with 3 unsaturated carbon atoms.) Several other naturally occurring vitamin K compounds have also been described. They are all either yellow oils or yellow crystalline solids, practically insoluble in water.
Vitamin K is manufactured in one form or another by bacteria, which do not ordinarily require it. The bacteria in the intestines of mammals produce enough so that normally the mammals have no need of it from outside sources. However, when absorption of fatty compounds is interfered with, as in intestinal disease or in liver disease involving interruption of bile flow, the vitamin becomes essential for man and mammals. Many birds require the vitamin, for their bacteria can not supply them with sufficient quantity.
Vitamin K is necessary for the clotting of the blood of higher animals. The reason for this is not clearly understood. To some extent opinions differ, but most authorities believe that this action of vitamin K is an indirect effect caused by the entrance into the blood of greater amounts of a substance prothrombin, the precursor of thrombin. Thrombin, which is regarded as an enzyme, is of primary importance in blood clotting.
Certainly the function of vitamin K can not be restricted to its effect on the clotting of blood. Obviously, the bacteria and the plants which produce it must have some need for it themselves. Experiments with isolated cells show that vitamin K is a very powerful protoplasmic clotting agent. This is not surprising in view of the fact that the clotting of protoplasm is in so many respects similar to the clotting of blood. Although menadione is but sparingly soluble in water, solutions of it cause a coagulation of the protoplasm of marine eggs. Menadione also produces clotting in muscle protoplasm.
The basic structure of a naphthoquinone is shown below:
This is a 1,4 naphthoquinone. The most active form of vitamin K, a form which can be prepared synthetically, is 2-methyl-1,4-naphthoquinone. This is sometimes called menadione. It does not occur naturally nearly as abundantly as vitamin K1, which resembles menadione except that instead of having a methyl group in the 3 position, it has a phytol group. (Phytol is a 20 carbon mono-unsaturated primary alcohol which can be obtained from the saponification of chlorophyll.) Vitamin K 2 also resembles menadione except that in the 3 position it has a difarnesyl group. (Farnesol is similar to phytol; it is a 15 carbon primary alcohol with 3 unsaturated carbon atoms.) Several other naturally occurring vitamin K compounds have also been described. They are all either yellow oils or yellow crystalline solids, practically insoluble in water.
Vitamin K is manufactured in one form or another by bacteria, which do not ordinarily require it. The bacteria in the intestines of mammals produce enough so that normally the mammals have no need of it from outside sources. However, when absorption of fatty compounds is interfered with, as in intestinal disease or in liver disease involving interruption of bile flow, the vitamin becomes essential for man and mammals. Many birds require the vitamin, for their bacteria can not supply them with sufficient quantity.
Vitamin K is necessary for the clotting of the blood of higher animals. The reason for this is not clearly understood. To some extent opinions differ, but most authorities believe that this action of vitamin K is an indirect effect caused by the entrance into the blood of greater amounts of a substance prothrombin, the precursor of thrombin. Thrombin, which is regarded as an enzyme, is of primary importance in blood clotting.
Certainly the function of vitamin K can not be restricted to its effect on the clotting of blood. Obviously, the bacteria and the plants which produce it must have some need for it themselves. Experiments with isolated cells show that vitamin K is a very powerful protoplasmic clotting agent. This is not surprising in view of the fact that the clotting of protoplasm is in so many respects similar to the clotting of blood. Although menadione is but sparingly soluble in water, solutions of it cause a coagulation of the protoplasm of marine eggs. Menadione also produces clotting in muscle protoplasm.
A fat-soluble vitamin: vitamin E
A third fat-soluble vitamin or group of vitamins is vitamin E, or perhaps one should say the vitamins E. There are very many substances with vitamin E activity, but the term vitamin E is restricted to the tocopherols. (The word tocopherol is derived from Greek words signifying child birth.) There are 4 tocopherols now known: alpha, beta, gamma and delta tocopherol. The formula for alpha tocopherol is:
Beta and gamma tocopherol have 1 less methyl group than alpha tocopherol and delta tocopherol has 2 less methyl groups.
Vitamin E is necessary for the reproduction of the rat and other mammals and birds. If the male rat is fed a diet lacking in vitamin E, the germ cells in the testis degenerate. In the absence of vitamin E, the female rat cannot give birth to its young; these degenerate and are resorbed. In some cases, muscular atrophy follows lack of vitamin E in the diet.
The mechanism whereby vitamin E functions in the body is still unknown." In the first place it may act as part of an enzyme system, and to this action its effect in preventing degeneration of muscle may be due. Secondly, the tocopherols exert another, less specific function in that they tend to prevent excessive oxidation. Thus, for example, they tend to preserve vitamin A and they may also prevent the necessary unsaturated fats from being oxidized.
Beta and gamma tocopherol have 1 less methyl group than alpha tocopherol and delta tocopherol has 2 less methyl groups.
Vitamin E is necessary for the reproduction of the rat and other mammals and birds. If the male rat is fed a diet lacking in vitamin E, the germ cells in the testis degenerate. In the absence of vitamin E, the female rat cannot give birth to its young; these degenerate and are resorbed. In some cases, muscular atrophy follows lack of vitamin E in the diet.
The mechanism whereby vitamin E functions in the body is still unknown." In the first place it may act as part of an enzyme system, and to this action its effect in preventing degeneration of muscle may be due. Secondly, the tocopherols exert another, less specific function in that they tend to prevent excessive oxidation. Thus, for example, they tend to preserve vitamin A and they may also prevent the necessary unsaturated fats from being oxidized.
Sterols - Vitamin D
A number of sterols have vitamin D activity, that is to say they prevent the occurrence of rickets in higher animals. The chemistry of the sterols is very complicated, and books on physiological chemistry may be consulted for structural formulae, etc. When the common sterol of fungi, ergosterol, is irradiated with ultraviolet rays, another sterol, calciferol, is produced. This is commonly referred to as vitamin D 2. (There is no D 1, for the original use of the term was a misnomer.) D 3 is 7-dehydrocholesterol. Numerous other antirachitic (rickets-preventing) substances have also been described. Whether or not a given sterol or sterol derivative has antirachitic action can only be determined by actual test.
Bacteria do not seem to require sterols. Some species of protozoan flagellates do; also Entamoeba histolytica, the ameba that causes human dysentery. Insects, in so far as they have been studied, require sterols, but they seem to need cholesterol, a cholesterol derivative, or a plant sterol; calciferol cannot usually be substituted for these.
In mammals and birds, vitamin D causes an increase in the deposition of calcium and phosphorus in the bones. This is apparently due, in part at least, to an increased absorption through the intestine. Using radioactive isotopes, Greenberg found that vitamin D promotes the absorption of calcium and strontium from the digestive tract. Sterols may act in the same way in promoting the passage of calcium through the walls of the insect intestine. Moreover, they may be concerned with the entrance of calcium into cells. This aspect of the subject has never been investigated.
Bacteria do not seem to require sterols. Some species of protozoan flagellates do; also Entamoeba histolytica, the ameba that causes human dysentery. Insects, in so far as they have been studied, require sterols, but they seem to need cholesterol, a cholesterol derivative, or a plant sterol; calciferol cannot usually be substituted for these.
In mammals and birds, vitamin D causes an increase in the deposition of calcium and phosphorus in the bones. This is apparently due, in part at least, to an increased absorption through the intestine. Using radioactive isotopes, Greenberg found that vitamin D promotes the absorption of calcium and strontium from the digestive tract. Sterols may act in the same way in promoting the passage of calcium through the walls of the insect intestine. Moreover, they may be concerned with the entrance of calcium into cells. This aspect of the subject has never been investigated.
Vitamin A is a yellow viscous oil
Vitamin A is a yellow viscous oil. Chemically, it is related to carotene, the common yellow pigment of plants. The generally accepted formula follows:
When carotene is eaten, it is converted to vitamin A. Because of this, it is sometimes called a provitamin. Another provitamin of vitamin A is kitol, a dihydric alcohol found in whale liver oil. The conversion of carotene to vitamin A occurs in the intestines of higher animals. The vitamin is then stored in the liver. The livers of polar bears and Arctic foxes are so rich in vitamin A that they are toxic. The toxicity is an example of what is known as hypervitaminosis.
Vitamin A has been synthesized in several different laboratories. There are really two forms of the vitamin. One form (A1) constitutes most of the vitamin content of the livers of salt water fishes. In the livers of fresh water fishes vitamin A 2 occurs. The 2 substances give slightly different colors with antimony trichloride and can be distinguished spectroscopically.
In higher animals, vitamin A is important for growth. When rats are deprived of vitamin A, the cornea of the eye becomes horny. This condition is known as xerophthalmia. It can occur also in children. Not only the corneal epithelium, but other types of epithelia are also adversely affected in vitamin A deficiency; this may lead to lessened resistance to infection. Vitamin A has a relation to vision. In man, vitamin A deficiency causes night blindness, but the effect is not as readily produced as formerly supposed.
In so far as they have been investigated, invertebrates, with the apparent exception of the snail Helix, do not seem to require vitamin A. Aside from its relation to vision, little is known as to the reason why vitamin A is necessary. Its presence in cells can be recognized with a fluorescence microscope because of the fact that in ultraviolet light it gives a green fluorescence.
When carotene is eaten, it is converted to vitamin A. Because of this, it is sometimes called a provitamin. Another provitamin of vitamin A is kitol, a dihydric alcohol found in whale liver oil. The conversion of carotene to vitamin A occurs in the intestines of higher animals. The vitamin is then stored in the liver. The livers of polar bears and Arctic foxes are so rich in vitamin A that they are toxic. The toxicity is an example of what is known as hypervitaminosis.
Vitamin A has been synthesized in several different laboratories. There are really two forms of the vitamin. One form (A1) constitutes most of the vitamin content of the livers of salt water fishes. In the livers of fresh water fishes vitamin A 2 occurs. The 2 substances give slightly different colors with antimony trichloride and can be distinguished spectroscopically.
In higher animals, vitamin A is important for growth. When rats are deprived of vitamin A, the cornea of the eye becomes horny. This condition is known as xerophthalmia. It can occur also in children. Not only the corneal epithelium, but other types of epithelia are also adversely affected in vitamin A deficiency; this may lead to lessened resistance to infection. Vitamin A has a relation to vision. In man, vitamin A deficiency causes night blindness, but the effect is not as readily produced as formerly supposed.
In so far as they have been investigated, invertebrates, with the apparent exception of the snail Helix, do not seem to require vitamin A. Aside from its relation to vision, little is known as to the reason why vitamin A is necessary. Its presence in cells can be recognized with a fluorescence microscope because of the fact that in ultraviolet light it gives a green fluorescence.
Vitamins, riboflavin, nicotinic acid, pantothenic acid form
Most of the work on vitamins has been stimulated by the practical needs of medicine and industry. The physician and the drug manufacturer are not ordinarily interested in the vitamin requirements of lower organisms, unless these organisms can conveniently be used in vitamin assay. Thus, as might be expected, there are vast gaps in our knowledge of the vitamin requirements of many large groups of animals. We know almost nothing of the vitamin needs of metazoan invertebrates other than insects. And we know very little about the vitamins necessary for fish, amphibia and reptiles. A wide field is open for such study, and many facts of interest may well be discovered. Some vitamins are required by practically all living organisms from bacteria to man; others are needed by only some forms and not others.
There has been much interest in the avitaminoses, that is to say the diseases caused by the lack of specific vitamins. Our knowledge in this field is almost entirely confined to higher animals. Thus we know that when the vitamins D are omitted from the diet, a child will develop rickets and so will a pig or a rabbit, a dog or a chicken. Accordingly, the vitamins D have been called the antirickets vitamins. But animals without bones such as insects or protozoa may also require vitamin D. From a knowledge of the reasons why this is so, we may be able to obtain additional information as to the way that vitamins function.
Much as is known about the vitamins, their chemistry, their occurrence in various foods, the diseases that follow their absence from the diet, there is still almost complete ignorance as to the exact nature of their action. A beginning has been made in the recognition of the fact that some vitamins such as riboflavin, nicotinic acid, and pantothenic acid form essential parts of some enzyme systems. We know also the end results of many types of vitamin deficiency. But to say that a vitamin is necessary for growth or that it prevents anemia tells us very little as to what it really does or why it is necessary. If we were to know how certain vitamins influence growth or prevent cell deterioration in the epithelial or nervous system, we would have basic information of great importance. Such information would be useful not only in the better understanding of the vitamins but also in the elucidation of various basic vital processes. The final interpretation of vitamin action must lie in an understanding of how the vitamins affect the cell protoplasm.
It is this aspect of the subject that will be stressed in the following discussion of individual vitamins. The general physiologist is not primarily interested in the relation of vitamins to human welfare, the foods a man should eat, or the benefits to be derived from adding this or that vitamin to the diet. Such information can be obtained in books on physiological chemistry, nutrition, or medicine. In discussing the individual vitamins, we shall not proceed in alphabetical order. This order has no other basis than the chronology of discovery. We shall consider first the fat-soluble and then the water-soluble vitamins. In general, especially in the case of the water-soluble vitamins, true chemical names have tended to supplant letters and subscripts. But in some instances, several chemical substances can and normally do supply a given vitamin need. In these instances the alphabetical name is sometimes more convenient.
There has been much interest in the avitaminoses, that is to say the diseases caused by the lack of specific vitamins. Our knowledge in this field is almost entirely confined to higher animals. Thus we know that when the vitamins D are omitted from the diet, a child will develop rickets and so will a pig or a rabbit, a dog or a chicken. Accordingly, the vitamins D have been called the antirickets vitamins. But animals without bones such as insects or protozoa may also require vitamin D. From a knowledge of the reasons why this is so, we may be able to obtain additional information as to the way that vitamins function.
Much as is known about the vitamins, their chemistry, their occurrence in various foods, the diseases that follow their absence from the diet, there is still almost complete ignorance as to the exact nature of their action. A beginning has been made in the recognition of the fact that some vitamins such as riboflavin, nicotinic acid, and pantothenic acid form essential parts of some enzyme systems. We know also the end results of many types of vitamin deficiency. But to say that a vitamin is necessary for growth or that it prevents anemia tells us very little as to what it really does or why it is necessary. If we were to know how certain vitamins influence growth or prevent cell deterioration in the epithelial or nervous system, we would have basic information of great importance. Such information would be useful not only in the better understanding of the vitamins but also in the elucidation of various basic vital processes. The final interpretation of vitamin action must lie in an understanding of how the vitamins affect the cell protoplasm.
It is this aspect of the subject that will be stressed in the following discussion of individual vitamins. The general physiologist is not primarily interested in the relation of vitamins to human welfare, the foods a man should eat, or the benefits to be derived from adding this or that vitamin to the diet. Such information can be obtained in books on physiological chemistry, nutrition, or medicine. In discussing the individual vitamins, we shall not proceed in alphabetical order. This order has no other basis than the chronology of discovery. We shall consider first the fat-soluble and then the water-soluble vitamins. In general, especially in the case of the water-soluble vitamins, true chemical names have tended to supplant letters and subscripts. But in some instances, several chemical substances can and normally do supply a given vitamin need. In these instances the alphabetical name is sometimes more convenient.
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