Biology

Carbohydrates Sugars and chains of sugar units are the most abundant consdtuent

of living matter. New carbohydrates are still being discovered, as

are new roles for them in normal biological processes and disease

The four major classes of com­pounds essential to life are nucle­ic acids, proteins, lipids and car­ bohydrates. Over the past 30 years the first three classes have received much attention from chemists and biologists, whereas during most of that time the carbohydrates were largely neglected, partly in the belief that their chemistry and biology had been fully worked out. In the past decade, however, research on carbohydrates has been revived and is now expanding rapidly. As a result of many new developments carbohydrate research is today broad and diverse.

The study of carbohydrates and their derivatives has greatly enriched chemis­ try, particularly with respect to the role of molecular shape and conformation in chemical reactions. Recent carbohy­ drate investigations have played a deci­ sive role in the characterization of vari­ ous antibiotics and antitumor agents. Such studies have led to the discovery of new biosynthetic reactions and enzymic control mechanisms and are contribut­ ing significantly to the understanding of many fundamental biological processes, for example the interaction of cells with their environment and with other cells. As a result revolutionary new methods for combating bacterial and viral infec­ tions and for targeting drugs on diseased cells and organs are being envisioned. Carbohydrate research has also pro­ vided a basis for recognizing the en­ zyme deficiency underlying several ge­ netic disorders and has led to the hope that they can be treated effectively. A common theme behind many of the recent findings, which is also a powerful driving force in carbohydrate research, is the realization that monosaccharides (the basic units of carbohydrates) can serve, as nucleotides and amino acids do, as code words in the molecular lan­ guage of life, so that the specificity of many natural compounds is written in monosaccharides.

Carbohydrates are sugars or (like starch and cellulose) chains of sugars. To most people sugar is the common household foodstuff, which to the chem­ ist is sucrose. Chemically the molecule

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by Nathan Sharon

of sucrose consists of two monosac­ charides, or simple sugars, glucose and fructose, that are hooked together; it is thus a disaccharide. More than 200 different monosaccharides have been found in nature, all of which are chemi­ cally related to gl ucose or fructose. As a rule they are white crystalline solids that dissolve readily in water. Some of them have not been obtained in amounts suffi­ cient for testing their sweetness, but they are still called sugars, as are the mon­ osaccharides that are found to be not sweet.

Glucose is the best-known’monosac­ chari de; indeed, it has probably been in­ vestigated more thoroughly than any other organic compound. It was un­ doubtedly known to the ancients be­ cause of its occurrence in granulated honey and wine must. References to grape sugar, which is glucose, are to be found in Moorish writings of the 12th century. In 1747 the German pharma­ cist Andreas Marggraf, whose isolation of pure sucrose from sugar beets is an example of the chemical art of the time at its best, wrote of isolating from raisins “eine Art Zucker” (a type of sugar) dif­ ferent from cane sugar; it was what is now called glucose. The action of acids on starch was shown to prod uce a sweet syrup from which a crystalline sugar was isolated by Constantine Kirchoff in 1811. Later workers established that the sugar in grapes is identical with the sug­ ar found in honey, in the urine of diabet­ ics and in acid hydrolysates of starch and cellulose. The French chemist Jean Baptiste Andre Dumas gave it the name glucose in 1838. The structure of gl u­ cose and of several other monosac­ charides, including fructose, galactose and mannose, was established by about 1900, mainly by the brilliant work of the German chemist Emil Fischer, who thereby laid the foundations of carbohy­ drate chemistry.

Monosaccharides rarely exist as such in nature. They are found in the form of various derivatives, from which they can be liberated by hydrolysis with aqueous mineral acids or with enzymes. The most abundant of the derivatives

are polysaccharides, which are made up of sugar units formed into giant mole­ cules that can consist of as many as 26,000 monosaccharides (as in cell u­ lose from the alga Valonia). Sugars also occur frequently as oligosaccharides, which are compounds made .up of from two to 10 monosaccharides. Sugars are frequently found in combination with other natural substances.

The “Water of Carbon”

The name carbohydrate was original­ ly assigned to compounds thought to be hydrates of carbon, that is, to consist of carbon, hydrogen and oxygen in the gen­ eral formula C”(H20),,. Indeed, glucose and other simple sugars such as galac­ tose, mannose and fructose do have the general formula CSHI20S. They are typ­ ical hexose monosaccharides, meaning that they have six carbon atoms. With the accumulation of more data the defi­ nition has been modified and broadened to encompass numerous compounds with little or no resemblance to the orig­ inal “water of carbon.” Carbohydrates now include polyhydroxy aldehydes, ke­ tones, alcohols, acids and amines, their simple derivatives and the products formed by the condensation of these different compounds through glycosid­ ic linkages (essentially oxygen bridges) into oligomers (oligosaccharides) and polymers (polysaccharides).

Much of the current interest in carbo­ hydrates is focused on such substances as glycoproteins and glycolipids, com­ plex carbohydrates in which sugars are linked respectively to proteins and lip­ ids. They are termed glycoconjugates. It should also be noted that in the excite­ ment about nucleic acids a simple fact is being forgotten: they too are complex carbohydrates, since monosaccharides are among their major constituents (ri­ bose in RNA and deoxyribose in DNA).

Carbohydrates are the most abundant group of biological compounds on the earth, and the most abundant carbohy­ drate is cellulose, a polymer of glucose; it is the major structural material of plants. Another abundant carbohydrate

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CELL-SURF ACE ROLE of a carbohydrate, mannose, is indicated in this scanning electron micrograph made by Fredric Silverblatt and Craig Kuehn of the Veterans Administration Hospital in Sepulveda, Calif. Cells from tissue on the inside of the human cheek occupy the

background of the micrograph; the white cylindrical objects are Esch­ erichia coli bacteria. The mannose, which is on the cell membrane, is not visible, but it is causing the E. coli to adhere to the tissue surface. Such adherence to surfaces is the first step in a bacterial infection.

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is chitin, a polymer of acetylglucos­ amine; it is the major organic compo­ nent of the exoskeleton of arthropods such as insects, crabs and lobsters, which make up the largest class of or­ ganisms, comprising some 900,000 spe­ cies (more than are found in all other families and classes together). It has been estimated that millions of tons of chitin are formed yearly by a single spe­ cies of crab!

Carbohydrates are also the fuel of life, being the main source of energy for living organisms and the central path­ way of energy storage and supply for most cells. They are the major prod ucts through which the energy of the sun is harnessed and converted into a form that can be utilized by living organisms. According to rough estimates, more than 100 billion tons of carbohydrates are formed each year on the earth from carbon dioxide and water by the process of photosynthesis. Polymers of glucose, such as the starches and the glycogens, are the mediums for the storage of ener­ gy in plants and animals respectively. Coal, peat and petroleum were probably formed from carbohydrates by microbi­ ological and chemical processes.

Carbohydrates comprise only about I percent of the human body; proteins comprise 15 percent, fatty substances 15 percent and inorganic substances 5 per­ cent (the rest being water). Nevertheless, carbohydrates are important constitu­ ents of the human diet, accounting for a high percentage of the calories con­ sumed. Thus some 40 percent of the cal­ orie intake of Americans (and some 50 percent of that of Britons and Israelis) is in the form of carbohydrates: glucose, fructose, lactose (milk sugar, a disaccha­ ride of glucose and galactose), sucrose and starch.

Sucrose is a major food sugar. Its world production rose from eight mil­ lion tons in 1900 to nearly 88 million in 1977. No other human food has shown an increase in production on this order in the same period. The amount of su­ crose produced by a country is an in­ dex of its average income. In the richer

e CARBON OXYGEN

o

countries, such as the U.S., Britain, Aus­ tralia and Sweden, the annual consump­ tion is between 40 and 50 kilograms of sucrose per person, whereas in the poor­ er ones, such as India, Pakistan and Chi­ na, it is five kilograms or less. It has of­ ten been suggested that the high sucrose diet may have detrimental effects on the health of people in developed countries, being responsible to some extent for the increase in such diseases as diabetes, obesity and dental cavities.

Carbohydrates are the raw materials for industries of great economic im­ portance, such as wood pulp and paper, textile fibers and pharmaceuticals. The principal industrial carbohydrate is un­ doubtedly cellulose: its worldwide use is estimated at 800 million tons per year. Polysaccharides with gelling properties, such as agar, pectic acid and carrageen­ ans, are important in the food and cos­ metic industries.

Research Difficulties

The major polysaccharides I have mentioned-cellulose, starch, glycogen and chitin-are relatively simple poly­ mers: they are homopolymers, made up of one type of monomer (glucose or ace­ tylglucosamine). This seeming simplici­ ty, perhaps even dullness, of structure is probably one of the reasons .carbohy­ drates seemed to lack interest.

Another important reason chemists tended to shy away from the study of carbohydrates stemmed from the many chemical problems encountered in deal­ ing with these materials. Sugars are mul­ tifunctional compounds with several hydroxyl (-OH) groups, usually four or five in the hexose sugars, most of which are of approximately equal chemical re­ activity. The manipUlation of a single selected hydroxyl group is often a seri­ ous problem to this day. Blocking one hydroxyl group or leaving one free can be achieved only with great difficulty and requires the careful design and exe­ cution of a complex series of reactions. The synthesis of a disaccharide is there­ fore a considerable achievement; trisac-

charides have rarely been synthesized, and there are only a few reports on the synthesis of higher saccharides.

By way of contrast, in protein chemis­ try peptide.s made up of dozens of amino acids can readily be synthesized, not only manually but also by automatic methods. At least three proteins, insulin (made up of 51 amino acids), ribonu­ clease (124) and lysozyme (129), have been synthesized. One reason for the rel­ ative ease of such syntheses is that the number of steps involved in the prepa­ ration of a peptide is considerably less than the number required for the syn­ thesis of an oligosaccharide of similar size. It is even more important that a far larger number of isomeric oligosaccha­ rides (the same in composition but dif­ ferent in structure) than of oligopeptides can be obtained from a given number of corresponding monomers.

An added complication for the chem­ ist is that whereas proteins and nucleic acids are linear polymers, polysaccha­ rides are commonly branched. This characteristic greatly increases the num­ ber of possible structures and therefore the difficulties of studying polysaccha­ rides. Luckily for carbohydrate chem­ ists many of the possible structures are apparently not formed in nature.

The recent revival of interest in carbo­ hydrates can be ascribed primarily to the introduction of much improved methods. Carbohydrate chemists in the first half of this century had to rely al­ most exclusively on carefully controlled chemical transformations and on opti­ cal measurements (chiefly polarimetry) in the investigation of the structures of monosaccharides and their derivatives. Work at that time was further limited by the lack of good separation techniques and by the need of a substantial quantity (a gram or more) of material for many of the experiments. The advent of chro­ matography in its various forms and of powerful instrumental analytical meth­ ods, such as nuclear-magnetic-reso­ nance spectroscopy (requiring only mil­ ligrams of material), mass spectrometry (requiring only micrograms) and X-ray-

THREE MONOSACCHARIDES are (left to right) glucose, fructose and galactose. Carbobydrates being sugars or cbains of sugars, mono­ saccbarides are tbe basic units of tbe cbains. Glucose, fructose, galac­ tose and many otber simple sugars fit tbe original definition of carbo-

hydrates as h)draks of carbon, consisting of carbon, bydrogen and oxygen in tbe general formula C”(H20),,. Witb glucose, fructose and galactose tbe formula is C6H 1206; they are hexoses: they have six carbon atoms. More than 200 monosaccharides have been found.

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© 1980 SCIENTIFIC AMERICAN, INC

me

GLENLIVET AGED 12 YEARS

© 1980 SCIENTIFIC AMERICAN, INC

diffraction analysis, and the availability of highly specific enzymes acting on car­ bohydrates have given rise to a com­ plete transformation in the approach to the problem of carbohydrate structure. Moreover, combinations of these tech­ niques can provide information faster, more conveniently, in greater detail and with smaller quantities of material than was formerly possible. Maurice Stacey of the University of Birmingham has observed that ascertaining the constitu­ tion of a new carbohydrate would have taken three years in the 1930’s but can now be done in less than three weeks.

New and Unusual Saccharides

One result of the introduction of the powerful new techniques was the dis­ covery of many new saccharides, both simple and complex. In recent years the number of rare sugars isolated from nat­ ural sources has increased rapidly. They have provided the carbohydrate chemist with new and challenging problems of structural determination and synthesis. I shall illustrate this state of affairs with examples from an area in which I have been active, the amino sugars: sugars in which one or more hydroxyls are re­ placed by an amino group.

In 1875 a young physician named George Ledderhose was working during the summer semester in the laboratory of Friedrich Wohler in Gottingen when Ledderhose’s uncle, Felix Hoppe-Sey­ ler, a noted physiological chemist, invit­ ed him to dinner. At his uncle’s sugges­ tion he took the remains of the lobster they had eaten back to the laboratory, where he found that the claws and the shell dissolved in hot concentrated hy-

_ CARBON C) OXYGEN o HYDROGEN

SUCROSE

drochloric acid and that on evaporation the solution yielded characteristic crys­ tals. He soon identified the crystalline compound as a new nitrogen-containing sugar, which he named giycosamin.

During the next 20 years much evi­ dence was gathered to indicate that the new sugar has a structure derived by the replacement of the hydroxyl group at­ tached to carbon No.2 in the glucose molecule by an amino group. With the synthesis, which was still not definitive, of the amino sugar by Emil Fischer and H. Leuchs in 1903 the problem of its structure appeared to have been solved. The structure of glucosamine was unequivocally established, howev­ er, only in 1939, when Norman Haworth achieved an unambiguous synthesis that proved Fischer was correcLin assigning the “gluco” structure to the amino sug­ ar. A second amino sugar, galactos­ amine, was isolated in 1914 by P. A. Levene and Frederick B. La Forge at the Rockefeller Institute for Medical Re­ search from acid hydrolysates of carti­ lage, tendon and aorta, but its structure was firmly established only in 1945, again attesting to the enormous difficul­ ties such substances present. At the time that was thought to be the end of the amino-sugar story. By 1960, however, some 20 new amino sugars had been dis­ covered. The number is now over 60.

The first of the “new” amino sugars, found in 1946, was N-methyl-L-glucos­ amine, a constituent of the antibiotic streptomycin. Soon many other new amino sugars were identified in antibiot­ ic substances. Indeed, some antibiotics have an oligosaccharide-like structure. They include the streptomycins, the neomycins and other aminoglycoside

STRUCTURE OF SUCROSE is depicted. Sucrose is common household sugar. It is a disac­ charide: it consists of two monosaccharide molecules (glucose and fructose) joined together.

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antibiotics such as the kanamycins and the paromomycins, all of which are employed clinically against bacterial in­ fections. Another aminoglycoside anti­ biotic is puromycin, a well-known in­ hibitor of protein synthesis. The potent and clinically useful antitumor agents daunomycin and adriamycin, which have proved to be effective in the treat­ ment of acute leukemia, are also amino­ glycosides; they contain the rare 3-ami­ no sugar daunosamine.

To learn more about the mode of ac­ tion of these antibiotics and to improve on them it is imperative to synthesize analogues with different amino-sugar constituents, because it is known that structural features of the sugar compo­ nents often exert a decisive influence on the pharmacological properties of the antibiotics. This objective has given strong impetus to the development of new methods of synthetic-amino-sugar chemistry and has opened the way to the preparation of new and improved anti­ biotics that are remarkably effective against microorganisms resistant to the natural amino glycoside antibiotics. In no case, however, are the monosaccha­ ride constituents alone effective in vitro in killing bacteria or in inhibiting the growth of tumors.

Interestingly enough, several disac­ charides such as trehalosamine are ac­ tive against bacteria. Herbert A. Blough and Robert L. Giuntoli of the University of Pennsylvania School of Medicine re­ ported last year that the monosaccha­ ride 2-deoxyglucose applied to the site of an infection is highly effective in the treatment of genital herpes infection, a widespread form of venereal disease caused by the herpes simplex virus, for which no cure had been available. The sugar is believed to interfere with the synthesis of glycoprotein in the virus by virtue of its similarity to mannose, an important constituent of the viral glyco­ proteins.

New amino sugars and other types of sugar have been isolated in recent years not only from antibiotics but also from other sources, in particular from the polysaccharides of bacteria. One of the most important is the 3-lactic-acid ether of glucosamine, known as muramic acid. This amino sugar, which is limited to bacteria, was isolated for the first time by R. E. Strange and F. A. Dark in Brit­ ain in 1956. (For a while it was nick­ named the strange and dark compound.) Its acetylated derivative, acetylmuramic acid, and acetylglucosamine form the polysaccharide backbone of the pepti­ doglycan in the wall of the bacterial cell.

Another new sugar is ribitol, a reduc­ tion product of ribose. It is a constituent of the teichoic acids, which were discov­ ered by James Baddiley in Britain in the 1950’s. Teichoic acids are polymers of ribitol phosphate or glycerol phosphate found in Gram-positive bacteria. In the cell wall of these organisms they act as

© 1980 SCIENTIFIC AMERICAN, INC

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immunological determinants and as re­ ceptors of bacteriophages, that is, virus­ es that infect bacteria.

An important sugar of unusual struc­ ture is neuraminic acid, the parent com­ pound of the sialic acids, which are ubiquitous in nature except for plants. Neuraminic acid is a nine-carbon sugar acid with an amino group in its mole­ cule. Today 20 sialic acids are known, most of which were discovered during the past decade by Roland Schauer of the University of KieI. They are among the major constituents of mucins, such as those secreted by the respiratory and urogenital tracts, and are also found in the eye socket. By virtue of their nega­ tive charge they impart to the mucin molecules an extended rodlike struc­ ture. They are therefore responsible for the high viscosity of the mucins. Only because of the mucins’ sialic acid can they act as lubricants for the rotation of the eyeball, preventing the cornea from drying out and protecting it from dam­ age by grains of dust.

In the oral cavity and the gastrointes­ tinal tract the viscous glycoproteins in­ corporating sialic acid envelop foods, making them slippery and protecting the tender mucous surfaces from mechani­ cal damage. In the cervical canal of the uterus a highly viscous plug of mucin keeps bacteria out of the uterine cavity and hence out of the abdominal cavity. This viscous barrier is lowered at the time of ovulation to admit spermatozoa. Glycoproteins rich in sialic acid that are secreted by mucous glands of the vagi­ na also lubricate both coitus and child­ birth.

A rare diamino sugar, the first of its kind, that I have been studying for the past 20 years is bacillosamine. I discov­ ered it in a polysaccharide of Bacillus Iichenz/ormis in 1958 while I was work­ ing in the laboratory of Roger W. Jean­ loz at the Massachusetts General Hospi­ tal. Only recently, through the joint ef­ forts of a number of co-workers, were we able to establish its structure. We then went on to synthesize the corre­ sponding galactose derivative in the be­ lief that it too must occur in nature. To our great satisfaction 2,4-diamino 2,4,- 6-trideoxygalactose was identified last year in natural products by workers in Stockholm and Tokyo.

A major breakthrough, which opened new horizons in biochemistry and had an immediate impact on medicine, was the discovery of sugar nucleotides and their manifold roles as intermediates in the biosynthesis of monosaccharides, oligosaccharides and polysaccharides and of complex carbohydrates. The first sugar nucleotide, uridine diphosphate glucose (UDP-glucose), was discovered by Luis F. Leloir and his co-workers in Argentina in 1949; for this discovery Leloir received a Nobel prize in 1970. At about the same time that Leloir de­ scribed UDP-glucose James T. Park and

e CARBON e OXYGEN

f3 LACTOSE

LACTOSE is a disaccharide consisting of glucose linked with galactose. It is the sugar of milk and therefore (with such other sugars as glucose, fructose and sucrose) is one of the carhohy­ drates making up a large part (40 percent in the U.S.) of the calorie intake in the human diet.

Marvin J. Johnson of the University of Wisconsin observed the accumulation of similar compounds in Staphylococcus aureus bacteria that had been exposed to penicillin.

More than 100 different sugar nucleo­ tides have now been identified. Most of them have the general structure of nu­ cleoside diphospho sugar with any of the five nucleosides: adenosine, guano­ sine, cytidine, uridine and deoxythymi­ dine. The sugar exhibits a large variety of structures, some of which are extreme­ ly rare.

Biosynthetic Intermediates

The nucleoside can be considered as a handle that holds the sugar in a form ready for transformation into other sug­ ars or for transfer to suitable acceptors. UDP-glucose is the sugar nucleotide most commonly found in biological ma­ terials and is the starting compound for the formation of numerous other sug­ ars. In many organisms it is converted into UDP-galactose, which is the source of galactose for the formation of lac­ tose. UDP-glucose is also the donor of glucose for the synthesis of gluco­ sides (for example phenyl-/3-glucoside), oligosaccharides (such as sucrose and trehalose), polysaccharides (including starch and glycogen) and other glucose­ containing compounds.

The discovery of sugar nucleotides led not only to the understanding of the biosynthesis of unusual monosaccha­ rides and of complex saccharides but also to the discovery in 1965 by Phillips W. Robbins of the Massachusetts In­ stitute of Technology and by Jack L. Strominger of the University of Wiscon­ sin School of Medicine of a new type of activated sugars: the lipid-linked sugars. They are sugar derivatives linked by a monophosphate or diphosphate bridge to polyprenols, long-chain unsaturated

lipids. One example of such a lipid is bactoprenol, which in the form of its sugar diphospho derivative is an inter­ mediate in the biosynthesis of bacterial lipopolysaccharides and peptidoglycan.

In 1970 Leloir demonstrated for the first time that similar compounds, the dolichol phosphates, participate in the biosynthesis of glycoproteins by animal cells. In bacteria the lipid-linked inter­ mediates, which are hydrophobic (wa­ ter-repelling), serve for the transport of activated sugars or oligosaccharides from the cytoplasm of the cell through the lipid-rich cell membrane to the cell surface, where polysaccharides such as the cell-wall peptidoglycan are laid down. In animals the role of these inter­ mediates remains to be established.

As a result of investigations of the participation of the lipid-linked sugars in the biosynthesis of complex carbohy­ drates, new mechanisms for the assem­ bly of biological polymers have been discovered. For example, with proteins and simple polysaccharides (such as gly­ cogen) the biosynthesis proceeds by the addition of a single monomeric unit, in its activated form, to the growing poly­ mer chain, whereas in complex carbohy­ drates the mechanism is often different. In the synthesis of the cell-wall pep­ tidoglycan a peptide derivative of the disaccharide acetylgl ucosamine-acetyl­ muramic acid is first synthesized on the lipid carrier. This repeating unit is sub­ sequently polymerized and is only then attached to a polymeric acceptor. A similar mechanism operates in the bio­ synthesis of bacterial lipopolysaccha­ rides, except that the repeating unit con­ sists of a trisaccharide of mannose, rhamnose and galactose.

In the biosynthesis of the carbohy­ drate units of glycoproteins linked to the amino acid asparagine an oligosaccha­ ride consisting of two residues of acetyl­ glucosamine, nine of mannose and three

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e CARBON o OXYGEN o HYDROGEN

CELLULOSE

e CARBON o OXYGEN o HYDROGEN

AMYLOSE (STARCH)

e CARBON o OXYGEN o HYDROGEN

GLYCOGEN (WITH BRANCHING)

THREE POLYSACCHARIDES are (from Ihe lop) cellulose, starch and glycogen. They are homopolymers, meaning that they are made up of one type of monomer. In each of the polysaccharides depicted the monomer is glucose. The individuality of these polysaccharides and others arises from the length of the polymer chain (which in cel-

98

lulose may run to several thousand units), the type of linkage between the sugar units and the occurrence of branches. Three basic units of each polysaccharide are shown here. Cellulose is a major structural component in plants. Starch and glycogen serve respectively in plants and animals for the storage of the energy that is derived from food.

© 1980 SCIENTIFIC AMERICAN, INC

of glucose is first assembled on a lipid carrier by a complex sequence of reac­ tions in which both sugar nucleotides and lipid-linked sugars participate. The preassembled oligosaccharide is trans­ ferred en bloc to specific asparagine res­ idues on the growing polypeptide chain and is then “processed” to its mature, final form. This processing includes the removal by special glycosidases of the glucose and most of the mannose and their replacement by tails consisting of sialic acid, galactose and acetylglucos­ amine (as has been found in many serum glycoproteins and in certain viral glyco­ proteins). The replacement proceeds by the stepwise addition of the individu­ al sugars from the corresponding sugar nucleotides; for example, acetylglucos­ amine is added by transfer from UDP­ acetylglucosamine and galactose from UDP-galactose.

Research on sugar nucleotides in rela­ tion to the biosynthesis of bacterial-cell­ wall peptidoglycan has led to the clarifi­ cation of the mechanism of action of penicillin, which is still the most useful antibiotic. The unique effectiveness of penicillin results from the fact that pep­ tidoglycan is not found in any organisms other than bacteria. It is therefore an excellent target for selective chemo­ therapeutic agents that kill the bacte­ ria without affecting their host.

Genetic Diseases

A completely different reason for the new wave of interest in carbohydrates stems from the fact that many of the hereditary or genetic diseases of man for which the molecular basis has been established are defects of carbohydrate metabolism, mostly of complex saccha­ rides. One of the diseases is galactos­ emia, a rare familial defect in galactose metabolism caused by the lack of a single enzyme: galactose phosphate uri­ dyl transferase. Because of the absence of this enzyme afflicted infants cannot utilize galactose or galactose-contain­ ing compounds, in particular lactose. Breast-feeding literally poisons such in­ fants. The galactose, which is ordinarily converted into glucose and eventually into energy, accumulates in the infant’s blood in the poisonous form of galac­ tose phosphate, causing severe neural retardation and often early death.

Mainly as a result of the efforts of Herman M. KaJckar and his collabora­ tors at the National Institute of Arthri­ tis and Metabolic Disorders in the late 1950’s the diagnosis of galactosemia can be made before the disease is far advanced. The procedure tests for the presence of the enzymes that metabolize galactose. If one of the enzymes is miss­ ing and the infant is given a diet free of galactose, all symptoms of galactosemia disappear and development becomes normal.

Most other genetic defects of carbo-

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