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Carbohydrates: Structure and Biological Function: Glucose, fructose, sucrose, starch and cellulose- these chemical names are common words in everyday use They are most abundant members of the large and important class of biomolecules called carbohydrates Biologist believe that the carbohydrates make up a higher percentage of biomass than any other biomolecule class The carbohydrates are defined as compounds having polyhydroxy aldehyde or ketone since they have reactive aldehyde and ketone functional groups and multiple hydroxyl groups The hydroxyl groups provide the possibility of strong intra or inter chain interactions via hydrogen bonds In addition to predominant elements carbon, hydrogen and oxygen, some carbohydrates also contain sulfur, nitrogen or phosphorus Like the other major classes of biomolecules (proteins, nucleic acids, lipids), the carbohydrates are found in all forms of life and serve many different functions: • The carbohydrates are probably best known for their role in energy metabolism. Some compounds in this class (for example, glucose and fructose) serve as fuel molecules for immediate use by organisms, where other compounds (starch and glycogen) are chemicals stores for future energy needs in plants and animals • Like proteins, some carbohydrates perform structural functions, providing scaffolding for bacterial and plant cell walls, connective tissue such as cartilage in animals and exoskeleton shell in arthropods • The monosaccharides ribose and deoxyribose, as components of the nucleic acids, serve a chemical structural role (RNA and DNA) and as polar sites for catalytic processes (RNA, ribozymes) • Carbohydrates are covalently combined with proteins and complex lipids on cell surfaces to act as informational markers for molecular roles in cell-cell recognition processes and in signal transduction Here we first introduce the unique structures and reaction of biologically important carbohydrates and then turn to their presence in proteins and involvement in biological processes Diseases associated with carbohydrates include: • Diabetes mellitus • Galactosemia - inability to metabolize galactose inherited defects in enzyme • Glycogen storage diseases - a group of inherited diseases characterized by deficient mobilization of glycogen or deposition of abnormal forms of glycogen leading to muscle weakness or even death • Lactose intolerance lactase deficiency leading to diarrhea and intestinal discomfort Classification: Monosaccharides and Related Compounds: • The simplest carbohydrates, sometimes referred to as monosaccharides or sugars, are either polyhydroxy aldehydes (aldoses) or polyhydroxy ketones (Ketoses) • They can be derived from poly alcohols (polyols) by oxidation of one carbinol group to a carbonyl group • For example, the simple three-carbon triol, glycerol, can be converted either to the aldotriose i.e. glyceraldehyde or to the ketotriose dihydroxyacetone, by loss of two hydrogens Fig 12.1, Zubay • Since the middle carbon of glyceraldehyde is connected to four different substituents, it is a chiral center leading to two possible forms of glyceraldehyde i.e. stereoisomers (enantiomer; D and L forms) • We may visualize the four, five and six carbon sugars (tetroses, pentoses ad hexoses) as arising from the triose through the stepwise condensation of formaldehyde to either glyceraldehyde or dihydroxyacetone • Indeed this may be the way in which sugars arose in prebiotic times but biosynthesis of sugars occurs by other means Fig 12.2, Zubay * Fig 12.3, Zubay Monosaccharides cyclize to form Hemiacetals; • Aldehyde can add hydroxyl compounds to the carbonyl group • If molecule of water is added, the product is an aldehyde hydrate and if a molecule of alcohol is added, the product is a hemiacetal. Further the addition of a second alcohol results in an acetal Fig 12.4, Zubay • The carbonyl group of a ketone reacts with an –OH group in a similar fashion to form a hemiketal P 202, Boyer 3rd Ed • Sugars readily form intramolecular hemiacetals in cases in which the resulting compound has a five or six member rings • Hemiacetal formation was first observed in optical studies on Dglucose • The optical rotation ([α]D) of a freshly dissolve sample of Dglucose changes with time because it possesses two stereoisomeric hemiacetal (anomers) that are interconvertible in solution Fig 12.5, Zubay • The optical rotation of a freshly prepared solution of either of these compounds eventually approaches an intermediate value that depends on the equilibrium between the two anomers P 202 1 -The α designation for the D series indicates that the aldehyde of the C-1 hydroxyl group is on the same side of the structure as the ring oxygen in Fisher projection while in β configuration the aldehyde is on the opposite side - When sugar is dissolved in water, the two hemiacetals are in equilibrium with the straight chain hydrated form - Conversion of one hemiacetal form into the other is called mutarotation - Equilibrium is reached without an added catalyst in a few hours at room temperature * • Hemiacetals with five member rings are called furanose and hemiacetal with six member rings are called pyranose • There are various way to represent glucose Fig 12.6, Zubay Many Monosaccharides are Physiologically Important; Table 14.2, Murray 27th Ed Table 14.3, Murray 27th Ed Reaction of Monosaccharides; • With several possible kinds of functional groups present in an aqueous carbohydrate solution (hydroxyl groups, hemiacetal or hemiketal and aldehyde or ketone groups), diverse chemical reactions and unique products can be expected • Here we will discuss those reactions that are either of biological significance or used for identification and analysis of carbohydrates • Oxidation-Reduction; o The complete metabolic breakdown of glucose to CO2 and H2O is a process involving several oxidation steps, the details of which will be discussed later on o The functional group most susceptible to oxidation is the aldehyde group, which produces a carboxylic acid group Many oxidizing agent including Tollens’ reagent [silver ammonia complex, Ag(NH3)+2 ] and cupric ion (Cu 2+), are used to identify the presence of reducing sugars o Reducing sugars are those that contain a free aldehyde group and are capable of reducing metal ions in solution Fig 7.11, Boyer 3rd Ed o Reduction of the aldehyde or ketone group of a carbohydrate is also of biological importance o The reduction of aldehyde group in glucose yields sorbitol, a sweetening agent o Another form of reduced carbohydrates are deoxysugars Fig 7.12, Boyer 3rd Ed • Esterification; o Esters are formed by reaction of hydroxyl groups with acids o dehydrogenase o The most important biological esters of carbohydrates are the phosphate esters made in the laboratory with phosphoric acid o In the cell, phosphate esters are produces not by using the very acidic phosphoric acid, but most often by transfer of phosphate group from ATP to carbohydrate hydroxyl group, a reaction catalyzed by enzymes called kinases Fig 7.13, Boyer, 3rd Ed • Amino Derivatives; o The replacement of a hydroxyl group on a carbohydrate by an amino group results in an unusual class of compounds, the amino sugars o Two amino sugars that occur within nature are D-2aminoglucose (glucosamine) and D-2-aminogalactose (galactosamine) Glucosamine and its acetylated derivatives, Nacetlyglucosamine and N-acetylmuramic acid are found as structural components of bacterial cell walls o Similarly, N-acetylglucosamine is a component of chitin, a polymer found in the exoskeleton of insects and crustaceans and o It is also a major structural unit of chondroitin sulfate, a polymeric component of cartilage o The acidic amino sugar N-acetylneuraminic acid (sialic acid), derived from the carbohydrate rhamnose, is a component of glycoproteins and glycolipids Fig 7.14, Boyer 3rd Ed Window of Biochemistry 7.1 Glycoside Formation; i. O-Glycosides o When carbohydrates are reacted with hydroxyl groups under anhydrous mildly acidic conditions, a new linkage, an O-glycosidic bond, is formed Fig 7.15, Glick 3rd Ed o The hydroxyl group of another carbohydrate molecule can substitute for the alcohol in the reaction, linking two monosaccharides to make disaccharides and polysaccharides o • • • • • • Fig 7.16, Boyer 3rd Ed Fig 7.17, Boyer 3rd Ed N-Glycosides o The N-H group of amines can substitute for hydroxyl groups and react at the anomeric carbon center of carbohydrates o This linkage is called an N-glycosidic bond o This type of bond is of paramount importance in the construction of nucleotides such as ATP and in the nucleic acids RNA and DNA Fig 7.18, Boyer 3rd Ed Glycosides are widely distribute in nature; the aglycone may be methanol, glycerol, a sterol, a phenol or a base such as adenine The glycosides that are important in medicine because of their action on the heart (cardiac glycosides) all contain steroids as the aglycone These include derivatives of digitalis and strophanthus such as ouabian, an inhibitor of the Na+-K+ ATPase of cell membrane P 259, Boyer 3rd Ed Other glycosides include antibiotics such as streptomycin Degradation product of cellulose Exclusively present in milk of mammals Abundant in sugar cane and sugar beat Degradation product of starch Polysaccharides; • Serving as monomeric units, the monosaccharides and their derivatives are linked together to form a wide variety of polysaccharides that play diverse biological role • The stability of the variety of O-glycosidic bond makes it possible for monosaccharides to combine into structurally distinct and biologically useful polymers • To define the structure of a polysaccharide, several structural features must be recognized: i. The identity of monomeric units ii. The sequence of monosaccharide residues (if more than one kind is present) iii. The type of glycosidic bonds linking the units iv. The approximate length of the chain (the approximate number of monosaccharide units) v. The degree of branching • Homopolysaccharides are composed of a single type of monosaccharide unit whereas • Heterosaccharides contain two or more types of monosaccharides • The term oligonucleotide is used to denote polysaccharides with small number of monosaccharides (usually fewer than 10) • Glucose and its derivative are most common monomeric units. However, other monosaccharides, including fructose, galactose and derivatives are found in a natural polysaccharides • In some polysaccharides, the individual strands are cross-linked by short peptides. These compounds are component of bacterial cell walls and called peptidoglycans • Storage Polysaccharides; o Plants and animals store the energy molecule glucose in starch and glycogen, respectively o These polysaccharides are stored in the cell in cytoplasmic packages called granules Fig 7.19, Boyer 3rd Ed o Starch is present in the chloroplasts of plants, where it is produced by photosynthetic energy and especially abundant in potatoes, corn and wheat o Glycogen granules are present primarily in liver and muscle cells of animals o Because of numerous hydroxyl groups on the two polysaccharides, much water is associated by hydrogen bonding In fact, each gram of glycogen stored in liver or muscle tissue is hydrated with 2 gram of water i. Starch A mixture of two types of polymeric glucose, amylose and amylopectin When starch is ingested in the human diet, its degradation begins in the mouth The salivary enzyme α-amylase catalyzes the hydrolysis of O-glycosidic bonds, yielding the disaccharides maltose and oligosaccharide products Fig 7.20, Boyer 3rd Ed ii. Glycogen Animals store glucose for energy metabolism in the highly branched polymer, Glycogen Fig 7.20, Boyer 3rd Ed This polymer is identical to amylopectin except that it has more numerous (1 6) branches i.e. about one every tenth glucose residue in the main chain and a much higher average molecular weight (several million) Fig 7.21, Boyer 3rd Ed o - Molecular weight of amylose may range from few thousand to 500,000 - The branch point occur on the average of every twenty fifth glucose residue - The average molecular weight of amylopectin is about 1 million - - - - - Like amylopectin, glycogen consists of a single reducing end and many non reducing ends This is of significance in the mobilization (release) of glucose units for energy metabolism The enzyme glycogen phosphorylase catalyzes the removal of glucose residues from the numerous non reducing ends, providing abundant supplies of glucose when necessary Although glycogen is present both in liver and muscle cells, it is much more abundant in hepatic cells, where it may account for as much as 10% of the wet weight and only about 1% of the weight of muscle cells is glycogen The extended chains and the angle of the α(1 4) glycosidic bond of amylose, amylopectin and glycogen make it possible for then to fold into tightly coiled helical structures Fig 7.22, Boyer 3rd Ed Approximately six glucose residues make up one turn of the helix Other minor form of storage polysaccharides are present in nature - Dextran, found in yeast and bacteria consists of glucose residues connected in to a main chain via α (1 6) glycosidic bonds with occasional branches formed by α (1 2), α (1 3) and α (1 4) glycosidic bonds Bacteria growing on teeth produce extra cellular daextran that accumulates and becomes an important component of dental plaque Inulin, a homo polymer of D-fructose connected by β (1 2) glycosidic linkages, is found in artichokes and other vegetables • Structural Polysaccharides o Some polysaccharides such as cellulose, chitin and mucopolysaccharide are synthesized inside cells but extruded to the outside to provide a protective wall or lubricative coating to cells o Cellulose is the major structural component of wood and plant fibers o This glucose polymer is extremely abundant in nature, making up over 50% of the organic matter in biosphere o It is unbranched polymer connecting D-glucose units together by β(1 4) glycosidic linkages o o o o o o o Fig 7.23, Boyer 3rd Ed Fig 12.11, Zubay The average molecule of cellulose contains between 10,000 and 15,000 glucose residues The β configuration of the glycosidic bonds allows cellulose to form very long and straight chains that differ from the helical coils of starch and glycogen The extended chains of cellulose can associate into bundles of parallel chains fibrils Fig 12.10 Zubay This strong and rigid networks, which provide the scaffolding for plant cell walls, are held together by intra and intermolecular hydrogen boning This strong, stabilized, sheet like arrangement of atoms make cellulose a useful product for clothing, paper, cardboard and building materials Although a portion of our diet consists of vegetables and fruits containing cellulose, we are unable to extract cellular energy from this glucose polymer Animal do not produce enzymes that can catalyze the hydrolysis of β(1 4) glycosidic bonds between the glucose residues in cellulose o o o o o o o Wood-rot fungi and some bacteria obtain nutrient glucose by synthesizing and secreting enzymes (cellulase) that catalyze the hydrolysis of the β(1 4) These organisms are largely responsible for the decaying of dead wood in forest Ruminant animals (cattle, sheep, goat, camels, giraffes) are able to use cellulose as a nutrient source because their second stomachs contain bacteria that secrete cellulases In a similar fashion, termites can digest wood cellulose because their intestinal tracts contain Trichomypha, a symbiotic microorganism that produces cellulase Cellulose and its derivatives do, however, perform an essential role in the diets of animals as bulk fiber or “roughage” to assist the digestion and absorption of nutrients Another important polysaccharide component of plant cell walls is pectin, a polyuronic acid, a C4 epimer of the glucose derivative, D-glucuronic acid Fig 7.24, Boyer 3rd Ed Pectin extracted from plans is used as a gelling agent in the preparation of jams and jellies o o o o o o o The protective exoskeleton of arthropods (insects, crabs, lobsters) are composed primarily of the un-branched homopolysaccharides chitin P 218, Boyer 3rd Ed This polymer is also found in smaller amounts in the cell walls of yeast, fungi and algae The monomeric building block of chitin is the glucose derivative N-acetylglucosamine, linked in β (1 4) glycosidic bonds Fig 7.25, Boyer 3rd Ed P 218, Boyer 3rd Ed Like cellulose, chitin exits in extended chains that are associated into fibers by intra and intermolecular hydrogen bonding Because human has no enzymes that can catalyze the hydrolysis of β (1 4) linkages in chitin, it is indigestible Some structural polysaccharides are found in connective tissue (cartilages and tendons) or extra cellular matrix (ground substance) of higher animals The extra cellular matrix is gel like martial that acts as glue to hold cells together A group of polymers, called mucopolysaccharides, provide a thin, viscous, jellylike coating to cells o The most abundant in this class of polysaccharides is hyaluronic acid which has alternating monomeric units of N-acetlyglucosamine and D- glucuronic acid Fig 7.26, Boyer 3rd Ed o Hyaluronic acid serves as a lubricant in the synovial fluid of joints and is found in the extra cellular matrix of connective tissues o Another component of the extra cellular matrix is chondroitin sulfate, a hetero-polymer mucopolysaccharides o Like hyaluronic acid, it is composed of two alternating monomer units, N-acetylgalactosamine sulfate and Dglucuronic acid Fig 7.27, Boyer 3rd Ed • Structural Peptidoglycans o The rigid cell walls of bacteria, which provide physical protection, are composed primarily of an un-branched heteropolymer of alternating N-acetylglucosamine and Nacetylmuramic acid o The monomer units are linked into an extended backbone by β(1 4) glycosidic bonds o The rigidity and strength of bacterial cell walls are consequences of a network of peptide cross-links between strands of the linear polysaccharides o The amino acid composition and sequence of the peptide links vary from bacterium to bacterium o In Gram-positive bacterium Staphylococcus aureus, two sets of peptides, a tetra-peptide and a penta-peptide of five glycine residues, form the cross-links Fig 7.28, Boyer 3rd Ed o Summary of the composition and biological roles of the polysaccharides is given in this table Table 7.3, Boyer 3rd Ed • Glycoproteins - Structure o Proteins that have covalently bonded carbohydrate units attached to them are called glycoproteins o These proteins are involved in many biological functions including immunological protection, cell-cell recognition events, blood clotting, signal transduction processes and host-pathogen interactions o o o Carbohydrate portion of a glycoprotein usually constitutes 1% to 30% of the total weight, although some glycoproteins contain as much as 50% to 60% carbohydrate The most common monosaccharides found in glycoproteins are glucose, mannose, galactose, fucose, Nacetylgalactosamine, N-acetylglucosamine and Nacetylneuraminic acid (sialic acid) Fig 7.29, Boyer 3rd Ed o o Sugars are attached to proteins as branched oligosaccharide units, usually containing fewer than 15 carbohydrates residues Two important types of covalent linkages involved in the attachment of sugars to protein Fig 7.30, Boyer 3rd Ed o Additional carbohydrates are usually linked to the first monosaccharide on the glycoprotein Fig 7.31, Boyer 3rd Ed o Glycoproteins with unique oligosaccharide compositions and sequences are said to be “information rich” They are frequently found on cell surfaces where they serve as markers to identify the type of cell o Recognition of surface oligosaccharides is involved in diverse processes blood type determination, antibody action, cancer initiation, turnover of aged proteins and viral growth o It has also been discovered that attaching sugar tails to medicinal proteins enhances the therapeutic potency of proteins o Many new discoveries about the structure and action of glycoproteins are coming from the study of proteins that act as “antifreeze agents” in the blood of arctic fish living in subzero waters o Glycoprotein – Function i. Glycoproteins and Cancer When cells transformed from a normal state to a malignant state, changes take place in the glycoproteins on the cell surface These changes usually caused in the cancerous cell by a deficiency of enzymes called glycosyltransferases that attach carbohydrates to membrane proteins by forming O- and Nglycosidic bonds o - Because of a phenomenon called contact inhibition, normal cells usually stop growing when their surface touch Cancerous cells with altered cell surfaces do not recognize the message to stop growing so they pile up on each other ii. Protein Turnover - - Oligosaccharides are also used to mark proteins for age Glycoproteins in the serum are constantly “turned over” with newly synthesized ones taking the place of the aged ones In general, removing of carbohydrate units from glycoproteins almost always increases their susceptibility to proteolytic degradation Fig 7.32, Boyer 3rd Ed Liver cells have on their surfaces receptor protein sites that recognize aged glycoproteins lacking sialic acid Such glycoproteins are taken up by liver cells and degraded by proteolytic enzymes to free amino acids iii. Viral Growth Many viruses including herpes simplex, hepatitis B, influenza and HIV contain protein on their surfaces that have potential sites for linkages of oligosaccharides Carbohydrates may be linked to these proteins using host cell enzymes to produce glycoproteins that are indistinguishable from those on host cells This allows the virus to thrive because it avoids immune surveillance by the host cell and can also attach and fuse to host cell receptors For example HIV envelop protein gp 120 has 20-25 asparagine residues that are potential site for attachment of oligosaccharide units by Nglycosidic linkage iv. Antifreeze Glycoproteins Fish living in the subzero waters of the Antarctic and Arctic are protected from freezing by the presence of antifreeze glycoproteins (AFGPs) in their blood The glycoproteins act by lowering the freezing temperature of water - - - Each AFGP has large number of repeating units consisting of tripeptide Ala-Thr-Ala and a disaccharide usually β-D-galactosyl-(1 3)-α -N-acetyl-D-galactosamine is covalently linked to each threonine hydroxyl group by an Oglycosidic bond Japanese Biochemists have found that the protein having only a single tripeptide unit with disaccharide causes a measurable lowing of the freezing temperature of water, although the naturally occurring glycoproteins usually have several tripeptide-disaccharide units They have shown by NMR spectroscopy that the glycoproteins fold to expose a polar, hydrophilic side (with carbohydrates) that interacts strongly with ice crystals, thus lowering the freezing temperature x ----------------------- x---------------------- x---------------------- x