Carbohydrates I & II Notes

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Saccharides

Saccharide is another name for a carbohydrate. Simple saccharides are the monosaccharides, commonly called sugars. Glucose is an example of a monosaccharide. Others are shown in Figure 11.2 and Figure 11.3. We use the terms monosaccharide, oligosaccharide, or polysaccharide to refer to compounds composed of a single sugar, several sugars linked together, or many sugars linked together, respectively.

The term carbohydrate derives from the fact that many of them have a formula that can be simplified to (CH2O)n. Some of these compounds are chemically modified, however, and do not fit the formula due to the modification.

Saccharides play a variety of roles in living organisms, including energy storage (monosaccharides and oligosaccharides), structural roles (polysaccharides), and cell identity (oligosaccharides).

Monosaccharide Nomenclature

Monosaccharides are the simplest sugars, having the formula (CH2O)n. The smallest molecules usually considered to be monosaccharides are those with n = 3.

Monosaccharides can be categorized according to their value of 'n,' as shown below:

 n

Category

3

Triose

4

Tetrose

5

Pentose

6

Hexose

7

Heptose

8

Octose

Monosaccharides can exist as aldehydes or ketones and are called aldoses or ketoses, respectively. For example, THIS shows the structures of glyceraldehyde, an aldo-triose, and dihydroxyacetone, a keto-triose. Glyceraldehyde and dihydroxyacetone have the same atomic composition, but differ only in the position of the hydrogens and double bonds.

Carbons in a monosaccharide are numbered such that the aldehyde group is carbon number one or the ketone group is carbon number two.

The three dimensional arrangement of atoms around a carbon atom are such that if four different groups are attached to it, they can be arranged in two different ways. Such a carbon is described as chiral or asymmetric. The two molecules with different three-dimensional arrangement are mirror images of each other, and the two different forms are called stereoisomers. For example, D-glyceraldehyde and L-glyceraldehyde (HERE) are mirror images of each other (stereoisomers) and cannot be superimposed on each other. Such molecules with these properties are called enantiomers. The designation 'D-' or 'L-' is an older nomenclature still used widely in biochemistry. It originally described whether the compound rotated a plane of polarized light to the right (D for dextro) or left (L for left). This is not absolute, however, because it depends on the reference compound chosen. The R-S nomenclature, which is an absolute naming scheme for organic chemistry will not be used here. The predominant monosaccharides found in nature have the 'D' configuration.

Sugars with more than one asymmetric carbon have many possible three dimensional configurations. In general a molecule with m chiral centers will have 2m stereoisomers. The multiple stereoisomeric forms means that not all stereoisomers will be mirror images of each other. Stereoisomers that are not mirror images of each other are called diastereomers.

Ketose-aldose pairs of sugars frequently are named by inserting the letters 'ul' in the name of the corresponding aldose to derive the name of the ketose. An example is erythrose - erythrulose.

Sugar Ring Structures

When sugars cyclize, they typically form furanose or pyranose structures. These are molecules with five-membered or six-membered rings, respectively. Cyclization creates a carbon with two possible orientations of the hydroxyl around it. Cyclization of an aldose occurs by intramolecular reaction with the aldehyde and alcohol groups to form a hemiacetal. Cyclization of a ketose occurs by intramolecular reaction with the ketone and alcohol groups to form a hemiketal. In either case, a new asymmetric carbon is created by the reaction and we refer to the carbon as the anomeric carbon and the two possible configurations as anomers. The two possible configurations of the hydroxyl group are called alpha and beta, which correspond to the hydroxyl being in the "down" and "up" positions, respectively, in standard projections. Anomers are capable of interconverting between alpha and beta positions in a process is called mutarotation IF the hydroxyl group of the hemiacetal or hemiketal is unaltered.

Figure 11.7 shows that a pyranose, such as glucose, has two common conformational isomers, referred to as the "boat" and "chair" form. For glucose (and most sugars), the chair form is more stable because the hydroxyls of carbons 1 and 2 are further removed and thus have less steric interference with carbons 3, 4, and 5. Figure 11.8 illustrates conformational isomers for the furanose ribose. These structures are different forms of the so-called Envelope conformation, designated as C3-endo and C2-endo.

Diastereomers

Chiral carbons (carbons covalently linked to 4 different entities) give rise to stereoisomers. Molecules that are stereoisomers have the same formula and the same structure, but have their atoms arranged in different ways in 3D space. For example, compare the structures of D-glyceraldehyde and L-glyceraldehyde. Notice that they are nonsuperimposable.

Common sugars typically have not one, but multiple chiral carbons. Glucose, for example, contains four chiral carbons. For a carbon with 'm' chiral carbons, the number of possible stereoisomers is 2m. Thus, for glucose, there are 16 possible stereoisomers. The form most commonly found in living organisms, D-glucose, has only one mirror image. In fact, any stereoisomer has only one mirror image. The other 14 stereoisomers of glucose that are not mirror images of it are called diastereomers. That is, diastereomers are stereoisomers that are not mirror images of each other.

Sugar ring structures can be written in a variety of ways. Figures 11.4 and 11.5 show both glucose and fructose in linear and circular projections. Linear projections are called Fischer projections and circular projections are called Haworth projections. Note that neither is exactly "anatomically correct", but give an approximation of the structure of each form.

Derivatives of Monosaccharides
Monosaccharides
can be chemically altered in several ways to provide new classes of compounds. These include:

Acids and Lactones - made by mild oxidation of an aldose, for example, to form an aldonic acid (see HERE). In metabolic pathways, oxidation at carbon 6 of glucose yields glucuronic acid. Sugars that react with cupric ion to become oxidized are called reducing sugars. Unmodified aldoses will be reducing sugars because the aldehyde is readily oxidized to a carboxyl group.

Alditols - made by reducing the carbonyl group of a sugar. The resulting polyhydroxy compounds are called alditols. Important ones include erythritol, D-mannitol, and D-glucitol (also called sorbitol).

Amino Sugars - made by replacing a hydroxyl of a sugar with an amine group. Two common examples are beta-D-glucosamine and beta-D-galactosamine (see HERE). Common molecules derived from these include beta-D-N-acetylglucosamine, muramic acid, N-acetylmuramic acid, -D-N-acetylgalactosamine, and N-acetyl-neuraminic acid (also called sialic acid). Amino sugars are often found in oligosaccharides and polysaccharides.

Glycosides - formed by elimination of water between the anomeric hydroxyl of a cyclic monosaccharide and the hydroxyl group of another compound. Glycosides do NOT undergo mutarotation in the absence of an acid catalyst, so they remain locked in the alpha or beta configuration. (Remember that the FREE hydroxyl group on the anomeric carbon can undergo a change in orientation from the alpha to beta position, or vice versa. This change is called mutarotation). Glycosidic bonds are very common in plant and animal tissues. Many glycosides are known. Some, such as ouabain or amygdalin are very poisonous. Others, such as the common oligosaccarides and polysaccharides found in our cells, are not.

Oligosaccharides

Glycosidic bonds between monosaccharides give rise to oligosaccharides and polysaccharides. The simplest oligosaccharides, the disaccharides, include compounds such as sucrose and lactose, which are referred to as sugars (like the monosaccharides). Other common disaccharides include trehalose, maltose, gentiobiose, and cellobiose.

Four features distinguish disaccharides from each other:

  1. The two specific sugar monomers and their stereoconfigurations
  2. The carbons involved in the linkage
  3. The order of the monomeric units, if they are different kinds
  4. The anomeric configuration of the hydroxyl group on carbon 1 of each residue

Oligosaccharides are also found as part of glycoproteins and play a role in cell recognition/identity. Oligosaccharides form the blood group antigens. In some cells, these antigens are attached as O-linked glycans to membrane proteins. Alternatively, the oligosaccharide may be linked to a lipid molecule to form a glycolipid. These oligosaccharides determine the blood group types in humans.

Polysaccharides

Polysaccharides are polymers of monosaccharide units. The monomeric units of a polysaccharide are usually all the same (called homopolysaccharides), though there are exceptions (called heteropolysaccharides). In some cases, the monomeric units are modified monosaccharides. Polysaccharides differ in the composition of the monomeric unit, the linkages between them, and the ways in which branches from the chains occur. Common polymers, their monomeric units, and linkages/branches are shown below:

Polysaccharide Name  Monomeric Unit Linkages
Glycogen D-Glucose alpha 1->4 links with extensive alpha1->6 branches
Cellulose D-Glucose beta 1->4
Chitin N-Acetyl-D-glucosamine beta 1->4
Amylopectin D-Glucose alpha 1->4 links with some alpha 1->6 branches
Amylose D-Glucose alpha 1->4

Linkages between the individual units require special enzymes to break them down. For example, the alpha 1-> 4 linkages between glucose units in glycogen, amylose, and amylopectin, are readily broken down by all animals, but only ruminants (cows) and related animals contain symbiotic bacteria with an enzyme (cellulase) that can break down the beta 1-> 4 linkages between individual glucose units in cellulose. As a result, the huge amount of cellulose in the biosphere is unavailable as an energy source to most animals.

The secondary structure of the polysaccharides range from the bent structure of starch and glycogen (HERE) to the planar structure of cellulose (see HERE).

Polysaccharides are used to some extent for energy storage in almost all higher organisms. Animals use glycogen. Plants use starch, which is composed of amylose and amylopectin. In both plants and animals, the polysaccharides used for energy storage are readily broken down into monomeric units that can be rapily metabolized to produce ATP. In addition to polysaccharides used for energy storage, plants use different polysaccharides, such as cellulose, for structural purposes in their cell walls. The exoskeleton of many arthropods and mollusks is composed of chitin, a polysaccharide of N-acetyl-D-glucosamine.

Polysaccharides containing a single sugar, such as glucose, are referred to as glucans. Others, which contain only mannose, are called mannans. Still others, containing only xylose, are called xylans. Glucans with structural roles include some in fungi, which have glucoses joined by beta 1->3 or beta 1->6 bonds.

Other plant polysaccharides include the xylans and the glucomannans. The xylans are polymers of D-xylopyranose, often with substituent groups attached. The glucomannans, on the other hand, are heteropolymers of glucopyranose and mannopyranose joined by beta 1->4 linkages with beta 1->6 branches to other substituents. The glucomannans and xylans are often grouped together and called hemicellulose.

Chitin is a homopolymer of N-acetyl-D-glucosamine, with units joined by beta 1-> 4 bonds. Chitin is found in organisms as diverse as algae, fungi, insects, arthropods, mollusks, and insects.

Glycosaminoglycans

Another group of polysaccharides of importance is the glycosaminoglycans. These are heteropolysaccharides containing either N-acetylgalactosamine or N-acetylglucosamine as one of their monomeric units. Examples include chondroitin sulfates and keratan sulfates of connective tissue, dermatan sulfates of skin, and hyaluronic acid. All of these are acidic, through the presence of either sulfate or carboxylate groups. Examples are shown in Figure 11.15.

A major function of glycosaminoglycans is formation of a matrix to hold together the protein components of skin and connective tissue in animals. An example is the proteoglycan complex (protein-carbohydrate complex) in cartilage

Hyaluronic Acid also acts in the body as a viscosity-increasing agent or lubricating agent in the vitreous humor of the eye and synovial fluid of joints.

Heparin is yet another highly sulfated glycosaminoglycan. Part of the repeating unit of its complex chain is shown here. Heparin is used medicinally to inhibit clotting in blood vessels.

Oligosaccharides and Polysaccharides as Cell Markers

Oligosaccharides play a role in cell recognition/identity. Oligosaccharides form the blood group antigens (HERE) by linkage to proteins in blood cell membranes forming glycoproteins or, in some cases, to lipids, forming glycolipids. Three different oligosaccharide structures give rise to the blood groups - A, B, and O. The base structure of each contains the structure of the O antigen. Specific glycosyltransferases add the extra monosaccharide to the O antigen to give rise to either the A or B antigen.

Molecules of the blood group antigens represent only a special case of a much more general phenomenon - cell marking by oligosaccharides. In multicellular organisms, different kinds of cells must be marked on their surfaces so that they can interact properly with other cells and molecules. The surface of many cells are nearly covered with polysaccharides, which are attached to either proteins or lipids in the cell membrane. Some animal cells have an extremely thick coating of polysaccharides called a glycocalyx.

The cell surfaces of many cancer cells are abnormal, which may account for the loss in tissue specificity that such cells commonly exhibit.

Properties of oligosaccharides that aid in their role as cellular markers:

They can present a wide variety of structures in relatively short chains. The multiple possible monomers, linkages, and branching patterns allow a vast, but specific vocabulary.

They are very potent antigens (antibodies can be elicited swiftly against them)

More than half of all eukaryotic proteins carry covalently attached oligosaccharide or polysaccharide chains. In glycoproteins, sugars are attached either through the amide nitrogen atom in the side chain of asparagine (termed N-linkage - see HERE) or to the oxygen atom in the side chain of serine or threonine (called O-linkage - see HERE). In the case of N-linkage, asparagine can accept an oligosaccharide only if the residue is part of an ASN-X-SER or ASN-X-THR sequence (X can be any residue). Thus, one can the predict possible N-glycoysylation sites in a protein sequence. The common carbohydrate core of all N-linked oligosaccharides is shown in Figure 11.20.

A very important further use of N-linked oligosaccharides is in intracellular targeting in eukaryotic organisms. Proteins destined for certain organelles or for excretion from the cell are marked specifically by oligosaccharides during posttranslational processing to ensure they arrive at their proper destinations. Some O-linked glycans appear to function in intracellular targeting and molecular and cellular identification. An example is found in the blood group antigens.

Roles of Endoplasmic Reticulum and Golgi Complex

Protein glycosylation occurs inside the lumen of the endoplasmic reticulum and the Golgi complex (Figure 11.23). Glycosylation occurs after a protein has entered the endoplasmic reticulum. N-linked glycosylation begins in the endoplasmic reticulum and then continues in the Golgi apparatus. O-linked glycosylation occurs exclusively in the Golgi apparatus.

Dolichol phosphate (structure HERE) provides a lipid structure on which oligosaccharides destined for attachment as N-linked glycosyl groups are synthesized. "Flipping" of the dolichol-phosphate-glycosyl complex facilititates its movement into the lumen of the endoplasmic reticulum. Recycling of dolichol pyrophosphate (released after the oligosaccharide complex is transferred to a protein) is targeted by the antibiotic bacitracin (inhibits phosphatase action on dolichol phosphate). Another antibiotic, tunicamycin inhibits the first step in synthesis of the process by inhibiting the addition of the first N-acetyl-glucosamine.

Transport vesicles carry proteins from the endoplasmic reticulum to the Golgi complex during the glycosylation process.

Mannose-6-phosphate (M6P) targets lysosomal enzymes to their destinations. Lysosomes are cellular organelles that degrade and recycle materials in cells. Synthesis of M6P is shown in Figure 11.24. People deficient in the phosphotransferase enzyme develop a disease called I-cell disease, which is characterized by the absence of eight acid hydroloases normally present in the lysozomes. Instead, these proteins lack M6P (containing mannose instead) and are found in abundance in the blood and urine.

Lectins

For oligosaccharides or polysaccharides to serve as recognition signals, there must be proteins that bind to them specifically. One such class is the immunoglobulins. Another very diverse group of saccharide-binding proteins is the lectins. In plants, lectins appear to play defensive roles and aid in adhering nitrogen-fixing bacteria to roots. In animals, lectins seem to be involved in interactions between cells and proteins of the intercellular matrix, such as collagen, and help to maintain tissue and organ structure. The molecular structures bound by various lectins is shown in Figure 11.28.

Hemagglutinin

Viruses bind to specific structures on the surfaces of cells. In the case of the influenza virus, the target residues are sialic acid (figure HERE) on cell surface glycoproteins. A viral protein called hemagglutinin binds to these sugar residues. Release of the virus from the sialic acid (to allow it to infect the cell) requires action of an enzyme called neuraminidase and this enzyme is the target of anti-influenza drugs.