Glycoconjugates PDF

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Printed by: [email protected]. Printing is for personal use only. No part of this book may be reproduced or transmitted without publisher's prior permission. Violators will be prosecuted. 8.2 Summary The pentose phosphate pathway coordinates three divergent needs of the cell: ribose synthesis, NADPH synthesis, and carbohydrate metabolism. In the first (oxidative) phase of the pentose phosphate pathway, G-6-P is oxidized into 6-phosphogluconate, and then into ribulose-5-phosphate and CO2. One molecule of NADPH is produced at each step. ai l.c om In the nonoxidative second phase of the pentose phosphate pathway, a molecule of ribulose-5-phosphate is isomerized to xylulose-5-phosphate. The subsequent reactions of the second phase are transaldolase and transketolase reactions that allow the rearrangement of these two pentoses into other aldoses and ketoses. The pentose phosphate pathway provides a way for carbohydrates to enter metabolism other than through glycolysis or gluconeogenesis. The NADPH produced in the pentose phosphate pathway is used in lipid biosynthetic pathways. The NADPH is also important in the oxidative response of some cells of the immune system and in maintaining a reducing environment in the cell by reducing oxidized glutathione dimers. Disruptions of these pathways can result in disease. Xylulose-5-phosphate is an important metabolic regulator; it activates protein phosphatase 2A, which in turn dephosphorylates and activates the transcription factor ChREBP, activating several genes involved in energy storage. 8.2 Concept Check ia nn ot ti1 3 8.3 Carbohydrates in Glycoconjugates @g m Generally, summarize the two stages of the pathway and what happens in each stage. Outline the reactions that occur in each stage and the products of those reactions. Explain how the flux through the pentose phosphate pathway coordinates diverse aspects of metabolism and provides for the different needs of the cell. Describe the roles that xylulose-5-phosphate and ChREBP play in carbohydrate metabolism. Carbohydrates are important as structural molecules, as ligands for protein receptors, and in signaling. They can be linked to proteins or lipids on the surface of the cell, and they are also found in macromolecular assemblies outside the cell. This section discusses four main classes of carbohydrate modifications, known as glycoconjugates. These include: Glycoproteins—membrane-bound or extracellular proteins with some amount of carbohydrate modification. Glycolipids—membrane phospholipids with an attached carbohydrate moiety. Proteoglycans—extensive mesh nets of polysaccharides joined to fibrous proteins. Peptidoglycans—lengthy chains of polysaccharides cross-linked by peptides and found in bacterial cell walls. 8.3.1 Glycoproteins in ag Section 8.4 discusses the assembly of these molecules into the extracellular matrix. m ar Glycoproteins are proteins with attached carbohydrate modifications. In eukaryotic cells, these modifications are made initially in the endoplasmic reticulum and are then continued in the Golgi complex. Most glycosylated proteins are secreted by the cell to the outside, or retained to lysosomes, or found as integral plasma membrane proteins; few glycosylated proteins are found in the cytosol or in other organelles. The carbohydrates found in glycoproteins can be either N-linked or O-linked. In N-linked glycoproteins, the carbohydrates are linked via an amide to the side chain of the amino acid asparagine. The consensus recognition sequence, the protein sequence that is recognized and glycosylated, is (Asn-X-Ser/Thr) where X is any amino acid. O-linked glycoproteins are linked via an acetal linkage between the sugar and the hydroxyl group of a serine, or threonine residue, or hydroxylated residues (hydroxylysine and hydroxyproline) (Figure 8.19). ia nn ot ti1 3 @g m ai l.c om Printed by: [email protected]. Printing is for personal use only. No part of this book may be reproduced or transmitted without publisher's prior permission. Violators will be prosecuted. FIGURE 8.19 An example of a glycoprotein. A. Glycoproteins are typically found exposed on the outer leaflet of the plasma membrane. B. and C. Proteins have carbohydrates attached via an asparagine (N-linked) or via a serine or threonine residue (O-linked). m ar in ag Numerous types of monosaccharides can be attached to proteins (Figure 8.20). In addition to some of the more familiar monosaccharides discussed in section 6.1 (glucose, mannose, galactose), there are aldoses (fucose and xylulose) and acetylated amino sugars. This last group includes N-Acetylglucosamine (GlcNAc), N-Acetylgalactosamine (GalNAc), and N-Acetylneuraminic acid (Neu5Ac or NANA). Neuraminic acid and its derivatives are types of sialic acid. It has been estimated that half of all proteins are glycosylated and these modifications range from less than 1% to 60% carbohydrate by mass. @g m ai l.c om Printed by: [email protected]. Printing is for personal use only. No part of this book may be reproduced or transmitted without publisher's prior permission. Violators will be prosecuted. ia nn ot ti1 3 FIGURE 8.20 Common carbohydrates found in glycoproteins. Shown are common examples of monosaccharides found in glycoproteins and their abbreviations. Note the amino sugars N-Acetylglucosamine, N-Acetylgalactosamine, and neuraminic acid (N-Acetyl sialic acid). Dashed boxes highlight differences among these structures. Examples of glycoproteins in ag The roles of glycosylations in proteins are still being elucidated. Some regulate the activity of enzymes or stability of proteins, and may be involved in protein folding. Some modified carbohydrates, such as mannose-6-phosphate, are involved in protein trafficking, that is, the organized movement and marshaling of proteins in the cell. Prokaryotes have limited ability to glycosylate proteins, and among eukaryotic species, there is variation in ability to glycosylate proteins. This difference is important if using bacteria or an insect cell line to produce protein for study, where improper or missing glycosylation can (and does) lead to misfolded or inactive proteins. ABO blood group antigens ar There are thousands of glycoproteins, and their functions in biochemistry are still being elucidated. This section discusses one example in which carbohydrate modification is important, the ABO blood groups. m The ABO blood group antigens are a series of carbohydrate modifications predominantly on a transmembrane protein found on the extracellular surface of erythrocyte plasma membranes (Figure 8.21). In the ABO system there are four blood groups: A, B, AB, and O. People with the O blood type have glycoproteins bound to a core pentasaccharide. Those with type A blood have an additional molecule of N-Acetylglucosamine, whereas those with type B have an additional molecule of galactose. Those with type AB blood have a combination of proteins with the A glycosylation and proteins with the B glycosylation. People with blood type O are known as universal donors because their blood can be given to anyone; their proteins lack these modifications and just have the core modification. People with blood type AB type are known as universal recipients because they can receive blood from anyone; their immune system recognizes both modifications as those of the recipients. m ar in ag ia nn ot ti1 3 @g m ai l.c om Printed by: [email protected]. Printing is for personal use only. No part of this book may be reproduced or transmitted without publisher's prior permission. Violators will be prosecuted. FIGURE 8.21 ABO blood group antigens. The ABO blood group antigens result from carbohydrate modifications on the surface of erythrocytes. People with the O antigen have the core carbohydrate shown. Those with the A blood type have an extra molecule of N-Acetylgalactosamine, while those with the B blood type have an extra molecule of galactose. People with the AB blood group have a mixture of glycoproteins with both modifications found. Receiving the wrong blood type elicits an immune response against the blood cells that are recognized as foreign; this can be fatal. Blood types are usually listed as an ABO letter or letters followed by a (+) or (−) symbol known as the rhesus factor, Rh. The Rh is a different protein that is coded for by a different gene and is positive or negative, indicating the presence or absence of this protein. One group of proteins that bind to and recognize specific glycosylations are lectins, plant glycoproteins that are discussed in Biochemistry: Lectins. Biochemistry Printed by: [email protected]. Printing is for personal use only. No part of this book may be reproduced or transmitted without publisher's prior permission. Violators will be prosecuted. Lectins Glycoproteins are proteins with attached carbohydrates; in contrast, lectins are proteins that recognize and bind tightly to specific carbohydrate sequences. Although lectins were first identified in plants more than 100 years ago, little is known about their function. Lectins may be important in cell adhesion to an extracellular matrix or in the defense of the host against a pathogen. In animals, lectins bind to mannose-6-phosphate residues on glycosylated proteins in the Golgi complex, and they assist in the sorting of these proteins. This process, known as protein trafficking, is a field of intense investigation. Lectins can be monomeric or multimeric proteins, and many are polyvalent (can bind to multiple carbohydrate chains at once). ai l.c om They are globular and have an average size of 40 to 75 kDa. Most lectins have at least one metal ion (either Mg2+ or Ca2+). The lectin concanavalin A from jack beans was found to have an almost identical amino acid sequence to another protein found in the same plants, differing only at the amino and carboxyl termini. Concanavalin A exhibits a property called circular permutation. In this process, after translation and folding, the amino and carboxyl termini of the protein end up in close proximity to one another and then join via a process that is unclear, creating a circular loop through the amino acid backbone. Some other part of the backbone is cleaved, generating new amino and carboxyl termini. @g m In the laboratory, lectins have been used in affinity purification techniques (discussed in the techniques section). Many of the best characterized lectins come from legumes, an abundant starting material for purification. The lectin can be purified from a sample, affixed to a column or resin, and then used as a means of isolating or purifying other glycosylated proteins. The use of lectins in the laboratory decreased when advances in antibody production and molecular biology made it possible to add affinity tags to proteins of interest. However, more recently, fluorescently labeled lectins and advances in fluorescent technology have helped lectins regain their place in the laboratory. ia nn ot ti1 3 Lectins have other applications. Many are categorized as agglutinins—compounds that make blood cells clump together. This happens as the lectins bind to the carbohydrate moiety of cell-surface glycoproteins. Because this binding is carbohydrate specific, lectins can be used to help identify the antigens, in this case, carbohydrate moieties, on the cell surface and perform blood typing. 8.3.2 Glycolipids in ag Although lectins are a useful research tool, not all lectins are benign. One of the first lectins to be purified in 1888 was ricin from castor beans. Ricin binds to glycoproteins on the cell and thus gains entry to the cell through endocytosis. Once inside the cell, ricin is a potent inhibitor of ribosome function. One of the ricin subunits is a glycosidase that cleaves an N-glycosidic bond within the 28S subunit of the ribosome, removing an adenine. This irreversibly damages the ribosome, blocking protein synthesis. The turnover number for this enzyme is 1,777 per minute; that is, the enzyme can inactivate as many as 1,777 ribosomes per minute. Inactivation of the ribosomes results in cell death, and exposure to ricin is often fatal. The lethal dose in humans can be as little as 1.75 μg, which can be obtained from as few as five castor beans. Ricin is suspected of having been used as a poison in espionage. In one of the more infamous assassinations of the Cold War, Bulgarian dissident Georgi Markov was poisoned with a microscopic ricintipped dart fired into his leg from an umbrella as he waited for a bus in London. Four days later he was dead. Autopsy results found a microscopic pellet in his leg containing a 0.2 mg dose of ricin that had failed to completely dissolve. Lipopolysaccharide m ar Glycolipids are amphipathic membrane lipids containing either a glycerol or sphingosine backbone with carbohydrate modifications. Most of these molecules are found on the outer leaflet of the plasma membrane, with the acyl chains of the lipid embedded in the membrane and the carbohydrate moiety exposed to the external environment. This section discusses four examples of glycolipids: lipopolysaccharides, glycosylphosphatidylinositol (GPI), cerebrosides, and gangliosides. Lipopolysaccharide is a component of the bacterial outer membrane. In gram-negative bacteria, it helps to maintain the integrity of the outer membrane; it also protects the outer membrane from lipases and makes it more resistant to attack from phages (bacterial viruses). In animals, however, lipopolysaccharide is toxic; it acts as a pyrogen, which induces fever and activates the immune system. Lipopolysaccharide is partially responsible for the septic shock that is sometimes seen in advanced infections. Lipopolysaccharide has three parts: an outer polysaccharide termed the O antigen, a core oligosaccharide, and lipid A, which is a bacterial lipid comprised of a dimer of glucosamine molecules to which multiple (usually six) fatty acids are attached via ester or amide linkages. The core oligosaccharide acts as an adapter between lipid A and the O antigen. The core can vary considerably, but it often contains one, two, or three monosaccharides attached to lipid A through a glycosidic linkage to the glucosamine group. The outer O antigen also varies from species to species but typically consists of linear combinations of galactose, mannose, rhamnose, and other hexoses. The O antigen is also linked via a glycosidic bond to the core carbohydrate (Figure 8.22). @g m ai l.c om Printed by: [email protected]. Printing is for personal use only. No part of this book may be reproduced or transmitted without publisher's prior permission. Violators will be prosecuted. ia nn ot ti1 3 FIGURE 8.22 Structure of lipopolysaccharide. Lipopolysaccharide is found in the outer membrane of bacteria. It consists of lipid A bound to a core series of carbohydrates, two ethanolamine groups (ETN), and a lengthy carbohydrate tail. Glycosylphosphatidylinositol m ar in ag Glycosylphosphatidylinositol, or GPI anchors are used by eukaryotic cells to anchor proteins to the outer leaflet of the plasma membrane (Figure 8.23). GPI contains a molecule of phosphatidyl inositol, a linker polysaccharide composed of glucosamine and several mannose residues, and a molecule of phosphoethanolamine attached to the protein. As in other carbohydrate-containing molecules, the polysaccharides may be modified with other groups (in this case, other fatty acids or carbohydrates). FIGURE 8.23 Structure of a glycosyl phosphoinositide (GPI) anchor. GPI anchors are used in eukaryotic cells to anchor proteins in the outer leaflet of the plasma membrane. The anchor consists of a molecule of phosphatidyl inositol to Printed by: [email protected]. Printing is for personal use only. No part of this book may be reproduced or transmitted without publisher's prior permission. Violators will be prosecuted. which a mannose-rich carbohydrate linker is attached. The mannose adapter is also linked to a phosphoethanolamine group, which is bound to a protein via an amide link to the carboxy terminus of the protein. Proteins to be affixed to a GPI anchor are translated into the ER, where a hydrophobic sequence at the protein's carboxy terminus attaches the protein to the ER membrane. This sequence is cleaved, and the resulting carboxy terminus is linked via an amide to the amine moiety of phosphoethanolamine, forming the GPI anchor. There are many different types of GPI-anchored proteins, for example, enzymes, adhesion molecules, and proteins found in cell– cell recognition. Several important signal transduction pathways employ GPI-anchored proteins to tether them to the plasma membrane. Cerebrosides and gangliosides m ar in ag ia nn ot ti1 3 @g m ai l.c om Cerebrosides and gangliosides are glycosylated sphingolipids (Figure 8.24). Cerebrosides have a single sugar, usually glucose or galactose, attached to the free hydroxyl group of ceramide through a glycosidic linkage. Gangliosides have an additional three to seven monosaccharides; these are often not linear and include at least one molecule of N-Acetylneuraminic acid (Neu5Ac). Printed by: [email protected]. Printing is for personal use only. No part of this book may be reproduced or transmitted without publisher's prior permission. Violators will be prosecuted. FIGURE 8.24 Structures of cerebrosides and gangliosides. Cerebrosides and gangliosides are glycosphingolipids that are found in higher concentrations in nervous tissue. A. Cerebrosides have the phospholipid ceramide joined to a single simple carbohydrate, while gangliosides have an oligosaccharide modification. B. Dysfunction in the enzymes (shown in blue) that produce or break down these molecules, lead to a variety of human diseases (shown in red). ia nn ot ti1 3 @g m ai l.c om Cerebrosides containing galactose (galactocerebrosides) and gangliosides are highly enriched in the central nervous system but are found to some extent in most tissues. Cerebrosides and gangliosides are internalized and degraded in lysosomes. There are several inborn errors of metabolism (Gaucher's, Tay-Sachs, Nieman-Pick type C, and Fabry's diseases) that involve a deficiency in cerebroside or ganglioside degradation. In these disorders, lysosomes fill with glycolipids; the result is developmental disorders and, in many cases, death (Figure 8.25). FIGURE 8.25 Lysosomal storage disorder. The lysosomes in the micrograph are filled with whorls of membrane, indicative of a lysosomal storage disorder. Medical Biochemistry ar Neuraminidase inhibitors in ag The Neu5Ac and other sialic acid derivatives found in gangliosides also have a role in infectious disease. For example, influenza virus has a protein on the surface of the virus called hemagglutinin that binds to sialic acid residues on the surface of cells. The virus uses this protein to gain entry and infect the cell. Recently, drugs have been developed that attempt to treat the spread of the flu virus through attacking these pathways. These are discussed in Medical Biochemistry: Neuraminidase inhibitors. m There is a disease that accounts for more than half a million deaths each year. It mutates out of control at such a rate that vaccination programs and health organizations constantly work to stay ahead of it. In any given year, this disease may infect as many as 20% of the population. It is easily transmitted through the air or contaminated surfaces, can jump from species to species, and may be transmitted and spread through agriculture and migrating birds. In 1918, an outbreak of this disease killed some 50 to 100 million people, more than half of whom were in their 20s and 30s. That outbreak killed more than 1% of the world's population and caused more deaths in its first 25 weeks than the AIDS pandemic did in its first 25 years. The disease is influenza, commonly known as the “flu.” Influenza is caused by the influenza A virus (Orthomyxoviridae), a single-stranded RNA virus that attacks the epithelial cells of the mucus membranes and respiratory tract. Release of pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α) and γinterferon cause some of the other symptoms of influenza, including fever, muscle aches, and overall tiredness. The influenza virus has an envelope—a lipid bilayer studded with glycoproteins—that surrounds an RNA core. The RNA is in about eight pieces, each of which codes for one or two genes. Two important glycoproteins, hemagglutinin and neuraminidase, are on the surface of the virus particle, or the virion. These two proteins are reflected in the name of the virus, such as H5N1 or H2N2. There are 17 different subtypes of hemagglutinin and 9 different subtypes of neuraminidase. Hemagglutinin is a carbohydrate-binding glycoprotein; essentially, it is a lectin. Hemagglutinin has two main roles in viral pathogenesis. It binds to sialic acid residues on the cell surface (particularly red blood cells and the epithelial cells of the upper respiratory tract); this binding fastens the virion to the host cell. The host cell uses endocytosis to internalize pieces of membrane, and viruses bound to sialic acid are internalized in this process. Inside the cell, these endosomes are processed as they normally Printed by: [email protected]. Printing is for personal use only. No part of this book may be reproduced or transmitted without publisher's prior permission. Violators will be prosecuted. would be. That is, proton pumps begin to acidify the endosome in preparation for fusion with other vesicles and transformation into a lysosome. However, in this instance, acidification of the contents is a trap. As the endosome is acidified, hemagglutinin changes in structure, forming a single α helix more than 60 amino acids long. The formation of this helix exposes a short hydrophobic peptide sequence at the end, which is thought to act as a molecular grappling hook, fastening into the endosomal membrane and facilitating fusion with the virion, releasing the viral contents into the cytoplasm of the host cell. Inside the host cell, ribosomes bind and translate the viral RNA into viral proteins, including an RNA-dependent RNA polymerase (viral polymerase). The viral polymerase and messages translocate to the nucleus, where the new viral messages are transcribed. These new messages are transported back to the cytosol, where they assemble with riboproteins and other viral proteins at the cell membrane. Viruses bud from the cell but are still bound to the membrane by hemagglutinin. Neuraminidase, the other glycoprotein of interest in this story, is a hydrolytic enzyme that cleaves sialic acid residues from the surface of the viral envelope and the cell. The removal of sialic acid enables the virus to leave the cell and infect other cells nearby; it also prevents viruses from binding to one another. @g m 8.3.3 Proteoglycans and non-proteoglycan polysaccharides ai l.c om One line of drug development for influenza is based on identifying and exploiting differences between the biology of the pathogen and the infected person. In the case of the influenza virus, the presence of neuraminidase is one of the differences. Drugs that inhibit neuraminidase act by blocking the function of the enzyme; that is, the drugs block cleavage of sialic acid groups. The four drugs for influenza currently on the market are competitive inhibitors of neuraminidase. The infected cells can still make mature viral particles, but the drugs render those particles unable to release and propagate the infection. Although these drugs are not cures for influenza, they tend to lessen the severity of the infection and reduce the time with symptoms by one day. ia nn ot ti1 3 Proteoglycans are a major component of the extracellular matrix. They have two major parts: a glycosaminoglycan, or GAG, which is a large polysaccharide consisting in part of amino sugars, and a protein core. One significant difference between glycoproteins and proteoglycans is the overall amount of carbohydrate. Although glycoproteins can have extensive carbohydrate modifications, they are still predominantly proteins. Proteoglycans, on the other hand, have far more carbohydrate than protein. Cross-linking in proteoglycans between proteins and carbohydrate chains creates an extensive macromolecular network. One non-proteoglycan carbohydrate worthy of mention is hyaluronic acid. This lengthy polysaccharide is comprised of amino sugars but lacks the protein component found in proteoglycans. m ar in ag Despite the amino groups on the carbohydrate moiety of proteoglycans, the molecule often carries an overall negative charge. This is due to oxidized carbohydrates via carboxylic acid groups, or sulfates being coupled to the carbohydrate. These negatively charged groups have sodium counter ions, which draw significant amounts of water into the structure. The ability to absorb water serves various functions, depending on the proteoglycan. Most proteoglycans are viscous, and many act as gels. Hence, some of these molecules can act as lubricants, keeping joints moving freely. Other proteoglycans form a much firmer gel and resist compaction, acting as shock absorbers. The layer of carbohydrate presents a partial barrier to both pathogens and cancerous cells, preventing or slowing their progression through a tissue (Figure 8.26). FIGURE 8.26 Structure of a proteoglycan. Proteoglycans consist of lengthy carbohydrate polymers linked to a core protein. Often these are all organized on a central molecule of the polysaccharide hyaluronic acid. Examples of glycosaminoglycans Printed by: [email protected]. Printing is for personal use only. No part of this book may be reproduced or transmitted without publisher's prior permission. Violators will be prosecuted. Examples of common glycosaminoglycans found in humans include: ai l.c om Heparan sulfate—this linear polysaccharide is comprised of repeating disaccharides, usually glucuronic acid and NAcetylglucosamine. The polysaccharide is sulfated at several locations in each disaccharide unit. Heparin is a related glycosaminoglycan that is enriched in iduronic acid and N-Acetylglucosamine. Heparan sulfate is found in the extracellular matrices of most animals. in ag ia nn ot ti1 3 @g m Chondroitin sulfate—this linear polysaccharide is comprised of repeating glucuronic acid and N-Acetylgalactosamine disaccharides. As with heparan, it is multiply sulfated on each residue (typically on the 4 and 6 position of each NAcetylglucosamine). Isomerization of glucuronic acid molecules into iduronic acid produces the molecule dermatan sulfate (a common component of epithelial tissues, such as skin and blood vessels). Chondroitin sulfate is found in materials of high tensile strength, such as tendons, cartilage, and the aorta. Many people currently take supplements of glucosamine and chondroitin for joint health, although their efficacy is debated. m ar Keratan sulfate—this linear polysaccharide is a polymer of galactose and N-Acetylglucosamine. It is typically less sulfated than chondroitin or heparan sulfate, having a single sulfate on C-6 of either monosaccharide. Keratan sulfate is found in bone, horn, and cornea. These three polysaccharides have a far greater degree of variability than is seen in other classes of biological molecules. The sequence of a nucleotide or protein, although not set in stone, is highly invariant. Considerable biochemical effort is placed on making sure that DNA is copied with high fidelity—few to no mistakes—or that proteins are synthesized without error. The same does not seem to hold for proteoglycans. Depending on the tissue, organism, or even sample, there can be variability in characteristics such as degrees of sulfation, incorporation of other monosaccharides, isomerization or epimerization of monomers Printed by: [email protected]. Printing is for personal use only. No part of this book may be reproduced or transmitted without publisher's prior permission. Violators will be prosecuted. in the chain, and length of the chain. Whether this variability has a distinct purpose in biochemistry and what it is selected for are unclear, although it is known that tampering with these ratios can be harmful. In 2008, a batch of heparin was contaminated with chondroitin that had been chemically oversulfated. Patients given this heparin died rapidly from anaphylaxis, the severe allergic response commonly associated with bee stings or peanuts in those who are severely allergic. Further characterization revealed that this modified polysaccharide can elicit a release of the vasodilator bradykinin. Although the mechanism of the release of bradykinin is still unknown, this example shows that the interactions of cells with glycosaminoglycans can be harmful, and strongly suggests that the degree of sulfation of these polysaccharides is not random. Hyaluronic acid is a non-proteoglycan matrix polysaccharide ia nn ot ti1 3 @g m ai l.c om Hyaluronic acid differs from the other polysaccharides discussed here, in that it is not a part of a proteoglycan. Rather, it is secreted as a lengthy linear polysaccharide of glucuronic acid and N-Acetylglucosamine. Molecules of hyaluronic acid can be huge, containing up to 25,000 monomers and ranging in molecular weight from several kilodaltons up to 20 million daltons. The average size ranges from 3 to 5 million daltons, depending on the tissue. Hyaluronic acid is synthesized by a complex in the plasma membrane and excreted from the cell as it is synthesized (whereas other glycosaminoglycans are added in the ER and Golgi complex). The protein components of proteoglycans vary widely Numerous matrix proteins have been found to be involved in proteoglycan formation. We will discuss several fibrous proteins found in the matrix and other common components of proteoglycans in the next section. 8.3.4 Peptidoglycans m ar in ag Peptidoglycans are the building blocks of the cell wall in bacteria. They are composed of a dimeric repeat of N-Acetylglucosamine (GlcNAc) and N-Acetylmuramic acid (MurNAc) in a β-1,4 linkage (Figure 8.27). Extending from each molecule of N-Acetylmuramic acid is a short (4 to 5 residue) peptide, linked through the oxygen on C-3. The amino acids found in the peptide vary by species, but include the L isomers of alanine and lysine, and the D isomers of glutamine, glutamic acid, and alanine. Please recall that the L isomers of amino acids are the common form found in proteins; D isomers are unusual and are found only in a few locations, such as the bacterial cell wall. ia nn ot ti1 3 @g m ai l.c om Printed by: [email protected]. Printing is for personal use only. No part of this book may be reproduced or transmitted without publisher's prior permission. Violators will be prosecuted. FIGURE 8.27 Structure of the peptidoglycan cell wall in gram-positive bacteria. Peptidoglycans consist of lengthy linear carbohydrate chains cross-linked by short peptides. While the carbohydrate and amino acid composition varies slightly across different phyla of bacteria, the overall structure is conserved. m ar in ag Cross-linking of these peptides with a pentaglycine linker by a transpeptidase provides a rigid net that gives the bacteria structure. Several antibiotics act by taking advantage of the chemistry of the bacterial cell wall. For example, penicillin and its derivatives irreversibly inhibit the transpeptidase, blocking formation of the peptide linkage between peptidoglycan chains in gram-positive bacteria (Figure 8.28). The chains of peptidoglycan in gram-negative