Biochemistry, 4th Edition P25 pot

7.4 What Is the Structure and Chemistry of Polysaccharides? 203 Cell Walls of Gram-Negative Bacteria In Gram-negative bacteria, the peptidogly- can wall is the rigid framework around which is built an elaborate membrane struc- ture (Figure 7.30). The peptidoglycan layer encloses the periplasmic space and is at- tached to the outer membrane via a group of hydrophobic proteins. As shown in Figure 7.31, the outer membrane of Gram-negative bacteria is coated with a highly complex lipopolysaccharide, which consists of a lipid group (anchored in the outer membrane) joined to a polysaccharide made up of long chains with many different and characteristic repeating structures (Figure 7.31). These many different unique units determine the antigenicity of the bacteria; that is, animal immune systems recognize them as foreign substances and raise antibod- ies against them. As a group, these antigenic determinants are called the O antigens, Gram-positive bacteria Polysaccharide coat Peptidoglycan layers (cell wall) Lipopoly- saccharide Cell wall Outer lipid bilayer membrane Peptidoglycan Inner lipid bilayer membrane (a) Gram-negative bacteria(b) FIGURE 7.30 The structures of the cell wall and membrane(s) in Gram-positive and Gram-negative bacteria. The Gram-positive cell wall is thicker than that in Gram-negative bacteria, compensating for the absence of a second (outer) bilayer membrane. Lipopolysaccharide D-Galactose OO Mannose Rhamnose Heptose KDO NAG Core oligo- saccharide O antigen Proteins Plasma membrane Peptidoglycan Outer cell wall Lipopolysaccharides Abequose Protein P P P P P P ᮣ FIGURE 7.31 Lipopolysaccharide (LPS) coats the outer membrane of Gram-negative bacteria.The lipid por- tion of the LPS is embedded in the outer membrane and is linked to a complex polysaccharide. 204 Chapter 7 Carbohydrates and the Glycoconjugates of Cell Surfaces and there are thousands of different ones. The Salmonella bacteria alone have well over a thousand known O antigens that have been organized into 17 different groups. The great variation in these O antigen structures apparently plays a role in the recognition of one type of cell by another and in evasion of the host immune system. Cell Walls of Gram-Positive Bacteria In Gram-positive bacteria, the cell exterior is less complex than for Gram-negative cells. Having no outer membrane, Gram- positive cells compensate with a thicker wall. Covalently attached to the peptido- glycan layer are teichoic acids, which often account for 50% of the dry weight of the cell wall. The teichoic acids are polymers of ribitol phosphate or glycerol phosphate linked by phosphodiester bonds. Animals Display a Variety of Cell Surface Polysaccharides Compared to bacterial cells, which are identical within a given cell type (except for O antigen variations), animal cells display a wondrous diversity of structure, consti- tution, and function. Although each animal cell contains, in its genetic material, the instructions to replicate the entire organism, each differentiated animal cell care- fully controls its composition and behavior within the organism. A great part of each cell’s uniqueness begins at the cell surface. This surface uniqueness is critical to each animal cell because cells spend their entire life span in intimate contact with other cells and must therefore communicate with one another. That cells are able to pass information among themselves is evidenced by numerous experiments. For example, heart myocytes, when grown in culture (in glass dishes), establish synchrony when they make contact, so that they “beat” or contract in unison. If they are re- moved from the culture and separated, they lose their synchronous behavior, but if allowed to reestablish cell-to-cell contact, they spontaneously restore their synchro- nous contractions. As these and many other related phenomena show, it is clear that molecular structures on one cell are recognizing and responding to molecules on the adjacent cell or to molecules in the extracellular matrix, the complex “soup” of connective proteins and other molecules that exists outside of and among cells. Many of these interactions involve glycoproteins on the cell surface and proteoglycans in the extracellular matrix. The “information” held in these special carbohydrate- containing molecules is not encoded directly in the genes (as with proteins) but is determined instead by expression of the appropriate enzymes that assemble car- bohydrate units in a characteristic way on these molecules. Also, by virtue of the several hydroxyl linkages that can be formed with each carbohydrate monomer, these structures are arguably more information-rich than proteins and nucleic acids, which can form only linear polymers. A few of these glycoproteins and their unique properties are described in the following sections. 7.5 What Are Glycoproteins, and How Do They Function in Cells? Many proteins found in nature are glycoproteins because they contain covalently linked oligosaccharide and polysaccharide groups. The list of known glycoproteins includes structural proteins, enzymes, membrane receptors, transport proteins, and immunoglobulins, among others. In most cases, the precise function of the bound carbohydrate moiety is not understood. Carbohydrate groups may be linked to polypeptide chains via the hydroxyl groups of serine, threonine, or hydroxylysine residues (in O-linked saccharides) (Figure 7.32a) or via the amide nitrogen of an asparagine residue (in N-linked saccharides) (Figure 7.32b). The carbohydrate residue linked to the protein in 7.5 What Are Glycoproteins, and How Do They Function in Cells? 205 C HOH O H H HO H CH 2 OH H NHCCH 3 O H H HO H CH 2 OH O O H OH H CH 2 C H NH Ser ␤-Galactosyl-1,3-␣-N-acetylgalactosyl-serine O HOCH 2 OH OH O O HH O HO H HO H CH 2 OH O H OH ␣-Mannosyl-serine (a) O-linked saccharides Man ␣ 1,2 ␣ 1,2 Man ␣ 1,2 Sia ␣ 2,3 or 6 Sia Gal ␤ 1,4␣ 2,3 or 6 Man ␣ 1,2 Man ␣ 1,3 Man ␣ 1,6 Gal Gal GlcNAc ␤ 1,4␤ 1,4 Man ␣ 1,3 ␣ 1,6 ␤ 1,2 ␤ 1,2␤ 1,2 GlcNAc GlcNAc ␣ 1,3 ␣ 1,6 ␣ 1,3 ␣ 1,6 Man ␣ 1,3 Man ␣ 1,6 ␤ 1,4 GlcNAc ␤ 1,4 ␤ 1,4 ␤ 1,4 GlcNAc GlcNAc ␤ 1,4 GlcNAc ␤ 1,4 GlcNAc GlcNAc High mannose Com p lex Hybrid (c) N-linked glycoproteins CH H Thr CH 3 CH 2 H Ser ␣-Xylosyl-threonine Man O C C NH O C C NH O O HO HO OH O HOCH 2 Man CH 2 O HO HO Man O HO HO OH O HOCH 2 O OH HOCH 2 O OH HOCH 2 Man O HN CH 3 NH Asn GlcNAc (b) Core oligosaccharides in N-linked glycoproteins ␣ 1,6 ␣ 1,3 ␤ 1,4 ␤ 1,4 O O C HN CH 3 GlcNAc O C CH 2 O C C H C N O H Asn Asn Asn Man Man Man Man Man Man Man Man FIGURE 7.32 The carbohydrate moieties of glycopro- teins may be linked to the protein via (a) serine or threonine residues (in the O-linked saccharides) or (b) asparagine residues (in the N-linked saccharides). (c) N-linked glycoproteins are of three types: high man- nose, complex, and hybrid, the latter of which combines structures found in the high mannose and complex saccharides. 206 Chapter 7 Carbohydrates and the Glycoconjugates of Cell Surfaces O-linked saccharides is usually an N-acetylgalactosamine, but mannose, galactose, and xylose residues linked to protein hydroxyls are also found (Figure 7.32a). Oligosac- charides O-linked to glycophorin (see Figure 9.10) involve N-acetylgalactosamine linkages and are rich in sialic acid residues. N-linked saccharides always have a unique core structure composed of two N-acetylglucosamine residues linked to a branched mannose triad (Figure 7.32b, c). Many other sugar units may be linked to each of the mannose residues of this branched core. O-linked saccharides are often found in cell surface glycoproteins and in mucins, the large glycoproteins that coat and protect mucous membranes in the respiratory and gastrointestinal tracts in the body. Certain viral glycoproteins also contain O-linked sugars. O-linked saccharides in glycoproteins are often found clustered in richly glycosylated domains of the polypeptide chain. Physical studies on mucins show that they adopt rigid, extended structures. An individual mucin molecule (M r ϭ 10 7 ) may extend over a distance of 150 to 200 nm in solution. In- herent steric interactions between the sugar residues and the protein residues in these cluster regions cause the peptide core to fold into an extended and relatively rigid conformation. This interesting effect may be related to the function of O-linked saccharides in glycoproteins. It allows aggregates of mucin molecules to form extensive, intertwined networks, even at low concentrations. These viscous networks protect the mucosal surface of the respiratory and gastrointestinal tracts from harmful environmental agents. There appear to be two structural motifs for membrane glycoproteins containing O-linked saccharides. Certain glycoproteins, such as leukosialin, are O-glycosylated throughout much or most of their extracellular domain (Figure 7.33). Leukosialin, like mucin, adopts a highly extended conformation, allowing it to project great dis- tances above the membrane surface, perhaps protecting the cell from unwanted in- teractions with macromolecules or other cells. The second structural motif is ex- emplified by the low-density lipoprotein (LDL) receptor and by decay-accelerating factor (DAF). These proteins contain a highly O-glycosylated stem region that sep- arates the transmembrane domain from the globular, functional extracellular domain. The O-glycosylated stem serves to raise the functional domain of the pro- tein far enough above the membrane surface to make it accessible to the extracel- lular macromolecules with which it interacts. Leukosialin O-linked saccharides Decay-accelerating factor (DAF) LDL receptor Globular protein heads Glycocalyx (10 nm) Plasma membrane FIGURE 7.33 The O-linked saccharides of glycoproteins appear in many cases to adopt extended conformations that serve to extend the functional domains of these proteins above the membrane surface. (Adapted from Jentoft, N., 1990.Why are proteins O-glycosylated? Trends in Bio- chemical Sciences 15:291–294.) 7.5 What Are Glycoproteins, and How Do They Function in Cells? 207 Polar Fish Depend on Antifreeze Glycoproteins A unique family of O-linked glycoproteins permits fish to live in the icy seawater of the Arctic and Antarctic regions, where water temperature may reach as low as Ϫ1.9°C. Antifreeze glycoproteins (AFGPs) are found in the blood of nearly all Antarctic fish and at least five Arctic fish. These glycoproteins have the peptide structure [Ala-Ala-Thr] n -Ala-Ala where n can be 4, 5, 6, 12, 17, 28, 35, 45, or 50. Each of the threonine residues is gly- cosylated with the disaccharide ␤-galactosyl-(1⎯→3)-␣-N-acetylgalactosamine (Figure 7.34). This glycoprotein adopts a flexible rod conformation with regions of threefold left-handed helix. The evidence suggests that antifreeze glycoproteins may inhibit the formation of ice in the fish by binding specifically to the growth sites of ice crystals, in- hibiting further growth of the crystals. N-Linked Oligosaccharides Can Affect the Physical Properties and Functions of a Protein N-linked oligosaccharides are found in many different proteins, including immuno- globulins G and M, ribonuclease B, ovalbumin, and peptide hormones. Many differ- ent functions are known or suspected for N-glycosylation of proteins. Glycosylation can affect the physical and chemical properties of proteins, altering solubility, mass, and electrical charge. Carbohydrate moieties have been shown to stabilize protein con- formations and protect proteins against proteolysis. Eukaryotic organisms use post- translational additions of N-linked oligosaccharides to direct selected proteins to A DEEPER LOOK Drug Research Finds a Sweet Spot A variety of diseases are being successfully treated with sugar-based therapies. As this table shows, several carbohydrate-based drugs are either on the market or at various stages of clinical trials. Some of these drugs are enzymes, whereas others are glycoconjugates. Drug Description Manufacturer Cerezyme (imiglucerase) Vancocin (vancomycin) Vevesca (OGT 918) GMK Staphvax Bimosiamose (TBC1269) GCS-100 GD0039 (swainsonine) PI-88 Adapted from Maeder,T., 2002.Sweet medicines.Scientific American 287:40–47. Additional References: Alper, J.,2001. Searching for medicine’s sweet spot. Science 291:2338–2343. Borman,S., 2007. Sugar medicine. Chemical & Engineering News 85:19–30. This enzyme degrades glycolipids, compensating for an enzyme deficiency that causes Gaucher’s disease. A very potent glycopeptide antibiotic that is typically used against antibiotic- resistant infections. It inhibits synthesis of peptidoglycan in the bacterial cell wall. A sugar analog that inhibits synthesis of the glycolipid that accumulates in Gaucher’s disease. A vaccine containing ganglioside GM2; it triggers an immune response against cancer cells carrying GM2. A vaccine that is a protein with a linked bacterial sugar; it is intended to treat Staphylococcus infection. A sugar analog that inhibits selectin-based inflammation in blood vessels. A sugar that blocks action of a sugar-binding protein on tumors. A sugar analog that inhibits synthesis of carbohydrates essential to tumor metastasis. A sugar that inhibits growth factor–dependent angiogenesis and enzymes that promote metastasis. Genzyme Cambridge, MA Eli Lilly Indianapolis, IN Oxford GlycoSciences Abingdon, UK Progenics Pharmaceuticals Tarrytown, NY NABI Pharmaceuticals Boca Raton, FL Texas Biotechnology Houston, TX GlycoGenesys Boston GlycoDesign Toronto, Canada Progen Darra, Australia 208 Chapter 7 Carbohydrates and the Glycoconjugates of Cell Surfaces various membrane compartments. Recent evidence indicates that N-linked oligosac- charides promote the proper folding of newly synthesized polypeptides in the endo- plasmic reticulum (see A Deeper Look on page 209). Oligosaccharide Cleavage Can Serve as a Timing Device for Protein Degradation The slow cleavage of monosaccharide residues from N-linked glycoproteins circu- lating in the blood targets these proteins for degradation by the organism. The liver contains specific receptor proteins that recognize and bind glycoproteins that are HO HOCH 2 O OH OH O HO HOCH 2 O O NH C CH 3 O CH C H CH 3 N H C N C N CH 3 H H HH 3 C H Ala Ala Th r ␤-Galactosyl-1,3-␣-N-acetylgalactosamine Repeating unit of antifreeze glycoproteins OC CO OC FIGURE 7.34 The structure of the repeating unit of antifreeze glycoproteins, a disaccharide consisting of ␤-galactosyl-(1⎯→3)-␣-N-acetylgalactosamine in glycosidic linkage to a threonine residue. Sia Gal GlcNAc Man Man GlcNAc AsnGlcNAc Gal GlcNAc Man Gal GlcNAc (Does not bind) (Binds tightly to liver asialoglycoprotein receptor) Sia Sia Gal GlcNAc Man Man GlcNAc AsnGlcNAc Gal GlcNAc Man Gal GlcNAc (Binds poorly) Sia Sia Gal GlcNAc Man Man GlcNAc AsnGlcNAc Gal GlcNAc Man Gal GlcNAc (Binds moderately) Sia Gal GlcNAc Man Man GlcNAc AsnGlcNAc Gal GlcNAc Man Gal GlcNAc Sialic acid Sialic acid Sialic acid FIGURE 7.35 Progressive cleavage of sialic acid residues exposes galactose residues. Binding to the asialoglyco- protein receptor in the liver becomes progressively more likely as more Gal residues are exposed. 7.6 How Do Proteoglycans Modulate Processes in Cells and Organisms? 209 ready to be degraded and recycled. Newly synthesized serum glycoproteins contain N-linked triantennary (three-chain) oligosaccharides having structures similar to those in Figure 7.35, in which sialic acid residues cap galactose residues. As these glycoproteins circulate, enzymes on the blood vessel walls cleave off the sialic acid groups, exposing the galactose residues. In the liver, the asialoglycoprotein recep- tor binds the exposed galactose residues of these glycoproteins with very high affin- ity (K D ϭ 10 Ϫ9 to 10 Ϫ8 M). The complex of receptor and glycoprotein is then taken into the cell by endocytosis, and the glycoprotein is degraded in cellular lysosomes. Highest affinity binding of glycoprotein to the asialoglycoprotein receptor requires three free galactose residues. Oligosaccharides with only one or two exposed galac- tose residues bind less tightly. This is an elegant way for the body to keep track of how long glycoproteins have been in circulation. Over a period of time—anywhere from a few hours to weeks—the sialic acid groups are cleaved one by one. The longer the glycoprotein circulates and the more sialic acid residues are removed, the more galactose residues become exposed so that the glycoprotein is eventually bound to the liver receptor. 7.6 How Do Proteoglycans Modulate Processes in Cells and Organisms? Proteoglycans are a family of glycoproteins whose carbohydrate moieties are pre- dominantly glycosaminoglycans. The structures of only a few proteoglycans are known, and even these few display considerable diversity (Figure 7.36). Those known range in size from serglycin, having 104 amino acid residues (10.2 kD), to versican, having 2409 residues (265 kD). Each of these proteoglycans contains one or two types of covalently linked glycosaminoglycans. In the known proteoglycans, the glycosaminoglycan units are O-linked to serine residues of Ser-Gly dipeptide sequences. Serglycin is named for a unique central domain of 49 amino acids com- posed of alternating serine and glycine residues. The cartilage matrix proteoglycan contains 117 Ser-Gly pairs to which chondroitin sulfates attach. Decorin, a small proteoglycan secreted by fibroblasts and found in the extracellular matrix of con- nective tissues, contains only three Ser-Gly pairs, only one of which is normally gly- cosylated. In addition to glycosaminoglycan units, proteoglycans may also contain other N-linked and O-linked oligosaccharide groups. Functions of Proteoglycans Involve Binding to Other Proteins Proteoglycans may be soluble and located in the extracellular matrix, as is the case for serglycin, versican, and the cartilage matrix proteoglycan, or they may be inte- gral transmembrane proteins, such as syndecan. Both types of proteoglycan appear to A DEEPER LOOK N-Linked Oligosaccharides Help Proteins Fold One important effect of N-linked oligosaccharides in eukaryotic or- ganisms may be their contribution to the correct folding of certain globular proteins. This adaptation of saccharide function allows cells to produce and secrete larger and more complex proteins at high levels. Inhibition of glycosylation leads to production of mis- folded, aggregated proteins that lack function. Certain proteins are highly dependent on glycosylation, whereas others are much less so, and certain glycosylation sites are more important for protein folding than are others. Studies with model peptides show that oligosaccharides can al- ter the conformational preferences near the glycosylation sites. In addition, the presence of polar saccharides may serve to orient that portion of a peptide toward the surface of protein domains. However, it has also been found that saccharides usually are not essential for maintaining the overall folded structure after a gly- coprotein has reached its native, folded structure. Source: Helenius, A., and Aebi, M., 2001. Intracellular functions of N-linked glycans. Science 291:2364–2369. 210 Chapter 7 Carbohydrates and the Glycoconjugates of Cell Surfaces function by interacting with a variety of other molecules through their glycosami- noglycan components and through specific receptor domains in the polypeptide it- self. For example, syndecan (from the Greek syndein, meaning “to bind together”) is a transmembrane proteoglycan that associates intracellularly with the actin cyto- skeleton (see Chapter 16). Outside the cell, it interacts with fibronectin, an extra- cellular protein that binds to several cell surface proteins and to components of the extracellular matrix. The ability of syndecan to participate in multiple interactions with these target molecules allows them to act as a sort of “glue” in the extracellu- lar space, linking components of the extracellular matrix, facilitating the binding of (a) Versican Hyaluronic acid– binding domain (link-protein-like) Chondroitin sulfate Protein core Epidermal growth factor–like domains COO – (b) Serglycin COO – Ser/Gly protein core Chondroitin sulfate (c) Decorin COO – Chondroitin/dermatan sulfate chain (d) Syndecan COO – Heparan sulfate Chondroitin sulfate Extracellular domain Cytoplasmic domain Transmembrane domain (e) Rat cartilage proteoglycan Chondroitin sulfate O-linked oligosaccharides Keratan sulfate N-linked oligosaccharides NH 3 + NH 3 + NH 3 + NH 3 + FIGURE 7.36 The known proteoglycans include a variety of structures.The carbohydrate groups of proteogly- cans are predominantly glycosaminoglycans O-linked to serine residues. Proteoglycans include both soluble proteins and integral transmembrane proteins. 7.6 How Do Proteoglycans Modulate Processes in Cells and Organisms? 211 cells to the matrix, and mediating the binding of growth factors and other soluble molecules to the matrix and to cell surfaces (Figure 7.37). Many of the functions of proteoglycans involve the binding of specific proteins to the glycosaminoglycan groups of the proteoglycan. The glycosaminoglycan-binding sites on these specific proteins contain multiple basic amino acid residues. The amino acid sequences BBXB and BBBXXB (where B is a basic amino acid and X is any amino acid) recur repeatedly in these binding domains. Basic amino acids such as lysine and arginine provide charge neutralization for the negative charges of glycosaminoglycan residues, and in many cases, the binding of extra- cellular matrix proteins to glycosaminoglycans is primarily charge-dependent. For example, more highly sulfated glycosaminoglycans bind more tightly to fibronectin. However, certain protein–glycosaminoglycan interactions require a specific carbo- hydrate sequence. A particular pentasaccharide sequence in heparin, for example, binds tightly to antithrombin III (Figure 7.38), accounting for the anticoagulant properties of heparin. Other glycosaminoglycans interact much more weakly. Proteoglycans May Modulate Cell Growth Processes Several lines of evidence raise the possibility of modulation or regulation of cell growth processes by proteoglycans. First, heparin and heparan sulfate are known to inhibit cell proliferation in a process involving internalization of the gly- cosaminoglycan moiety and its migration to the cell nucleus. Second, fibroblast growth factor binds tightly to heparin and other glycosaminoglycans, and the (Outside) Fibronectin Binding site Binding site Growth factor bound to heparan sulfate in matrix Growth factor receptor (Inside) Cytoskeleton (actin) Membrane heparan sulfate proteoglycan Chondroiton sulfate proteoglycan Extracellular matrix Integrin receptor for fibronectin FIGURE 7.37 Proteoglycans serve a variety of functions on the cytoplasmic and extracellular surfaces of the plasma membrane. Many of these functions appear to involve the binding of specific proteins to the glycosaminoglycan groups. OH HNR'' OSO 3 – O O OH OH O OO O COO – OR' OSO 3 – HNSO 3 – OH OSO 3 – OH HNSO 3 – O OSO 3 – (*) O COO – O O FIGURE 7.38 A portion of the structure of heparin, a car- bohydrate having anticoagulant properties. It is used by blood banks to prevent the clotting of blood during do- nation and storage and also by physicians to prevent the formation of life-threatening blood clots in patients re- covering from serious injury or surgery. This sulfated pen- tasaccharide sequence in heparin binds with high affin- ity to antithrombin III, accounting for this anticoagulant activity.The 3-O-sulfate marked by an asterisk is essential for high-affinity binding of heparin to antithrombin III. 212 Chapter 7 Carbohydrates and the Glycoconjugates of Cell Surfaces heparin–growth factor complex protects the growth factor from degradative en- zymes, thus enhancing its activity. There is evidence that binding of fibroblast growth factors by proteoglycans and glycosaminoglycans in the extracellular ma- trix creates a reservoir of growth factors for cells to use. Third, transforming growth factor ␤ has been shown to stimulate the synthesis and secretion of pro- teoglycans in certain cells. Fourth, several proteoglycan core proteins, including versican and lymphocyte homing receptor, have domains similar in sequence to those of epidermal growth factor and complement regulatory factor. These growth factor domains may interact specifically with growth factor receptors in the cell membrane in processes that are not yet understood. Proteoglycan O Ser Xyl Gal Gal O GluA O GluNAc O GluA O GluNAc O O Ser Gal Gal NeuNAc NeuNAc O Gal O GluNAc O Gal O O Ser GalNAc GlcNAc Gal Gal NeuNAc NeuNAc N Asn GlcNAc GlcNAc Man Man Man GlcNAc GlcNAc Gal Gal NeuNAc NeuNAc GalNAc Core protein Link protein Hyaluronic acid Carboxylate group Core protein Hyaluronic acid Link protein O-linked oligosaccharides N-linked oligosaccharides Chondroitin sulfate Keratan sulfate Sulfate group FIGURE 7.39 Hyaluronate (see Figure 7.28) forms the backbone of proteoglycan structures, such as those found in cartilage.The proteoglycan subunits consist of a core protein containing numerous O-linked and N-linked glycosaminoglycans. In cartilage, these highly hydrated proteoglycan structures are enmeshed in a network of collagen fibers. Release (and subsequent re- absorption) of water by these structures during com- pression accounts for the shock-absorbing qualities of cartilaginous tissue. . N-linked oligosaccharides to direct selected proteins to A DEEPER LOOK Drug Research Finds a Sweet Spot A variety of diseases are being successfully treated with sugar-based therapies. As this table. medicines.Scientific American 287:40–47. Additional References: Alper, J.,2001. Searching for medicine’s sweet spot. Science 291:2338–2343. Borman,S., 2007. Sugar medicine. Chemical & Engineering News 85:19–30. This. degrades glycolipids, compensating for an enzyme deficiency that causes Gaucher’s disease. A very potent glycopeptide antibiotic that is typically used against antibiotic- resistant infections.