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Varki A, Cummings RD, Esko JD, et al., editors. Essentials of Glycobiology
This thing covers the simple building blocks of glycans and fundamental considerations regarding glycan structure by presenting chemical concepts. Settings of linking glycans and also structural explicate of the very same are disputed to administer the groundwork for expertise longer glycans (Chapter 3).
INTRODUCTION to GLYCAN TERMINOLOGY
In this book, and in the previously editions, the ax glycan is used. Still, a hold of surname are frequently used to describe sugar polymers in other textbooks and also the literature. In the 19th century, sugar-based building materials were described as carbohydrates, or “hydrates the carbon,” the are based on the basic formula Cx(H2O)n that likewise possess a carbonyl group, either an aldehyde or a ketone. Monosaccharides are the most basic of this polyhydroxylated carbonyl compounds (saccharide is derived from the Greek word because that sugar or sweetness).
Monosaccharides room joined together to give rise come oligosaccharides or polysaccharides. Typically, the ax “oligosaccharide” refers to any kind of glycan that contains less 보다 20 monosaccharide residues associated by glycosidic linkages. The term “polysaccharide” is generally used to denote any linear or branched polymer consists of monosaccharide residues, such as cellulose (Chapters 14 and also 24). Thus, the relationship of monosaccharides to oligosaccharides or polysaccharides is analogous to the of amino acids and proteins, or nucleotides and also nucleic mountain (polynucleotides).
The term “glycoconjugate” is frequently used to explain a macromolecule that includes monosaccharides covalently connected to protein or lipids. The prefix “glycol” and the suffixes “saccharide” and also “glycan” indicate the existence of carbohydrate constituents (e.g., glycoproteins, glycolipids, and proteoglycans). Simply as is observed v proteins in nature, additional structural diversity can be imparted to glycans by modifying their hydroxyl teams with phosphate, sulfate, or acetyl esters and/or your amino groups with acetyl or sulfate groups.
A carbohydrate might be termed “complex” if that contains much more than one form of monosaccharide structure unit. The glucose-based polymer cellulose is an example of a “simple” carbohydrate, whereas a galactomannan polysaccharide, composed of both galactose and also mannose, is an example of a complicated carbohydrate. However, also so-called basic glycans, such together cellulose and also starch, regularly have very complex molecular frameworks in 3 dimensions. The term facility carbohydrates consists of glycoconjugates, conversely, the ax carbohydrates per se would certainly not. Additional nomenclature problems are spanned in this chapter and Chapter 3. A more detailed and comprehensive listing that carbohydrate nomenclature rules has been released (see McNaught 1997 and also Varki et al. 2015 in further Reading in ~ the finish of this chapter), and also Online postposition 1B.
MONOSACCHARIDES: straightforward STRUCTURES and STEREOISOMERISM
The group of monosaccharide structures started in the late 19th century v the pioneering occupational of Emil Fischer. All simple monosaccharides have actually the general empirical formula Cx(H2O)n, wherein n is one integer varying from 3 to 9. As pointed out briefly in thing 1, every monosaccharides covers a chain the chiral hydroxymethylene units, which terminates at one finish with a hydroxymethyl group and also at the various other with one of two people an aldehyde team (aldoses) or an α-hydroxy ketone team (ketoses). Glyceraldehyde is the most basic aldose and also dihydroxyacetone is the simplest ketose (Figure 2.1). The frameworks of glyceraldehyde and also dihydroxyacetone are unique in that glyceraldehyde contains an asymmetric (chiral) carbon atom (Figure 2.1), whereas dihydroxyacetone walk not. With the exemption of dihydroxyacetone, all monosaccharides have at least one asymmetric carbon atom, the total number being equal to the number of internal (CHOH) teams (n−2 because that aldoses and n−3 for ketoses through n carbon atoms). The variety of stereoisomers corresponds to 2k, where k equates to the number of asymmetric carbon atoms. For example, one aldohexose v the basic formula C6H12O6 and four asymmetric carbon atom (i.e., four (CHOH) groups) can be described in 16 possible isomeric develops (Figure 2.1).
Structures of glyceraldehyde and also dihydroxyacetone. (A) Fischer projection. (B) D- and L-glyceraldehyde. The chiral main carbon in glyceraldehyde offers rise come two feasible configurations that the molecule, termed D and L.
The numbering of carbon atoms complies with the rules of necessary chemistry nomenclature. The aldehyde carbon is described as C-1 and also the carbonyl team in ketoses is referred to as C-2. The all at once configuration (D or L) of each sugar is determined by the absolute configuration of the stereogenic facility furthest native the carbonyl team (i.e., through the highest possible numbered asymmetric carbon atom; this is C-5 in hexoses and also C-4 in pentoses). The construction of a monosaccharide is most easily determined by representing the framework in a Fischer projection. If the five (or various other non-H group) is on the appropriate in the Fischer projection, the overall configuration is D. If the five (or various other non-H group) is top top the left, the overall configuration is l (Figure 2.2). This figure additionally shows D- and L-glucose in the cyclic type (chair conformation) found in solution. Most vertebrate monosaccharides have actually the D configuration v the exemption of fucose and iduronic acid (IdoA) together sugars. The Fischer projections displayed in figure 2.3 illustrate the acyclic structures of every D-aldoses v the aldohexose group.
Fischer projections for the acyclic develops of the D collection of aldoses, varying from triose to hexose.
Any 2 sugars the differ only in the configuration about a single chiral carbon atom are referred to as epimers. Because that example, D-mannose is the C-2 epimer the D-glucose, vice versa, D-galactose is the C-4 epimer that D-glucose (Figure 2.4). Monosaccharide name are frequently abbreviated; most usual are three-letter abbreviation for straightforward monosaccharides (e.g., Gal, Glc, Man, Xyl, Fuc). There space nine common monosaccharides found in vertebrate glycoconjugates (Figure 2.4). Once included into a glycan, these ripe monosaccharide structure blocks deserve to be more modified come generate added sugar structures. For example, glucuronic mountain (GlcA) deserve to be epimerized at C-5 to create IdoA. Many an ext monosaccharides exist in glycoconjugates indigenous other types and as intermediates in metabolism. We usage a symbolic notation because that the monosaccharides that are many abundant in vertebrate glycoconjugates (see chapter 1).
Common monosaccharides uncovered in vertebrates. N-Acetylneuraminic acid is the many common kind of sialic acid.
MONOSACCHARIDES EXIST mainly IN CYCLIC FORM
Monosaccharides exist in solution as one equilibrium mixture the acyclic and cyclic forms. The portion of each kind depends on the street structure. The cyclic form of a monosaccharide is characterized by a hemiacetal group formed by the reaction of one of the hydroxyl teams with the C-1 aldehyde or ketone. For reasons of chemistry stability, five- and six-membered rings space most frequently formed from acyclic monosaccharides. Generally, aldohexoses form six-membered rings via a C-1—O—C-5 ring closure; ketohexoses type five-membered rings via a C-2—O—C-5 ring closure; aldohexoses kind five-membered rings with a C-1—O—C-4 ring closure (Figure 2.5). A five-membered cyclic hemiacetal is labeling a furanose and a six-membered cyclic hemiacetal is referred to as a “pyranose.”
Cyclization that acyclic D-glucose to type pyranose and furanose structures. The cyclization reaction produce both the α and also β anomers (i.e., C-1 epimers).
Formation that Hemiacetals
Monosaccharides can likewise be represented as Haworth projections in i beg your pardon both five-and six-membered cyclic structures are portrayed as planar ring systems, with the hydroxy teams oriented either over or listed below the plane of the ring (Figure 2.6). Although not truly representative the the three-dimensional framework of a monosaccharide, the Haworth representation has been used since the late 1920s together an easy-to-draw formula that permits a quick evaluation the stereochemistry around the monosaccharide ring. The Haworth representations are preferably drawn with the ring oxygen atom in ~ the height (for furanose) or the optimal right-hand edge (for pyranose) that the structure; the numbering of the ring carbons increases in a clockwise direction.
Conversion indigenous Fischer to Haworth projection. Each hydroxyl group projected to the appropriate in the Fischer projection points down in the Haworth formula.
For any D sugar, the switch of a Fischer projection into a Haworth forecast proceeds together follows: (1) any groups (atoms) that space directed to the best in the Fischer framework are offered a bottom orientation in the Haworth structure, (2) any groups (atoms) that are directed come the left in the Fischer structure are offered an increase orientation in the Haworth structure, and also (3) the terminal —CH2OH group is given an upward orientation in the Haworth structure. For an l sugar, (1) and (2) room the same, however the terminal —CH2OH team is projected downward.
The planar Haworth structures room distorted representations of the actual molecules. The preferred conformation that a pyranose ring is the “chair” conformation, similar to the framework of cyclohexane. The conversion from Haworth estimate to chair conformation leaves the downward or upward orientation that ring substituents unaltered. Two chair conformations deserve to be distinguished and also designated as 4C1 and also 1C4, respectively (Figure 2.7A), and also these conformers can interconvert by a procedure called the “ring flip.” The first numeral in the chair conformer designation (superscript) indicates the number of the ring carbon atom over the “seat of the chair (C)” and also the second numeral (subscript) shows the variety of the ring carbon atom below the aircraft of the chair (spanned by C-2, C-3, C-5, and also the ring O). Chair conformations space designated from structures with the ring oxygen atom in the optimal right-hand edge of the ring “seat,” leading to the clockwise figure of the ring numbering. To identify the stereochemistry in the chair form as it coincides to the Fischer projection, one can locate C-6 and then map along the carbon skeleton the the sugar, bisecting the C—O and C—H bonds created from every atom. The five (or OR) and H groups are found on the right (R) or left (L) sides, just as in the Fischer projection (Figure 2.8).
Chair conformations. (A) β-D-Glucose in Haworth projection and also in that 4C1 and 1C4 chair conformations; (B) envelope and also twist conformations for a five-membered ring structure.
Conversion from Fischer come chair estimate formula; (R) right; (L) left. Red arrows illustrate the path to follow follow me the street backbone when correlating the stereochemistry that the Fischer estimate with the chair conformation.
The an ext structurally accurate chair representations are wanted to Haworth projections for illustrating pyranoses. However, Haworth projections room convenient and are commonly used to depict furanoses. The furanose ring is rather flexible and also not entirely flat in any kind of of its energetically favored conformations; for example, it has actually a slim pucker as soon as viewed indigenous the side, as watched in the representations of the so-called envelope and twist (or skew) conformations (Figure 2.7B). Due to the fact that furanoses can take on many low-energy conformations, researcher have embraced the Haworth projection as a simple way to stop this complexity.
When cyclized into rings, monosaccharides acquire second asymmetric center derived indigenous the carbonyl carbon atom (Figure 2.5). The brand-new asymmetric center is termed the “anomeric carbon” (i.e., C-1 in the ring form of glucose). 2 stereoisomers are formed by the cyclization reaction due to the fact that the anomeric hydroxy team can assume two possible orientations. When the construction (R or S) room the exact same at the anomeric carbon and the stereogenic center furthest native the anomeric carbon, the monosaccharide is defined as the α anomer. Once the configurations space different, the monosaccharide is characterized as the β anomer (Figure 2.9). Uneven the other stereocenters top top the monosaccharide ring, which room configurationally stable, the anomeric facility can experience an interconversion of stereoisomers via the procedure of mutarotation. Catalyzed by dilute mountain or base, the reaction proceeds through the reverse of the cyclization reaction. The monosaccharide ring opens up up and also then recloses to form a ring v the various other anomeric construction (Figure 2.5). The ax mutarotation derives native the rapid change in optical rotation (denoted <α> D) the is observed once an anomerically pure type of a monosaccharide is liquified in water. Because that example, β-D-glucopyranose shows an early rotation the +19°, vice versa, the α anomer mirrors an early rotation that +112°. Once either anomer is enabled to undergo the mutarotation reaction, one equilibrium mixture include both anomers is obtained, creating a rotation the +52.5°.
Oxidation and Reduction
Generally, the acyclic (aldehyde or ketone) type of a monosaccharide is only existing in minor amounts in one equilibrium mixture (<0.01%). Nevertheless, the open-chain aldehydes or ketones deserve to participate in chemistry reactions that drive the equilibrium and eventually consume the sugar.
Aldoses and also ketoses to be historically described as “reducing sugars” since they responded positively in a chemical test that effected oxidation of your aldehyde and hydroxyketone functionalities, respectively. The carboxylic acid developed by oxidation that the aldehyde in an aldose is referred to as a glyconic acid (e.g., gluconic mountain is the oxidation product of glucose). The is also possible to oxidization the hydroxyl teams of monosaccharides, most notably the terminal OH team (i.e., C-6 of glucose). In this reaction, a glycuronic mountain is produced, and if both terminal groups are oxidized, the product is a glycaric acid. The three acids acquired from D-glucose are illustrated in number 2.10. This compounds have a propensity to undergo intramolecular cyclization reactions, best yielding six-membered lactones. Two examples of lactonization are presented in number 2.11. Oxidized creates of monosaccharides can be found in nature. Because that example, GlcA is an abundant component of plenty of glycosaminglycans (see chapter 17).
The carbonyl teams of aldoses and ketoses additionally can be reduced with salt borohydride (NaBH4) to kind polyhydroxy alcohols, described as alditols. This reaction is widely provided to present a radiolabel in ~ C-1 that the monosaccharide by reduction through NaB3H4 (Figure 2.11).
Schiff base Formation
The aldehyde and also ketone teams of monosaccharides can likewise undergo Schiff base development with amines or hydrazides, creating imines and hydrazones, respectively (Figure 2.12). This reaction is often used to conjugate the monosaccharide to protein (via your lysine residues) or to biochemical probes such together biotin hydrazide. It need to be detailed that the imines created with amino groups are not secure to water and also are typically reduced v sodium cyanoborohydride (NaCNBH3) in a procedure termed reductive amination.
Conjugation that a monosaccharide to an amino group by formation of an imine. The to fill circle to represent any tiny molecule or macromolecule comprise an amine.
As aldehydes, reducing sugars can also form Schiff bases v amino groups of the lysine residues in proteins. This nonenzymatic process that web links glycans to proteins is termed “glycation” and also is distinctive from “glycosylation,” which entails the formation of a glycosidic bond in between the sugar and protein. Glycation products can undergo further reactions that cause the development of protein cross-links, and also these deserve to have pathogenic after-effects (i.e., they room immunogenic and adjust the nature of the protein). Glycation commodities of glucose accumulate at greater levels in diabetics than in healthy and balanced individuals due to the fact that of elevated blood glucose levels. These modified proteins room thought to underlie few of the pathologies connected with diabetes.
Glycosidic link Formation
Two monosaccharide units can be joined together by a glycosidic bond—this is the basic linkage amongst the monosaccharide structure blocks uncovered in all oligosaccharides. The glycosidic bond is formed between the anomeric carbon of one monosaccharide and a hydroxyl group of another. In chemical terms, a hemiacetal team reacts v an alcohol team to type an acetal. Glycosidic bonds have the right to be created with virtually any type of hydroxylated compound, including basic alcohols such as methanol (Figure 2.13) or hydroxy amino acids such as serine, threonine, and also tyrosine. Indeed, glycosidic linkages space formed in between sugars and also these amino acids within protein to kind glycoproteins (see Chapters 9 and also 10). Favor the hemiacetal, the acetal or glycosidic can exist in two stereoisomeric forms: α and β. But unlike the hemiacetal, the acetal is configurationally steady under most conditions. Thus, as soon as a glycosidic bond is formed, its construction is maintained indefinitely. Furthermore, no oxidation or reduction can take location at an anomeric center that is connected in a glycosidic bond. Prefer acetals in general, glycosidic bonds have the right to be hydrolyzed in dilute acid, generating the constituent monosaccharides indigenous oligosaccharides.
Glycosidic bond construction is the main challenge the glycan synthesis and also immense efforts have been devoted to high-yielding and also stereoselective glycosylation reactions. Summary of glycan synthesis strategies is provided in Chapters 53 and 54.
Methylation that Hydroxyl Groups
The hydroxyl groups present in both monosaccharides and also oligosaccharides have the right to be chemically modified without affecting the glycosidic linkages. Methylation is offered in the structural evaluation of glycans (see thing 50). Natural products containing partly methylated glycans room known and a variety of methyltransferases have been identified.
Esterification the Hydroxyl Groups
A variety of various enzymes can esterify the hydroxyl groups of glycans to transiently differ glycan structure. Esterification is sometimes required for interaction with various other biomolecules. The most important varieties of sugar esters in nature space phosphate esters (including diphosphate esters), acyl esters (with acetic mountain or fatty acids), and sulfate esters. Acyl esters deserve to sometime migrate to other hydroxyl teams on the exact same monosaccharide.
Deoxygenation the Hydroxyl Groups
The replacement of monosaccharide hydroxyl groups with hydrogen atoms forms deoxysugars. Nature has advanced reductases to execute this reaction in one step, vice versa, chemically multistep procedures are required. Deoxygenation of ribose in ~ a ribonucleotide to form the 2-deoxyribonucleotide is a vital reaction in DNA biosynthesis. Fucose (Fuc), one of the common vertebrate monosaccharides, is deoxygenated at C-6 during its biosynthesis indigenous mannose (Chapter 5).
Many monosaccharides save on computer N-acetamido groups, such as GlcNAc, GalNAc, and also NeuNAc. Cost-free amino groups, formed by de-N-acetylation of the N-acetamido group, room rare and found in heparan sulfate (HS) (Chapter 17), glycosylphosphatidylinositol (GPI) anchors (Chapter 12), neuraminic acid (Chapter 15) and in countless bacterial glycan structures (Chapter 20). Amino groups can be modified with sulfates, similar to hydroxyl groups, as discovered in HS.
A variety of linkages deserve to be formed in between two monosaccharides. The glycosidic link can give rise to two possible stereoisomers at the anomeric carbon the one sugar (α or β). Second, the many hydroxyl teams of the various other sugar allow several possible regioisomers. 2 glucose residues because that example, can be joined together in numerous ways, as portrayed by maltose (Glcα4Glc) and gentiobiose (Glcβ6Glc) (Figure 2.14). These isomers have very different three-dimensional structures and biological activities. Finally, a monosaccharide can engage in much more than 2 glycosidic linkages, for this reason serving as a branchpoint. The usual occurrence that branched order (as opposed to the direct sequences that are discovered in nearly all peptides and also oligonucleotides) is distinct to glycans and contributes to their structural diversity.
The partnership of the glycosidic bond come oligosaccharides is analogous to the connection of the peptide bond come polypeptides and the phosphodiester bond come polynucleotides. However, amino acids and nucleotides are connected in just one fashion during the formation of polypeptides and nucleic acids, respectively; there is no stereochemical or regiochemical diversity in these biopolymers. The number of monomeric residues had in one oligosaccharide is designated in the nomenclature—disaccharide, trisaccharide, and so on. Simply as polypeptides have amino and also carboxyl termini and also polynucleotides have actually 5′ and 3′ termini, oligosaccharides have actually a polarity the is defined by their reducing and nonreducing termini (Figure 2.15). The reducing finish of the oligosaccharide bear a cost-free anomeric facility that is not involved in a glycosidic bond and thus maintain the chemistry reactivity of the aldehyde. However, it continues to be described as reducing finish even once it is involved in a link (e.g., come the hydroxyl the serine or threonine in glycoproteins). Frameworks are frequently written indigenous the nonreducing end on the left toward the reducing end on the right. For some structures, over there is no reduce end. Because that example, the typical disaccharides sucrose and also trehalose have glycosidic linkages between the anomeric centers of two monosaccharide constituents (Figure 2.16).
The glycosidic linkage is the most flexible part of a disaccharide structure. Conversely, the chair configuration of the ingredient monosaccharides is relatively rigid, the torsion angles roughly the glycosidic shortcut (φ, ψ, and ω; figure 2.17) deserve to vary. Thus, a disaccharide that well-defined main structure can embrace multiple conformations in systems that differ in the loved one orientation that the 2 monosaccharides. The combination of structure rigidity and also flexibility is usual of facility carbohydrates and also essential to their biological functions.
Torsion angles that specify the conformation of the glycosidic linkages φ, ψ, and also ω. (A) Newman forecast along the C1—O1 bond illustrating φ for the 1-6 glycosidic bond. (B) Newman forecast along the C6′—O1 (more...)
Glycans are connected to various other biomolecules, such as lipids or amino mountain within polypeptides, v glycosidic linkages to type glycoconjugates (see Chapters 9, 10, 11, and also 12). Glycans are frequently referred to together the glycone of a glycoconjugate and the noncarbohydrate ingredient is named the aglycone. The glycan might be a mono- or one oligosaccharide.
In conclusion, monosaccharide building blocks have the right to be linked to miscellaneous regio- and also stereochemistries, and also the result oligosaccharides deserve to be assembled top top protein or lipid scaffolds (see chapter 3).
The authors recognize contributions to previous execution of this chapter by Carolyn R. Bertozzi and also David Rabuka and appreciate useful comments and also suggestions from Rahul Bhattacharya, Natalie Silmon De Monerri, Steve M. Fernandes, and Alexandra Walker.
El Khadem HS. 1988. Carbohydrate chemistry: Monosaccharides and their oligomers. Academic, san Diego.
Allen HJ, Kisailus EC. 1992. Glycoconjugates: Composition, structure, and also function. Marcel Dekker, brand-new York.
Bill MR, Revers L, Wilson IBH. 1998. Protein glycosylation. Kluwer Academic, Boston.
Boons G-J. 1998. Carbohydrate chemistry. Blackie academic and Professional, London.
Stick RV. 2001. Carbohydrates: The sweet molecule of life. Academic, new York.
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