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7.1: Monosaccharides and Disaccharides

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    14955
  • Carbohydrate or glycan biochemistry is very complex and difficult, owing to the stereochemical complexity of simple sugars, the large number of positions on the sugars used to form linkages between other sugars to create polymers, the large number of chemical modification to base sugars, and the lack of a genetic template to instruct gycan polymer formation.  It is no wonder that our understanding of complex glycans has developed after that of the chemically simpler polymers like nucleic acids and proteins.

    Essentials of Glycobiology, 3rd edition, is a free online book written by and for those interested in glycobiology. Here are some modern definitions taken direclty from the glossary of that book:

    Sugar:  A generic term often used to refer to any carbohydrate, but most frequently to low-molecular-weight carbohydrates that are sweet in taste. Table sugar, sucrose, is a nonreducing disaccharide (Fruβ2-1αGlc). Oligosaccharides are sometimes called “sugar chains” and individual monosaccharides in a sugar chain are sometimes referred to as “sugar residues.”

    Carbohydrate:  A generic term used interchangeably in this book with sugar, saccharide, or glycan. Includes monosaccharides, oligosaccharides, and polysaccharides, as well as derivatives of these compounds.

    Glycan: A generic term for any sugar or assembly of sugars, in free form or attached to another molecule, used interchangeably  with saccharide or carbohydrate.

    Monosaccharides Structures

    The above definition of sugar needs some further nuance.  From a chemical perspective, sugars can be defined as polyhydroxy-aldehydes or ketones. Hence the simplest sugars contain at least three carbons. The most common are the aldo- and keto-trioses, tetroses, pentoses, and hexoses. The simplest 3C sugars are glyceraldehye and dihydroxyacetone.

    FisherProj_Perspect_3CSugars2.svg

     

    Glucose, an aldo-hexose, is a central sugar in metabolism. It and other 5 and 6C sugars can cyclize through intramolecular nucleophilic attack of one of free hydroxyl groups on the carbonyl carbon of the aldehyde or ketone. Such intramolecular reactions occur if stable 5 or 6 member rings can form. The resulting rings are labeled furanose (5 member) or pyranose (6 member) based on their similarity to furan and pyran. On nucleophilic attack to form the ring, the carbonyl O becomes an OH which points either below the ring (α anomer) or above the ring (β anomer).

    The figure below shows different representations of the linear and cyclic forms of the sugars D-glucose, D-ribose and D-fructose

    glcfrccycliz.svg

    Monosaccharides in solution exist as equilibrium mixtures of the straight and cyclic forms. In solution, glucose (Glc) is mostly in the pyranose form, fructose is 67% pyranose and 33% furanose, and ribose is 75% furanose and 25% pyranose. However, in polysaccharides, Glc is exclusively pyranose and fructose and ribose are furanoses.

    Sugars can be drawn in the straight chain form as either Fischer projections or perspective structural formulas.

    In the Fisher projection, the vertical bonds point down into the plane of the paper. That's easy to visualize for 3C molecules. but more complicated for bigger molecules. For those draw a wedge and dash line drawing of the molecule. When determining the orientation of the OHs on each C, orient the wedge and dash drawing in your mind so that the C atoms adjacent to the one of interest are pointing down. Sighting towards the carbonyl C, if the OH is pointing to the right in the Fisher project, it should be pointing to the right in the wedge and dash drawing, as shown below for D-erthyrose and D-glucose.

    Figure: Orienting OH groups in wedge and dashing drawings of simple straight chain sugars

    fisherpersp4.png

     

    Cyclic forms can be drawn either as the Haworth projections, which shows the molecule as cyclic and planar with substituents above or below the ring) or the more plausible bent forms (showing Glc in the chair or boat conformations, for example). b-D-glucopyranose is the only aldohexose which can be drawn with all its bulky substituents (OH and CH2OH) in equatorial positions, which probably accounts for its widespread prevalence in nature.

    GlcChair.svg

     

    Haworth projections are more realistic than the Fisher projections, but you should be able to draw both structures. In general, if a substituent points to the right in the Fisher structure, it points down in the Haworth. if it points left, it points up. In general, the OH on the -anomer points down (ants down) while on the β-anomer it points up. (butterflies up).

    choalphabeta2.svgα

    In the Haworth projections, the bulky R group of the next carbon after the carbon whose OH group engaged in a nucleophilic attach on the carbonyl carbon to form the ring O is pointed up if the OH engaged in the attach was on the right hand side in the straight chain Fisher diagram (as in α-D-glucopyranose above when the CH2OH group is up) but is pointed down if the OH engaged in the attach was on the left hand side in the straight chain Fisher diagram (as in α-D-galactofuranose above when the (CHOH)CH2OH group is down). The rest of the OH groups still follow the simple rule that if they are pointing to the right in the Fisher straight chain form, they point down in the Haworth form.

     

    The most common monosaccharides (other than glyceraldehyde and dihydroxyacetone), which you will encounter most frequently are shown below.

    sugarstoknow.svg

    The mirror image of D-Glc is L-Glc. For common sugars, the prefix D and L refer to the center of asymmetry most remote from the aldehyde or ketone. By convention, all chiral centers are related to D- glyceraldehyde, so sugar isomers related to D-glyceraldehyde at their last asymmetric center are D sugars.

    The figure below shows multiple renderings of common hexoses.

     

    CHOMonomers.svg

     

    Isomers

    Sugars can exists as either configurational isomers (interconverted only by breaking covalent bonds) and conformational isomers. The figure below reviews different types of isomers.

    IsomerFlowChart.svg

    The configurational isomers include enantiomers (stereoisomers that are mirror images of each other), diastereomers (stereoisomers that are not mirror images), epimers (diastereomers that differ at one stereocenter), and anomers (a special form of stereoisomer, diastereomer, and epimer that differ only in the configuration around the carbon which was attacked in the intramolecular nucleophilic attack to produces the α and β isomers).

    sugarisomers.svg

     

    Sugars can also exist as conformational isomers, which interchange without breaking covalent bonds. These include chair and boat conformations of the cyclic sugars.

    BetaDGlcChairConformers.svg

     

    Monosaccharide Derivatives

    Many derivatives of monosaccharides are found in nature. These include

    • oxidized forms in which the aldehyde and/or alcohol functional groups are oxidized to carboxylic acids
    • phosporylated forms in which phosphate is added by ATP to form phosphoester derivatives
    • amine derivatives such as glucosamine or galactosamine
    • acetylated amine derivatives such as N-Acetyl-GlcNAc (GlcNAc) or GalNAc
    • lactone forms (intramolecular esters) in which an OH group attacks a carbony C that was previously oxidized to a carboxylic acid
    • condensation products of sugar derivatives with lactate (CH3CHOHCO2-) and pyruvate, (CH3COCO2- ), both from the glycolytic pathway, to form muramic acid and neuraminic acids, (also called sialic acids), respectively.

    Here are some simple monosaccharide derivatives

    sugarderiv.svg

     

    Here are some addition oxidative derivatives of glucose shown in Fischer projections.

    redoxderivativesofGlc.svg

     

    Another important derivation of monosaccharides sialic acids.  One, N-acetylmuramic acid, found in bacterial cell walls, consists of GlcNAc in ether link at C3 with lactate, while  another, N-acetylneuraminic acid results from an intramolecular cyclization of a condensation product of ManNAc and pyruvate.

    SialicAcid.svg

     

    Sugars are very complicated as the linkages and substituents are so diverse. An example of these subtle differences can be seen in the difference in sialic acids between humans and chimps.

    sialicacid_Humans_Chimps.svg

     

    What happens when non-vegan humans eat animal products (meat, milk) with N-glycoyl neuraminic acids (Neu5Gc)? Some gets incorporated into human membrane glycans. Sialic acids on surface proteins can serve as "receptors" that allowing binding of self-cells as well as foreign cells or proteins that have evolved to bind them. A toxin, SubAB, secreted by E. Coli 0157, can bind Neu5Gc. Hence eating meat products can make us more susceptible to bacteria that recognize Neu5Gc.

    Formation of Hemiacetals, Acetals, and Disaccharides

    Monosaccharides that contain aldehydes can cyclize through intramolecular nucleophilic attack of an OH at the carbonyl carbon in an addition reaction to form a hemiacetal (hemiketal if attack on a ketone). On the addition of acid (which protonates the anomeric OH, forming water as a potential leaving group), another alcohol can add forming an acetal (or ketal from a ketone) with water leaving.

    hemiacetalchemistry.svg

     

    If the other alcohol is a second monosaccharide, a dissacharide results. The acetal (or ketal) link bonding to the two monosaccharides is called a glycosidic link. Links between the two sugars can be either α (if the OH on C1 involved in the glycosidic link is pointing down) or β (if the O on C1 involved in the glycosidic link is pointing up). Since sugars contain so many OH groups which can act as the "second" alcohol in acetal (or ketal) formation, links between sugars can be quite diverse. These include α and β forms of 1-2, 1-3, 1-4, 1-5, 1-6, 2-2, etc. links. Here are examples of dissacharides:

    • maltose: Glc(α 1,4)Glc, which can be considered a dissaccharide hydrolysis product of the polysaccharide glycogen or starch (discussed in the section)
    • cellobiose:  Glc(Glc(α 1,4)Glc 1,4)Glc, which can be considered dissaccharide hydrolysis product of cellulose.
    • lactose: Gal(β 1,4)Glc, also known as milk sugar.  .
    • sucrose: Glc(α 1,2)Fru. Since Fru is attached through the anomeric OH of this ketose, the Fru is not in equilibrium with its straight chain keto form, and hence sucrose is a nonreducing sugar.

    The differences between lactose and sucrose are illustrated below. Note that the β-D-fructofuranose ring is flipped (left to right as in turning one of your hands over) compared to the Figure 2 above.

     

    disacchformation.svg

    Acetal links between sugars in glycans can be hydrolyzed by water (catalyzed by H+) just as with the other key biological polymers, proteins and nucleic acids.

    The disaacharide described above that are linked through a 1,4 linkage are called reducing sugars since they can act as reducing agent in a process when they themselves get oxidized.  For example, in lactose, since galactose is attached to glucose through the OH on C4, the anomeric glucose carbon, C1, could revert to the noncyclic aldehyde form. This aldehyde is susceptible to oxidation by reagents (Benedicts Solution - with citrate, Fehlings reagent - with tartrate) as these reagents are subsequently reduced.  In both reagents, reducing sugars reduce a basic blue solution of CuSO4 (Cu2+) to a brick red precipitate of \(\ce{Cu2O}\) (Cu+). Sugars (monosaccharides, dissacharides and polysaccharides) which can form an aldehyde at C1 or have an α-hydroxymethyl ketone group which can isomerize to an aldehyde under basic conditions (such as fructose) are called reducing sugars. These oxidizing agent are mild and react with aldehydes and not ketones

     

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