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7.2: Polysaccharides

  • Page ID
    14956
  • Polysaccharides contain many monosaccharides in glycosidic links, and may contain many branches. They serve as either structural components or energy storage molecules. Polysaccharides consisting of single monosaccharides are homopolymers. Among the most common are starch, glycogen, dextran, cellulose and chitin.  We'll discuss these grouped together based on whether the acetal link is alpha or beta.

    α 1,4 main chain links

    Starch and Glycogen: These polysacharides are polymers of glucose linked in α 1,4 links with α 1,6 branches. Starch, found in plants, is subdivided into amylose, which has no branches, and amylopectin which does. Starch granules consist of about 20% amylose and 80% amylopectin.  Glycogen,  the main CHO storage in animals, is found in muscle and liver, and consists of glucose residues in α 1,4 links with lots of α 1,6 branches (many more branches than in starch). test

    Here are various ways to render in 2D the chemical structure of a branched glycogen and starch fragment, as shown in the figure below.

    links_StarchGlyco_Chair_WedgeDash.svg

    The top part of the figure shows the Haworth structure.  Two glucose residues, shown in red and blue, or shown below in the more modern and informative chair and wedge/dash representations.

    Here is an iCn3D model of 10 glucose monosaccharides in a 1,4 linkage with 5 glucose residue 1,6 branch at glucose 6 of the main chain.  It would be found in starch (amylopectin) and glycogen.

     

    We can show the structure in the iCn3D model in a diagrammatic fashion in which glucose is represented as a blue circle with the acetal/glycosidic/glucosidic linkages between the monosaccharides written between the circles.  The 14A label  shows that the acetal linkage is an alpha 1,4 link.  

    clipboard_ebf0f46bcdb19ec5e4ca1e01e4693777f.png

    The linkages are written in variety of conventions.  These include 14A, 14α, 4A and 4α.  The between many sugars is often a 1,x link where x is 2,3, 4, 5 or 6.  In those cases the 1 can be omitted.  The program used to generate most of the images in this text uses the both numbers and the letter A or B.

    What makes carbohydrates so complex is their 3D structures.  Like proteins and nucleic acids, they can adopt a myriad of conformations.  As the monomeric units are so homogeneous, especially in homopolymers, it is difficult to get crystal structures for them so models are often used.  

    Studies have shown that the simple starch fraction amylose α 1,4 polymer of glucose, often envisioned as a straight chain, can adopt three main conformations.  The are double-helical A- (found mostly in cereals),double helical B-(found mostly in tubers) amyloses and single-helical V-amylose (or simply A, B and V structures).  The A and B do NOT represent alpha or beta in this classification system.  The A and B forms consist of double helices aligned in a parallel fashion with about 6 glucoses per turn.  The helices appear to be left or right handed.  This ambiguity might result from lack of crystal structures.  

    In contrast, a well defined structure of the V helix is known.  It folds into a left handed helix with 6 glucoses per turn and a pitch of about 8Å.  Unlike alpha helices of proteins and the double stranded helix of DNA, the center of the helix is NOT packed tightly and can accommodate small molecules.  One is iodine (actually triiodide, I3-), which when bound in amylose with a sample of starch exhibits a dark blue color.   This is basis for the use of starch indicators that you may have used in titration reactions in introductory biology and chemistry and analytical chemistry.

    In proteins, alpha helices might self-associate during folding to form a 4-helix bundle.  Likewise, the helices in V-amylose can associate into bundles.  The figure below shows the actual structure of a V-amylose, cycloamylose 26 (pdb ID1C58).  It consists of a linear cycloamylose strand of 26 glucose monomers, which has collapsed to form secondary structure with 6-residue helices that are packed together into a tertiary structure of 4-helix bundle. The blue sphere "cartoon" color coding of each glucose residue is used to denoted glucose and corresponds to the blue circles used above in the diagrammatic representation above. 

    https://structure.ncbi.nlm.nih.gov/i...6tghM5HMTypm88

    Rotate the model to explore it.  Trace the chains by following the blue sphere symbolic representation for glucose as you trace the main chain.  Rotate it to view down the helix axes to see the 4 holes that can each accommodate a  I3-.  In the menu button (=), choose Style, Chemicals, Sphere to see a spacefilling models that shows the holes within each helix.  To reiterate, there is no unoccupied volume within either a protein alpha helix or a double-stranded DNA molecule. 

    The well known macrocyclic compound cyclodextrins (example α-cyclodextrin) are structures equivalent to one turn of V-amylose.  The V-amylose helix is stabilized in part by hydrogen bonds from donors and acceptors within the helix from the OH3 on the ith glucose and the OH2 on the ith+1 glucose as well as from the OH6 on ith glucose and OH2 on the ith + 6 glucose.  

    In vivo, glycogen is synthesized by attachment of glucose monomers to a core protein called glycogenin.  The figure below shows a model of a glycogen particle with glycogenin at its core.

    Glycogen_GlycogeninStructure.jpg

    The dimeric protein glycogenin is an enzyme which autoglucosylates itself in a stepwise fashion.  The first glucose is added at Tyr 195. At some point, the active site must get buried and the protein can no longer add more monomers.   

    It makes great chemical sense to store glucose residues as either glycogen or starch, which is one large molecule. A review of colligative properties would inform you that if all the glucose was stored as the monosaccharide, a great osmotic pressure difference would be found between the outside and inside of the cell. It makes more sense to have glycogen exist as a many-branched linear polymer which is a single molecule. When glucose is needed, it is cleaved one residue at a time from all the branches (at the nonreducing ends), producing a large amount of free glucosein a short time.

    Phi/Psi angles can also be described for the starch/glycogen main chain (around the acetal O) in a fashion comparable to that for proteins (around the alpha carbon). The phi torsion angle describes rotation around the C1-O bond of the acetal link, while the psi angle describes rotation around the O-C4 bond of the same acetal link, with the glucopyranose ring considers as a rigid rotator (just as the 6 atoms in the planar peptide bond unit). The most extended form of a glucose polymer occurs when the glycosidic link is β 1,4 (as in cellulose), which forms linear chains. This would be analogous to the more extended parallel beta strand (phi/psi angles of -1190, -1130) and antiparallel beta strands (phi/psi angles of  -1390, +1350) of proteins. The α 1,4 linked main chain of glycogen and starch causes the chain to turn and form a large helix, into which can fit iodine (or I3-), which turns starch purple.  The less extended structure is analogous to the less extend protein alpha helix, which has phis/psi angles of -570,-470.

    The figure below shows phi/psi angles for acetal/glycosidic linkage in the glucoside dissacharide maltose, is shown below.

    phpsiGlcGlcalpha.svg

    α 1,6 main chain links

    Dextran is a branched polymer of glucose in α 1,6 links with α 1,2, α 1,3, or α 1,4 linked side chain.  This polymer is used in some chromatography resins. The figure below shows chair structures (A) and wedge/dash structures for dextran showing the main chain α 1,6 link with one α 1,3 branch. 

    dextran.svg

     

    Depending on its molecular weight, it is soluble in water, forming viscous solutions, and organic solvents. It also used as a food thickener and  stabilizer.  It is syntheized by lactic acid forming bacteria using sucrose as an energy source.  Most uses are commercial

     

    β 1,4 links

    Celluose, a structural homopolymer of glucose in plants, has of β 1,4 main chain links without branching. Multiple chains are held together by intra and inter-chain H-bonds. It is the most abundant biological molecule in nature.  Various rendering of 4 glucose residues in cellulose are shown below.  Haworth structures are not shown. Instead  more chemically informative chair and wedge/dash structures are used.  It's important to see the structure display in many forms, since different presentation of the structure can be found in different sources.

    cellulosemultiplereps2.svg

    In A, the most common chair representation, the 2nd and 4th residues from the right hand end are flipped versions of the residues 1 and 3.  Residues 1 and 2 are colored coded red and blue for clarity.  This unit is repeated to generate the full chain.  The top part of A show a simplified version of the flip of the red ring to produce the blue ring so help you see that they are indeed identical structures..

    The same structure as in A is shown in the left part of B in wedge/dash from (looking down on the ring).  The right hand side of B shows a variant of the left hand side of B that is generated by simple 1800 rotation around the bond indicated in the left of B

    In C, the simple repeat is shown without the chain flips in A and B.   The acetal/glycosidic/glucosidic bond seems to be shown in a straight line in the chair structures (a bit confusing and structurally disceptive) but is shown more clearly in the adjacent wedge/dash structure.

    All of the structures are correct, but the one shown in A is most often used. 

    One long chain of starch can interact with other chains in a structure stabilized by intrachain and interchain hydrogen bonds.  Different sources display different hydrogen bonds.  Some common ones are shown below.

     

    Insert final figure

    These chains align in parallel and twist to form larger cellulose fibers.  A model of a web of cellulose chains is given below.

    Chitin

    The glycan is the major component in exoskeletons of anthropods and mollusks. It is a β 1,4 linked polymer of N-acetylglucose (GlcNAc).  Compare this to cellulose which is a β 1,4 linked polymer of glucose. What a difference an N-acetyl substituent makes! 

    The basic chemical structures of chitin is shown below just in chair form.

    chitin.svg

    Here is the symbolic representation of chitin.

    chitinsymbols.png

    A New visual nomenclature for glycobiology

    Before we go further into the complexities of glycan structure, let explore the widely accepted symbolic nomenclature to show the structure and linkages succinctly. The Consortium for Functional Glycomics (2005) has proposed a scheme based on  specific colored geometric shapes for each, as shown for the example glycan shown below.

    This nomenclature has recently been updated in Appendix 1B of Essentials of Glycobiology, 3rd Edition (Glycobiology 25(12): 1323�1324, 2015. doi: 10.1093/glycob/cwv091 (PMID 26543186) and is summarized in the table below.

    GlycanSymbols

    Glycosaminoglycans - Heteropolysaccharides with dissacharide repeating units

    Many polysaccharides consist of repeating dissacharides units. A major class of polysaccharides with dissacharide repeats include the glycosaminoglycans (GAGs), all which contain one amino sugar in the repeat and in which one or both of the sugars contain negatively charged sulfate and/or carboxyl groups. The extent and position of sulfation varies widely between and within GAGs. GAGs are found in the vitreous humor of the eye and synovial fluid of joints, and in connective tissue like tendons, cartilage, etc, as well as skin. They are found in the extracellular matrix and are often covalently attached to proteins to form proteoglycans.   From a birds eye view, they are all elongated polyanions.

    They and their structures are very complicated and exceedingly diverse. This makes them difficult to understand for those who want clear and unambiguous structures.  From a biological perspective, they present in their local environment an incredibly diverse array of potential binding sites for ligand (both small and large).  Because of these they also have functions in cell signaling. In addition, someGAGs are free standing, other are covalently attached to proteins (a bit like glycogen is attached to glycogenin).  These large molecules are called proteoglycans.  We will discuss this later in chapter 7.x when we discuss the "carbohydrate code"

    Here are the ring structures and descriptions of important GAGs.  The common dissacharide repeat unit is shown twice for each structure, with the knowledge that sulfations patterns may differ for the dissacharide repeats in the actual chains.  Note also that the first member of the each dissacharide repeat shows the ring flipped along the vertically (top to bottom) as was shown in the structures for other beta-linked glycans  (cellulose, chitin) above. 

    In a long chain, selecting which is the repeating dissacharide unit is a bit relative, as shown in the figure below for the repeating disssacharide sequence of N-acetylglucosamine (blue square) and N-acetylgalactosamine (yellow square).  

    clipboard_ed36b5c9ad3f0da8d8c07b160d41c3cf2.png 

    In the top, the repeating units (blue-yellow) are connected to each other through beta 1,4 links while in the bottom, the connection of the repeating unit (yellow-blue) is beta 1,3.  Without knowing the full chain, the best choice of annotating the repeating unit is illusive. What's most important however is to note the alternating acetal/glycosidic links through the whole sequence.  In the figures below different dissacharide repeats are highlighted. 

    Hyaluronic acid

    This is a polymer of glucuronate (β 1,3) GlcNAc. It offers a backbone for attachment of protein and other GAGs.  It's the only GAG without sulfate. The figure below shows a tetrasaccharide fragment with two dissacharide repeats.  The internal acetal/glycosidic link of the illustrated disaccharide repeat is β 1,3 while the connection between the disaccharides is β 1,4.  For one last time, the vertical flip of the glucuronic acid is shown to allow a better understanding its flipped presentation in the actual GAG.

     

    hyaluronicacid.svg

    Hyaluronic acids is found in a variety of locations including synovial fluid, the extracellular matrix and skin, where it helps control skin moisture.  It is  water soluble and displays twin antiparallel left-oriented helices.  Covalent conjugates of the chemotherapeutic drugs doxorubicin and camptothecin linked to hyaluronic acid, whose overall structure is similar to  "worm-like micelles", have been used successfully to treat skin cancers.

    Keratan sulfate

    This GAG contains repeats of N-acetyl-D-glucosmine-6-phosphate in β 1,3 link to D-galactose or D-galactose-6-sulfate.  The link between Gal and the modified glucosamine is β 1,4.  Keratin sulfate is highest abundant in the cornea  of the eye but is also found in other connective tissues such as bone, cartilage and tendon, as well as in the 
    central and peripheral nervous system.

    The figure below shows a tetrasaccharide containing two repeating dissacharides.

    keratansulfate.svg

     

    Chondrotin sulfate

    D-glucuronate (β 1->4) GalNAc-4 or 6-sulfate.  It's found in connective tissue matrix as well as cell surface (in the form of proteoglycans) and basement membranes, as well as intracellular granule.  A tetrasacccharide showing two disaccharide repeats is shown below.

     

    chondrotinsulfate.svg

     

    Dermatan sulfate

    This GAG is similar to chondroitin sulfate.  It is first made as a polymer of the dissacharide unit of D-gluconic and N-acetyl-D-galactosamine.  The gluconic acid is epimerized to L-iduronic acid, followed by sulfation.  

    dermatansulfate.svg

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    Heparin

    This GAG containss a highly trisulfated dissacharide repeat as shown in the figure below. Note the the moelcule can contain glucuronate or iduronate, and the degree of sulfation of the chains varies.  (Remember that there is not genetic code the specifies the actual sequence or sulfation patten.  

     

    heparin.svg

     

    Most people are familiar with the anticlotting properties of heparin administered as a drug.  Heparin case in a way as a catalyst to accelerate the inhibition of the enzyme thrombin, which cleaves fibrinogen and activates platelets to form clots, by the blood protein antithrombin III.  Heparin works in two ways to facilitate thrombin inactivation.  It has a specific binding site for antithrombin III which causes a conformation in the protein, making it a more effect inhibitor.  Thrombin, a positively-charged serine protease, can bind the heparin, a polyanion, nonspecifically.  When it does, it go diffuse along the heparin chain, where it can find bound antithrombin III much more quickly than it the inhibitor was free in the blood.  Heparin effectlly changes the search path of thrombin from a 3D to a 1D search.

    The iCn3D model belows shows the amino acids in antithrombin III within seven angstroms of a bound heparin 5mer (1NQ9). Dotted lines represent hydrogen bonds and salt bridges between the two.   Heparin is highlighted in yellow

     

    https://structure.ncbi.nlm.nih.gov/i...fnvt6YfbJovat8

     

    Agarose

    Agarose is the main polysaccharide component derived from red algae.  Agarose is a polymer of a disaccharide repeat of (1,3)-β-D-galactopyranose-(1,4)-3,6-anhydro-α-L-galactopyranose, is often used for a gelable solid phase for electrophoresis of nucleic acid and as a component of chromatography beads.  As with starch, which is present as mixtures of amylose and amylopectin,  agarose is often found wih agaropectin, which is a sulfated galactan.  A tetrasaccharide fragment with two dissacharide repeats is shown below.

    agarose.svg

     

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