THE STRUCTURE OF CARBOHYDRATESDr. Ferchmin 2012

The objectives of this lecture are three:a) To put you in “a molecular mind set”.b) “Review” some concepts learned in organic chemistry.c) Familiarize you with carbohydrate molecules involved in metabolism.

Summary of this handout:1) Definition of carbohydrate.2) Asymmetric carbon, Fischer projection formulas. 3) D and L series.4) Mutarotation, Haworth formulas and anomers.5) Examples of monosaccharides. Fructose, mannose, galactose, deoxysugars,

aminosugars, glucuronic and gluconic acids. 6) Glycosides and disaccharides. Lactose, maltose, isomaltose, cellobiose,

sucrose7) Homo- and heteropolysaccharides. Glycogen !!!!8) Glycosaminoglycans (formerly called mucopolysaccharides).You will find two versions of this handout at http://www.ferchmin.org

Carbohydrates are polyalcohols of ketones or aldehydes and simple derivatives (like carboxylic acids or amino sugars), and polymers. Carbohydrates can be considered as 'carbon hydrates', the empirical formula is Cn(H2O)n. There is one water molecule

per carbon atom. Carbohydrates are also called sugars or saccharides. The thousands of different carbohydrates found in nature are stereoisomers, derivatives or polymers of a rather small number of monosaccharides. For that reason, the concept of isomerism is important to understand carbohydrates.

Functions of carbohydratesEnergy Glucose is the circulating sugar in blood and the energy source for most organs. Glycogen is one of the most important energy stores. Oxidation of glucose to CO2 and H2O is the central energy yielding process. Structural Polysaccharides are used as shock absorbers and lubricants in joints and as adhesives between cells. Signaling Sugars associated with proteins or lipids are involved in cell signaling. Sugars are involved in cell-cell interactions, immunological responses and determine the metabolic role of many proteins.

Stereoisomery of carbohydrates is produced by the asymmetric carbon. The asymmetric carbon is tetrahedral and has 4 ≠ substituents.

These three pictures show molecules that are enantiomers or mirror images of each other

To make it easier to write Fischermade the Fischer convention:You must apply it to each and allthe asymmetric carbons of a molecule.

Or to make it simpler you may use the projection formula

The smallest sugars with an asymmetric carbons are shown below:

Conceptually speaking D-glyceraldehyde originates the series of D-carbohydrates, and reciprocally L-glyceraldehyde the L series.

Aldoses are derivatives of glyceraldehyde

The asymmetric carbons in a hexose have to be viewed one by one.Glucose is a carbohydrate of 6 carbons

Asymmetric carbons rotate polarized light: Ordinary light vibrates in all possible planes.  When ordinary light is filtered by certain crystals a single plane of polarized light is obtained.  Polarized light traveling through a solution of an asymmetric compound, such as sugar, can rotate the plane of polarized light.  The degree of rotation is directly proportional to the concentration of the asymmetric compound.  Substances that rotate the plane of polarized light are called "optically active." 

Rotation to the left is indicated as l and to the right as d. Contrary to intuition the levo or dextro rotation provides no clue whether a sugar is from the L or D series.Confusion comes from the fact that D-glyceraldehyde was originally designated D because it rotated the polarization plane +13.5º degrees and L-glyceraldehyde because it rotated -13.8º degrees to the left. Each asymmetric carbon of a molecule has its own contribution to the total rotation of polarized light.

Ketoses are derivatives of dihydroxyacetone

MUTAROTATION

Pyranoses and furanoses

The terms pyranose and furanose come from the ‘similarity’ to pyran and furan to the rings formed by mutarotation.

- D-Glucopyranose β- D-Fructofuranose

β-D-Glucopyranose

β-D-Glucofuranose -D-Glucofuranose

-D-Glucopyranose

63% 36%

0.1%

<1% <1%

There are three manners to write the formula of monosaccharides.This actually represents how our concept of structure evolved

We will be repeating several concepts and practice them:

We will need this concept to understand certain molecules

Enantiomers are mirror images of each other; see below D- and L-glucose.

Chair model of glucose showing the axial and equatorial substituents.

C5 is L. Therefore C6 is below the ring

Since this is an L series sugar all is ≠ and anomeric –OH is above ring and it is

β anomer

anomer

Mutarotation in the case of fructose

The case of galactose

Ribose and “derivatives” of carbohydrates

2-[18-F] Fluoro-2-deoxy-D-glucose (FDG)

2-deoxy-D-glucose is a non metabolizable form of glucose and its 18-F derivative is used for imaging.

C1 of aldoses or C2 of ketoses is prone to be oxidized at the expense of other compounds including a reagents containing a cupric salt.Monosaccharides are reducing when their reducing C is free or in the form of hemiacetal

Reducing and nonreducing monosaccharides

Acetals are not reducing because they are not in equilibrium with the open form and there is no carbonyl group to be oxidized. Acetals between monosaccharides and non-carbohydrate molecules are called glycosides.Acetals between monosaccharides are called mono, di, tri or polysaccharides

Ouabain

Ouabain is an inhibitor of the sodium/ potassium pump

What can you say about this monosaccharide?

GLYCOSIDES

Sugar chains are often linked to proteins by glycosidic bonds as shown below:

This is an O glycosidic bond

This is a N glycosidic bond

All nucleosides and nucleotides are N-glycosides of ribose or deoxyriboseand the corresponding purine or pyrimidine.

Sucrose is not a reducing monosaccharide.

The bond is glucose 1 →fructose 2β. Sucrose accounts for 15% of the calories in our diet. It is the main cause of dental cavities, contributes to obesity and diabetes

Disaccharides: are dimers of monosaccharides, either aldoses or ketosesYou must be acquainted with: maltose, isomaltose, lactose, sucrose and cellobiose.

Repeating unit in cellulose. Notice the β bond.

Glucose is the reducing monosaccharide. Notice the β bond.

Repeating unit in starch and glycogen. Notice the bond

Repeating unit at branching points in starch and glycogen. Notice the bond.

It is present in milk

POLYSACCHARIDESHomopolysaccharides are polymers of the same monosaccharide. Heteropolysaccharides are polymers of different monosaccharides. Complex carbohydrates are important cell constituents. The cell membrane have oligosaccharides that stabilizes protein conformation, protects against proteolysis, etc. In the erythrocyte, extracellular oligosaccharides are responsible for the blood groups. The ABO blood group antigens are the product of presence of absence of elongation enzymes (transferases).

HOMOPOLYSACCHARIDES:In plants the main form of storage of carbohydrates is STARCH, a mixture of:a) amylose: about 2,500 molecules of glucose bound by α(1-4) bonds forming a linear molecule.b) amylopectin: about 50,000 molecules of glucose bound by α(1-4) bonds with α(1-6) branching bonds every about 30 molecules of glucose. Amylopectin resembles glycogen although it is less branched.

Glycogen is a polymer of molecules of glucose bound by α(1-4) bonds with α(1-6) branching bonds every about 4-5 glucose residues. It could be considered as a polymer of maltose and isomaltose. You must know its structure because we will spend some time studying glycogen synthesis and break down. There are several diseases of glycogen storage. Below are shown two representations of glycogen.

Glycogen and starch are storage homopolysaccharides that contain -D-glucose and form a helix in space.

Cellulose is a linear polymer of β-D-glucose that is stabilized by inter-chain hydrogen bonds that give stability to the molecule. Cellulose forms a straight chain not a helix. Cellulose is not a source of calories for humans because the glycosidic bond is β and not α.

Heteropolysaccharides

Glycosaminoglycans, formerly called mucopolysaccharides, are a group of heteropolysaccharides composed of a repeating disaccharide unit usually formed by an uronic acid and an aminated sugar (glucosamine or galactosamine). They are variously substituted with negatively charged groups and are usually linked with other macromolecules forming large molecular aggregates. Those long negatively charged chains are hydrated and since the charges repel each other the chains are separated by water making the glycosaminoglycans excellent lubricants and shock absorbers.

Heparin and heparan sulfates: More than 70 % of heparin is a repeating disaccharide unit of L-iduronic linked to D-glucosamine. It is sulfated on the N of the glucosamine and on hydroxyl groups of both sugars. Heparin is the most acidic of all glycosaminoglycans. Heparan sulfate is very similar but has D-glucuronic instead of L-iduronic. Heparan is less acidic than heparin

Chondroitin sulfates 4S and 6S and dermatan sulfate. Chondroitin 4S and 6S are the most abundant glycosaminoglycans. They are composed of D-glucuronic acid and N-acetyl-D-galactosamine. They are sulfated on position 4 or 6 respectively. Both structures can be found on the same chain. Dermatan sulfate has L-iduronic acid in addition to D-glucuronic.

Chondroitin 4S Dermatan sulfate

Keratan sulfate. Closely associated with chondroitin sulfates in some connective tissues. The remarkable feature is the absence of glucuronic or iduronic acids. It contains galactose and N-acetyl-glucosamine.

Chondroitin 6S has the S03- on carbon 6

Hyaluronic acid. Is the least acidic of all glycosaminoglycans. It is fairly homogeneous containing N-acetyl-glucosamine and D-glucuronic. Does not contain sulfate

Attachment of glycosaminoglycans to proteins

Proteoglycan aggregateThe fig shows the macromolecular structure formed by proteins andglycosaminoglycans.

Intervertebral disk

Recommendations: You will be using the following formulas during the course. The formulas of the monosaccharides you must be familiar with are shown below. Those labeled with * are frequently used and you should memorize the formulas.

D-glucose* D-galactose*D-fructose* D-mannoseD-glucosamine* D-mannosamineD-galactosamine* D-ribose*dihydroxyacetone* D-glyceraldehyde*D-erithrose lactose D-ribose* sucrosemaltose* cellobiose2-deoxy-D-ribose* D-glucuronic*L-iduronic sialic or neuraminic acid

Actually, you should only remember glucose and ribose. The rest is reasoning and remembering basic concepts.

I will give you the Fischer projections of aldoses for the 1st exam and will test your ability to reason rather than your short-term memory

You must have a good understanding of the structure of glycogen* (types of bonds) because of its metabolic role and because you will use its structure to understand several metabolic diseases.

You must have a general idea about the composition of heparin, heparan sulfate, chondroitin and dermatan sulfates, keratan sulfate and hyaluronic acid. You must relate the structure to the function. New cell signaling functions of glycosaminoglycans are being discovered and the new functions are quite “mysterious”. Remember that glycosaminoglycans were previously called mucopolysaccharides. When associated with proteins they form proteoglycans.

Things to remember: Things to remember:

The following concepts must be understood:Isomer, stereoisomer, epimer, mutarotation, anomer (α and β), reducing carbohydrate, conformation as different from configuration, glycoside, pyranose, furanose, disaccharide, polysaccharide, homo-, and heteropolysaccharide, N-acetyl, deoxy, amino, D and L.