Saccharides IMonosaccharides

Derivatives of monosaccharides

Oligosaccharides

Medical ChemistryLecture 9 2007 (J.S.)

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Saccharides (glycids)are polyhydroxyaldehydes, polyhydroxyketones, or substances that give such compounds on hydrolysis.

Definition:

Classification:

POLYSACCHARIDES

polymeric

Give monosaccharides when hydrolyzed

GLYCANS

Basal units

MONOSACCHARIDES polyhydroxyaldehydes polyhydroxyketones

OLIGOSACCHARIDES

2 – 10 basal units

GLYCOSES (sugars)water-soluble, sweet taste

Don't use the historical misleading term carbohydrates, please. It was primarily derived from the empirical formula Cn(H2O)n and currently is taken as incorrect, not recommended in the IUPAC nomenclature (even though it can be found in numerous textbooks till now).

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Saccharides

occur widely in the nature, present in all types of cells

– the major nutrient for heterotrophs

– energy stores (glycogen, starch)

– components of structural materials (glycosaminoglycans)

– parts of important molecules(nucleic acids, nucleotides, glycoproteins, glycolipids)

– signalling function (recognition of molecules and cells, antigenic determinants)

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Monosaccharidesare simple sugars that cannot be hydrolyzed to simpler compounds.

Aldoses Ketoses Simple derivatives(polyhydroxyaldehydes) (polyhydroxyketones) modified monosaccharides

are further classified according to thenumber of carbon atoms in their chains:

glyceraldehyde (a triose) dihydroxyacetone tetroses tetruloses pentoses pentuloses hexoses hexuloses heptoses … heptuloses …

deoxysugars amino sugars uronic acids

other simple derivatives

alditols glyconic acids glycaric acids

Trivial names for stereoisomers

glucose (i.e. D-glucose) fructose (i.e. D-fructose) L-idose L-xylulose, etc.

Systematic names(not used in biochemistry) comprisetrivial prefixes according to the configuration:e.g., for glucose D-gluco-hexose, for fructose D-arabino-hexulose

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Stereoisomerism in monosaccharidesSecondary alcoholic groups CH-OH in monosaccharides arestereogenic centres. Monosaccharides are chiral compounds and, therefore, most of them are optically active.

Stereogenic centres are mostly carbon atoms that bind four different groups; those atoms are oft called "asymmetric" carbon atoms.

If there are more (n) stereogenic centres in the given molecule,the maximal number of stereoisomers equals 2n.

Each of those stereoisomers has its enantiomer (mirror image) so that there will be a maximum of 2n / 2 pairs of enantiomers.

Stereoisomers that differ from the particular pair of enantiomers are diastereomers of the pair.

In contrast to enantiomers, diastereomers differ in their properties and exhibit different values of specific optical rotation.

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are structural formulas that describe the configuration of particular stereoisomers.When a plane formula of an aldose with four stereogenic centres is drawn anywhere,e.g.,

Fischer projection formulas

an hexose

it is necessary to see a spatial arrangement of the atoms andassess it according to the established rules:

– the least number carbon (carbonyl group in monosaccharides) is drawn upwards,

– the carbon chain is directed downwards;then on each stereogenic centre

– the bonds to neighbouring carbon atoms written above and below are projected from beneath the plane of drawing (the carbons are behind the plane),

– the horizontal bonds written to the left and right are projected from above the plane of drawing, they are in front of plane

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Assigning configurations D- and L- (from Latin dexter and laevus) at stereogenic centres is carried outby comparison with the configurations of D- and L-glyceraldehyde (see optical isomerism, lecture 5-A).

Without changing the configuration, Fischer formulas may only be turned 180° in the plane of the paper.

Monosaccharides are classified as D- or L-sugars according to configuration at the configurational carbon atom – the chiral carbon with the highest numerical locant (i.e. the assymetric carbon farthest from the aldehyde or ketone group):

D-aldose L-ketose

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D-allose D-glucose

What is that?

D-mannoseL-glucose

Enantiomers, diatereomers, epimers

L-Glucose is enantiomer of D-glucose because of having opposite configuration at all centres of chirality.

Are there, among the following sugars, some diastereomers

of D-allose that are not epimers of it?

Is there any epimer of D-mannose?

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Stereogenic centres in molecules of monosaccharides are the cause of their optical activity. Solutions of mono- and oligosaccharides turn the plane of polarized light.Optical activity is measured by using polarimeters andusually expressed as specific optical rotation [α]D

20.

Dextrorotatory substances are marked (+), laevorotatory (–).

Configurations at stereogenic centres other than configurational carbon cannot be deduced from the assignment to D- or L-sugars.

Unfortunately, configurations of several most important monosaccharides have to be remembered.

There is no obvious relation between the assignment D- or L-and either the values or direction of optical activity.See tables 11 and 12.

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D-glyceraldehyde

D-erythrose D-threose

D-ribose D-arabinose D-xylose D-lyxose

D-allose D-altrose D-glucose D-mannose D-gulose D-idose D-galactose D-talose

D- Aldosesstereochemical relations

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D-(–)-erythrose D-(–)-threose

D-(–)- arabinose D-(+)-xylose D-(–)-lyxose

D-(+)-allose D-(+)-altrose D-(–)-gulose D-(–)-idose D-(+)-talose

D- Aldosesoptical rotation

D-(+)-glyceraldehyde

D-(–)-ribose

D-(+)-glucose D-(+)-mannose D-(+)-galactose

(+) dextrorotatory

(–) laevorotatory

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D-(–)-erythrulose

D-(+)-xylulose

D-(+)-psicose D-(+)-sorbose D-(+)-tagatose

D- Ketosesstereochemical relations

dihydroxyacetone

D-(–)-fructose

D-(–)-ribulose

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Cyclic forms of monosaccharides

Monosaccharides (polyhydroxyaldehydes and polyhydroxy-ketones) undergo rapid and reversible intramolecular additionof some properly located alcoholic group to carbonyl groupso that they form cyclic hemiacetals.

Monosaccharides exist mainly in cyclic hemiacetal forms,in solutions the acyclic aldehydo- or keto-forms are in minority.

al-D-glucose a hemiacetal, pyranose ring

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In this way, six- or five-membered rings can originate.In pyranoses, there is the tetrahydropyran (oxane) ring, tetrahydrofuran (oxolane) ringin furanoses.

In the acyclic forms, carbon of the carbonyl group is achiral,but this carbon becomes chiral in the cyclic forms. Two configurations are possible on this new stereogenic centrecalled anomeric (or hemiacetal) carbon so that the cyclization results in two epimers called α or β anomers:

α-anomer β-anomer

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The configuration of - anomer is the same as the configuration at anomeric reference carbon; in monosaccharides comprising five and six carbon atoms (pentoses and hexoses, pentuloses and hexuloses), the anomeric reference carbon is the configurational carbon. α-Anomers in Fischer formulas of D-sugars have the anomeric hydroxyl localized on the right.

The configuration of β-anomers is opposite, the anomeric hydroxyl is written on the left in Fischer formulas of D-sugars.

The hemiacetal hydroxyl group is called the anomeric hydroxyl.

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In solutions, all five forms of a hexose or hexulose occur;the cyclic forms usually prevail.

E.g., in the aqueous solution of D-glucose equilibrated at 20 °C, there is approximately 62 % -D-glucopyranose,

36 % -D-glucopyranose, < 0.5 % -D-glucofuranose,

< 0.5 % -D-glucofuranose, and < 0.003 % aldehydo-D-glucose.

If D-glucose is crystallized from methanol or water, the pureα-D-glucopyranose is obtained; crystallization of D-glucose fromacetic acid or pyridine gives the β-D-glucopyranose. These pureforms exhibit mutarotation, when dissolved: α-D-Glucopyranose just after dissolution exhibits [α]D

20 = + 112°, the β-form[α]D

20 = + 19°. After certain time period, [α]D20 of both solutions will settle at the

same equilibrium value of + 52°. This change can be explained by opening of thecyclic homicidal to the acyclic aldehyde. which can then recyclize to give eitherthe α or the β form till an equilibrium is established.

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Epimers – are those diastereomers that differ in configurationat only one centre of chirality, they have the same configuration at all stereogenic centres except one.

Don't confuse:

Enantiomers (optical antipodes) – stereoisomers that are not superimposable mirror images of each other, the configurations at all stereogenic centres are exactly opposite.All their chemical and physical properties are the same but the direction of optical rotation.

Anomers (α or β) represent a special kind of epimers, they have identical configuration at every stereogenic centre but they differ only in configuration at anomeric carbon atom.

Diastereomers – stereoisomers that are not enantiomers of one another. They have different physical properties (melting points, solubility, different specific optical rotations) so that they are viewed as different chemical substances.

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Haworth projection formulas

α-D-glucopyranose

Fischer projection Haworth projetion(the usual basal position)

– the rings are projected as planes perpendicular to the plane of drawing,

– carbon atoms of the rings and hydrogens attached to them are not shown,

– each of the formulas can be drawn in four positions, one of which is taken as the basal position (used preferentially).

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Rules for drawing Haworth projection formulas (the basal position):

C

1

OH

pyranose ring of a hexose

C1

OH

furanose ring of a hexose

C C2

OH

furanose ring of a hexulose

– The anomeric carbon atom (C-1, in ketoses C-2) on the right;

– oxygen atom in the ring is "behind", i.e. carbon atoms are numbered in the clockwise sense;

Then, – hydroxyl groups and hydrogens on the right in the Fischer projection are down in the Haworth projection (below the planeof the ring), and conversely, hydroxyls on the left in Fischer formulas means up in Haworth formulas;

– the terminal –CH2OH group is up for D-sugars (for L-sugars, it is down).

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α-D-glucopyranose can be drawn in four different positions:

The basal position: Position obtained by rotation of the "model"round a vertical axis

O

Positions obtained by tilting the "model„ over: because the numberingof carbons is then counter-clockwise, the groups on the right in Fischerprojection as well as the terminal –CH2OH are up in those Haworth formulas:

or

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al-D-glucoseα-D-glucopyranoseβ-D-glucopyranose

β-D-glucofuranose α-D-glucofuranose

Four different cyclic forms of glucose(all are depicted in the basal position)

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Four different cyclic fructose forms

α-D-fructofuranoseβ-D-fructofuranose

keto-D-fructose

β-D-fructopyranose α-D-fructopyranose

(all are depicted in the basal position)

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Conformation of pyranoses

α-D-glucopyranose-4C1 β-D-glucopyranose-4C1

The chair conformation of six-membered rings is more stable than the boat one.From two possible chair conformations, that one prevails, in which most of thevoluminous groups (-OH, -CH2OH) are attached in equatorial positions.

steric hindrance

boat conformation 4C1-chair conformation 1C4-chair conformation

E.g., conformations of β-D-glucopyranose:

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Physical properties of simple sugarsMultiple hydrophilic alcoholic groups in the molecules, therefore – non-electrolytes, – generally crystalline solids with a high melting temperature, – very soluble in water, – most of them exhibit optical activity.More or less sweet to the taste.

Saccharides Synthetic sweeteners

Sucrose

Glucose

Fructose

Lactose

1.0

0.5

1.5

0.3

Glucitol

Aspartame a)

Saccharin c)

Neotame b)

0.5

180

550

8000

a) methyl ester of the dipeptide aspartyl-phenylalanineb) methyl ester of the dipeptide N-(3,3-dimethylbutyl)aspartyl-phenylalaninec) 2-sulfobenzoic imide

Sweetness related to the sweetness of sucrose

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Common reactions of monosaccharides

Carbonyl group– is responsible for formation of cyclic forms (intramolecular hemiacetals) – the hemiacetal (anomeric) hydroxyl may form acetals called glycosides in reactions with alcohols, phenols, thiols, and amines

– gives sugar alcohols called alditols by reduction (hydrogenation),

– aldoses can give glyconic acids by oxidation

– can take part in the aldol condensation that gives rise to -C–C- bond.

Alcoholic groups– give ethers by alkylation,

– form esters in reactions with acids,

– primary alcoholic group gives glycuronic acid by oxidation,

– as polyhydric alcohols, monosaccharides undergo oxidative cleavage.

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Other reactions of saccharides

– Monosaccharides are unstable in alkaline solutions, at pH < 9 may form epimers or other isomers, at pH > 9, when heated, they are cleaved.

– In strongly acidic solutions, pentoses and hexoses are dehydrated to derivatives of furan-2-carbaldehyde (2-furaldehyde); in oligosaccharides and polysaccharides, acids cleave glycosidic

bonds by hydrolysis.

– All monosaccharides and some of oligosaccharides are reducing sugars; they are easily oxidized, e.g. in Benedict´s

test, if they have a free aldehyde group or an hemiacetal hydroxyl (see Practicals).

27D-fructose

Reduction of monosaccharides results in formation of

D-glucose D-glucitol

D-mannitol

alditols (sugar alcohols):

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Oxidation of monosaccharides

a glyconic acid(aldonic)

an aldose

a glycaric acid

(aldaric)

a glycuronic acid(uronic acid)

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D-Glucose

(dextrose, grape sugar) is in the form of polysaccharides (cellulose, starch, glycogen) the most abundant sugar in thenature.

Important monosaccharides

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D-Galactose

is the 4-epimer of glucose.

It occurs as component of lactose in milk and in dairy products(hydrolysis of lactose in the gut yields glucose and galactose),and as a component of glycoproteins and glycolipids.

D-Galactoseβ-D-Galactopyranose

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D-Ribose

β-D-ribofuranose β-D-ribopyranose

is the most important pentose – a component of nucleotidesand nucleic acids:

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D-fructose

D-Fructose

(laevulose, fruit sugar) is the most common ketose, present in many different fruits and in honey. A considerable quantities of this sugar are ingested chiefly in the form of sucrose.

β-D-fructofuranose β-D-fructopyranose

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Simple derivatives of monosaccharides

Esters

base

nucleoside 5´-phosphate fructose 1,6-bisphosphate

glucose 1-phosphateglucose 6-phosphate

with phosphoric acid are intermediates in metabolismof saccharides, constituents of nucleotides, etc-

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Deoxysugars

Deoxyribose (2-deoxy-β-D-ribose) is a constituent of nucleotides in DNA

L-Fucose (6-deoxy-L-galactose) is, e.g., present in some determinants of blood group antigens, and in numerous glycoproteins

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Amino sugarsare important constituents of saccharidic components of glyco- proteins and glycosaminoglycans.

N-acetylgalactosamineα-D-glucosamine N-acetylglucosamine

glucosamine(2-amino-2-deoxy-D-glucose)

fructose

CH–

CH=O

NH2

CH–OH

CH2–OH

HO–CH

CH–OH

CH–OH

CH2–OH

HO–CH

CH–OH

C=OCH2–OH

The basic amino groups –NH2 of amino sugars are nearly always "neutralized“ by acetylation in the reaction with acetyl-coenzyme A,so that they exist as N-acetyl-hexosamines. Unlike amines, amides (acetamido groups) are not basic.

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HC=O

HO–CH

HC–OH

CH2–OH

NH2–CH

HC–OH

C=OCOOH

CH2

HC–OH

HO–CH

HC–OH

CH2–OH

NH2–CH

HC–OH

CH3

C=O

COOH

is an aminononulose (ketone) as well as glyconic acid, 5-amino-3,5-dideoxynonulosonic acid.

It originates in the cells by condensation of pyruvate (in the form of phosphoenolpyruvate) with mannosamine:

Neuraminic acid

mannosamine

pyruvate

neuraminic acid

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Sialic acids are constituents of saccharidic components of glycolipids (gangliosides) and glycoproteins.

Sialic acidsis the group name used for variousacylated derivatives of neuraminic acid (N- as well as O-acylated).

The most common sialic acid is N-acetylneuraminic acid:

neuraminic acid a sialic acidN-acetylneuraminic acid

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Glycuronic acids (uronic acids)

D-galacturonic acidD-glucuronic acid

D-Glucuronic acidoriginates in human bodies by oxidation of activated glucose (UDP-glucose).It is a component of glycosaminoglycans in connective tissue and somehydrophobic waste products and xenobiotics are eliminated from the bodyafter conjugation with glucuronic acid.

D-Galacturonic and L-iduronic acids occur also as components of numerous glycoproteins and proteoglycans.

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Glyconic acidsare polyhydroxycarboxylic acids obtained by oxidation of the aldehydegroup of aldoses. E.g., glucose gives gluconic acid:

In the body, glucose (activated to glucose 6-phosphate) is dehydrogenated in theenzyme-catalyzed reaction to phosphogluconolactone that gives phosphogluconate by hydrolysis. This reaction (the initial reaction of the pentose phosphate pathway) is very important as a source of NADPH.

D-gluconic acid gluconate

1/2 O2

glucose 6-phosphate

– P

D-glucono-1,5-lactone

– P

D-glucono-1,4-lactone

– PNADP+ NADPH+H+

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L- Ascorbic acid

It is a weak diprotic acid (endiols are acidic), which has outstanding reducing properties. It can be very easily oxidized, to dehydroascorbic acid, namely in alkaline solutions.

Ascorbate acts as a cofactor of several enzymes and a powerful hydrophilic antioxidant. It is essential only for humans, primates, and guinea pigs.

– 2H– 2H

L-gulose L-gulonic acid L-gulono-1,4-lactone

L-ascorbic acid dehydro-L-ascorbic acid

(2,3-dehydro-L-gulono-1,4-lactone, vitamin C) is derived from L-gulonic acid.

Deducing of the structure of ascorbate:

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+ HO-CH3

– H2O

glycosidicbond

GlycosidesCyclic forms of saccharides, relatively unstable hemiacetals, canreact with alcohols or phenols to form acetals called glycosides.

The hemiacetal hydroxyl group (the anomeric hydroxyl) on the anomeric carbon is replaced by an alkoxy (or aryloxy) group.The bond between the anomeric carbon and the alkoxy group is called the glycosidic bond or O-glycosidic bond, at need.

Similarly, glycosidic bonds can be formed by reaction with an amino group, N-glycosidic bonds, or with a sulfanyl group, S-glycosidic bonds

Example:

α-D-glucopyranose methanol methyl-α-D-glucopyranoside

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Names of glycosidesare formed in two different ways.Both kinds of names have to denominate the type of glycosidic bond (α or β).

Formation of a glycosidic bond disables anomerizationon the anomeric carbon atom that takes part in the glycosidic bond.

The group that remains after taking offthe anomeric hydroxyl is called glycosyl.

E.g., α-D-glucopyranosyl (α-glucosyl):

1 The name of only the alkyl or aryl is used instead of the name of alkoxy or aryloxy group that replaces anomeric hydroxyl and the suffix –e in the following name of the saccharide is changed to –ide.

2 The name of a respective glycosyl is placed before the name of a compound that gives its alcoholic or phenolic hydroxyl, sulfanyl or amino group,.

Examples: 9-β-D-ribosyl-adenine, O-β-D-galactosyl-5-hydroxylysine.

Examples: phenyl-α-D-glucopyranoside, propyl-β-D-fructofuranoside.

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Classification of glycosides

Hologlycosidesare glycosides that give only monosaccharides by hydrolysis -O-glycosidic bonds bind various number of monosaccharides.

Oligosaccharides – consist of as much as approximately tenmonosaccharides; the most common are disaccharides.

Polysaccharides comprise up to many thousands monosaccha-ride units bound through glycosidic bonds. Those units areeither of the same kind in homopolysaccharides, ormay be of several kinds in heteropolysaccharides.

Heteroglycosidesin which nonsaccharidic components called aglycones or geninsare linked to saccharides through glycosidic bond.This bond may be not only O-glycosidic but also N-glycosidic or S-glycosidic.

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Disaccharidesare the most common disaccharides, in which two monosaccharidesare linked through glycosidic bond. There are two types of these sugars –reducing and nonreducing disaccharides.

Reducing disaccharidesare formed by a reaction between the anomeric hydroxyl of onemonosaccharide and a alcoholic hydroxyl group of another, sothat this second monosaccharide unit retains its anomeric hydroxyl,the reducing properties, it may anomerize and exhibits mutarotation.

Their names take the form D-glycosyl-D-glycose (with specificationof the glycoside bond).

Nonreducing disaccharidesBoth anomeric hydroxyl are linked in the glycosidic bond (calledanomeric bond), neither unit has its anomeric hydroxyl. They cannotreduce Benedict's reagent and cannot mutarotate.

Their names have the form D-glycosyl-D-glycoside.

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Maltose

Reducing disaccharides

(4-O--D-glucopyranosyl-D-glucopyranose, malt sugar)is obtained by the partial hydrolysis of starch or glycogen. Two molecules of glucose are linked through (1→4) glycosidic bond, further hydrolysis results in only glucose. Maltose is laevorotatory.Crystalline maltose is the β-anomer and exhibits mutarotation, when dissolved..

β-maltose4-O--D-glucopyranosyl-β-D-glucopyranose

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Isomaltosemay be viewed as a constituent of glycogen and amylopectin placed at branching points of the long chains connected through α(1→4) bonds.

α-isomaltose6-O--D-glucopyranosyl-α-D-glucopyranose

(1→6) glycosidic bond

6

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Cellobiose(4-O-β-D-glucopyranosyl-D-glucopyranose) is obtained by the partial hydrolysis of cellulose. Two molecules of glucose are linked through β(1→4) glycosidic bond, further hydrolysis results in only glucose. Cellobiose is dextrorotatory.

4

β-cellobiose4-O--D-glucopyranosyl-β-D-glucopyranose

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Lactose

(4-O-β-D-galactopyranosyl-D-glucopyranose, milk sugar)is the major sugar in human and cow's milk. Equimolar mixture of glucose and galactose is obtained by hydrolysis of β(1→4) glycosidic bonds.Lactose is dextrorotatory. Crystalline lactose is the α-anomer andexhibits mutarotation, when dissolved.

α-lactose4-O--D-galactopyranosyl-α-D-glucopyranose

β

4

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1

2

β

α

Nonreducing disaccharidesSucrose (saccharose)

(-D-fructofuranosyl--D-glucopyranoside, beet or cane sugar) isthe ordinary table sugar. Both hemiacetal hydroxyl groups of fructose and glucose are involved in the (β2↔α1) glycosidic bond (called occasionally anomeric glycosidic bond).

Sucrose is dextrorotatory and cannot mutarotate.When hydrolyzed, an equimolar mixture ofglucose and fructose results that is laevorotatory(invert sugar), because the anomers of fructoseare stronger levorotatory than the dextrorotatoryanomers of glucose.

sucrose-D-fructofuranosyl--D-glucopyranoside

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obtained X-ray structural analysis of crystalline table sugar

Real conformation of a sucrose molecule