Lehninger Carbo

I would feel more optimistic about a bright future for man if he spent
less time proving that he can outwit Nature and more time tasting her
sweetness and respecting her seniority.
—E. B. White, “Coon Tree,” 1977
7
Carbohydrates and Glycobiology
7.1 Monosaccharides and Disaccharides 235 Oligosaccharides consist of short chains of mono-
saccharide units, or residues, joined by characteristic
7.2 Polysaccharides 244 linkages called glycosidic bonds. The most abundant are
the disaccharides, with two monosaccharide units.
7.3 Glycoconjugates: Proteoglycans, Glycoproteins,
Typical is sucrose (cane sugar), which consists of the
and Glycolipids 252 six-carbon sugars D-glucose and D-fructose. All common
7.4 Carbohydrates as Informational Molecules: monosaccharides and disaccharides have names ending
with the suffix “-ose.” In cells, most oligosaccharides
The Sugar Code 257
consisting of three or more units do not occur as free en-
7.5 Working with Carbohydrates 263 tities but are joined to nonsugar molecules (lipids or
proteins) in glycoconjugates.
The polysaccharides are sugar polymers contain-
C arbohydrates are the most abundant biomolecules on ing more than 20 or so monosaccharide units; some have
Earth. Each year, photosynthesis converts more than hundreds or thousands of units. Some polysaccharides,
100 billion metric tons of CO2 and H2O into cellulose such as cellulose, are linear chains; others, such as
and other plant products. Certain carbohydrates (sugar glycogen, are branched. Both glycogen and cellulose
and starch) are a dietary staple in most parts of the world, consist of recurring units of D-glucose, but they differ in
and the oxidation of carbohydrates is the central energy- the type of glycosidic linkage and consequently have
yielding pathway in most nonphotosynthetic cells. Carbo- strikingly different properties and biological roles.
hydrate polymers (also called glycans) serve as structural
and protective elements in the cell walls of bacteria and
plants and in the connective tissues of animals. Other car-
7.1 Monosaccharides and Disaccharides
bohydrate polymers lubricate skeletal joints and partici- The simplest of the carbohydrates, the monosaccha-
pate in recognition and adhesion between cells. Complex rides, are either aldehydes or ketones with two or more
carbohydrate polymers covalently attached to proteins or hydroxyl groups; the six-carbon monosaccharides glu-
lipids act as signals that determine the intracellular loca- cose and fructose have five hydroxyl groups. Many of the
tion or metabolic fate of these hybrid molecules, called gly- carbon atoms to which hydroxyl groups are attached are
coconjugates. This chapter introduces the major classes chiral centers, which give rise to the many sugar
of carbohydrates and glycoconjugates and provides a few stereoisomers found in nature. We begin by describing
examples of their many structural and functional roles. the families of monosaccharides with backbones of
Carbohydrates are polyhydroxy aldehydes or ketones, three to seven carbons—their structure and stereoiso-
or substances that yield such compounds on hydrolysis. meric forms, and the means of representing their three-
Many, but not all, carbohydrates have the empirical formula dimensional structures on paper. We then discuss several
(CH2O)n; some also contain nitrogen, phosphorus, or sulfur. chemical reactions of the carbonyl groups of monosac-
There are three major size classes of carbohydrates: charides. One such reaction, the addition of a hydroxyl
monosaccharides, oligosaccharides, and polysaccha- group from within the same molecule, generates cyclic
rides (the word “saccharide” is derived from the Greek forms having four or more backbone carbons (the forms
sakcharon, meaning “sugar”). Monosaccharides, or that predominate in aqueous solution). This ring closure
simple sugars, consist of a single polyhydroxy aldehyde creates a new chiral center, adding further stereochemi-
or ketone unit. The most abundant monosaccharide in cal complexity to this class of compounds. The nomen-
nature is the six-carbon sugar D-glucose, sometimes re- clature for unambiguously specifying the configuration
ferred to as dextrose. Monosaccharides of four or more about each carbon atom in a cyclic form and the means
carbons tend to have cyclic structures. of representing these structures on paper are therefore
235
236 Carbohydrates and Glycobiology
H O H
C H C OH H O H O
H O H H C OH C O C C
C H C OH HO C H HO C H H C OH CH 2
H C OH C O H C OH H C OH H C OH H C OH
A A
H C OH H C OH H C OH H C OH H C OH H C OH
H H CH2OH CH 2OH CH 2OH CH2OH
D-Glyceraldehyde, Dihydroxyacetone, D-Glucose, D-Fructose, D-Ribose, 2-Deoxy-D-ribose,
an aldotriose a ketotriose an aldohexose a ketohexose an aldopentose an aldopentose
(a) (b) (c)
FIGURE 7–1 Representative monosaccharides. (a) Two trioses, an aldose

described in some detail; this information will be useful
and a ketose. The carbonyl group in each is shaded. (b) Two common
as we discuss the metabolism of monosaccharides in Part hexoses. (c) The pentose components of nucleic acids. D-Ribose is a
II. We also introduce here some important monosaccha- component of ribonucleic acid (RNA), and 2-deoxy-D-ribose is a com-
ride derivatives encountered in later chapters. ponent of deoxyribonucleic acid (DNA).
The Two Families of Monosaccharides Are Aldoses

and Ketoses structures on paper, we often use Fischer projection
formulas (Fig. 7–2). In Fischer projection formulas,
Monosaccharides are colorless, crystalline solids that are horizontal bonds project out of the plane of the paper,
freely soluble in water but insoluble in nonpolar solvents. toward the reader; vertical bonds project behind the
Most have a sweet taste. The backbones of common mono- plane of the paper, away from the reader.
saccharides are unbranched carbon chains in which all the
carbon atoms are linked by single bonds. In the open-chain
form, one of the carbon atoms is double-bonded to an oxy-
gen atom to form a carbonyl group; each of the other car- Mirror
CHO CHO
bon atoms has a hydroxyl group. If the carbonyl group is at
an end of the carbon chain (that is, in an aldehyde group)
the monosaccharide is an aldose; if the carbonyl group is
H
at any other position (in a ketone group) the monosaccha- OH
H OH
ride is a ketose. The simplest monosaccharides are the
two three-carbon trioses: glyceraldehyde, an aldotriose,
and dihydroxyacetone, a ketotriose (Fig. 7–1a).
Monosaccharides with four, five, six, and seven car- CH2OH
CH2OH
bon atoms in their backbones are called, respectively, tet-
roses, pentoses, hexoses, and heptoses. There are aldoses
and ketoses of each of these chain lengths: aldotetroses
and ketotetroses, aldopentoses and ketopentoses, and so Ball-and-stick models
on. The hexoses, which include the aldohexose D-glucose
and the ketohexose D-fructose (Fig. 7–1b), are the most CHO CHO
common monosaccharides in nature. The aldopentoses D- H C OH HO C H
ribose and 2-deoxy-D-ribose (Fig. 7–1c) are components CH2OH CH2OH
of nucleotides and nucleic acids (Chapter 8). D-Glyceraldehyde L-Glyceraldehyde
Monosaccharides Have Asymmetric Centers Fischer projection formulas
All the monosaccharides except dihydroxyacetone con- CHO CHO

tain one or more asymmetric (chiral) carbon atoms and
thus occur in optically active isomeric forms (pp. 16–17). H C OH HO C H
The simplest aldose, glyceraldehyde, contains one chiral CH 2OH CH2OH
center (the middle carbon atom) and therefore has two D-Glyceraldehyde L-Glyceraldehyde
different optical isomers, or enantiomers (Fig. 7–2).

Perspective formulas
KEY CONVENTION: One of the two enantiomers is, by con- FIGURE 7–2 Three ways to represent the two enantiomers of glycer-
vention, designated the D isomer, the other the L isomer. aldehyde. The enantiomers are mirror images of each other. Ball-and-
As for other biomolecules with chiral centers, the ab- stick models show the actual configuration of molecules. Recall (see
solute configurations of sugars are known from x-ray Fig. 1–17) that in perspective formulas, solid wedge-shaped bonds
crystallography. To represent three-dimensional sugar point toward the reader, dashed wedges point away.
7.1 Monosaccharides and Disaccharides 237
Three carbons Four carbons Five carbons

H O H O H O H O
H O H O C C C C
H O C C H C OH HO C H H C OH HO C H
C H C OH HO C H H C OH H C OH HO C H HO C H
H C OH H C OH H C OH H C OH H C OH H C OH H C OH
CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH
D-Glyceraldehyde D-Erythrose D-Threose D-Ribose D-Arabinose D-Xylose D-Lyxose
Six carbons
H O H O H O H O H O H O H O H O
C C C C C C C C
H C OH HO C H H C OH HO C H H C OH HO C H H C OH HO C H
H C OH H C OH HO C H HO C H H C OH H C OH HO C H HO C H
H C OH H C OH H C OH H C OH HO C H HO C H HO C H HO C H
H C OH H C OH H C OH H C OH H C OH H C OH H C OH H C OH
CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH
D-Allose D-Altrose D-Glucose D-Mannose D-Gulose D-Idose D-Galactose D-Talose
D-Aldoses
(a)
FIGURE 7–3 Aldoses and ketoses. The series of (a) D-aldoses and
(b) D-ketoses having from three to six carbon atoms, shown as projec- Three carbons Four carbons
tion formulas. The carbon atoms in red are chiral centers. In all these CH2OH
D isomers, the chiral carbon most distant from the carbonyl carbon has CH2OH C O
the same configuration as the chiral carbon in D-glyceraldehyde. The
C O H C OH
sugars named in boxes are the most common in nature; you will en-
counter these again in this and later chapters. CH2OH CH2OH
Dihydroxyacetone D-Erythrulose
In general, a molecule with n chiral centers can have

2n stereoisomers. Glyceraldehyde has 21 2; the aldo-
hexoses, with four chiral centers, have 24 16 stereoiso- Five carbons Six carbons
mers. The stereoisomers of monosaccharides of each
CH2OH CH2OH
carbon-chain length can be divided into two groups that CH2OH
differ in the configuration about the chiral center most C O C O
C O
distant from the carbonyl carbon. Those in which the H C OH HO C H
configuration at this reference carbon is the same as H C OH
H C OH H C OH
that of D-glyceraldehyde are designated D isomers, and H C OH
H C OH H C OH
those with the same configuration as L-glyceraldehyde CH2OH
are L isomers. When the hydroxyl group on the refer- CH2OH CH2OH
D-Ribulose
ence carbon is on the right in a projection formula that D-Psicose D-Fructose
has the carbonyl carbon at the top, the sugar is the D iso-
mer; when on the left, it is the L isomer. Of the 16 possi- CH2OH CH2OH
ble aldohexoses, eight are D forms and eight are L. Most CH2OH C O C O
of the hexoses of living organisms are D isomers. C O H C OH HO C H
Figure 7–3 shows the structures of the D stereoiso-
HO C H HO C H HO C H
mers of all the aldoses and ketoses having three to six
carbon atoms. The carbons of a sugar are numbered be- H C OH H C OH H C OH
ginning at the end of the chain nearest the carbonyl CH2OH CH2OH CH2OH
group. Each of the eight D-aldohexoses, which differ in D-Xylulose D-Sorbose D-Tagatose
the stereochemistry at C-2, C-3, or C-4, has its own
name: D-glucose, D-galactose, D-mannose, and so forth D-Ketoses
(Fig. 7–3a). The four- and five-carbon ketoses are (b)
1 1 1 3 3
CHO CHO CHO O OH HO R OR
2 2 2 1 2 1 2 1 2
HO C H H C OH H C OH R C HO R R C OR R C OR H2O
3 3 3 H 3
HO C H HO C H HO C H H HO R H
H
4
C OH H
4
C OH HO
4
C H Aldehyde Alcohol Hemiacetal Acetal
5 5 5
H C OH H C OH H C OH
6 6 6 4 4
CH2OH CH2OH CH2OH OH HO R OR
D-Mannose D-Glucose D-Galactose 1 3 1 3 1 3
R C O HO R R C OR R C OR H2O
(epimer at C-2) (epimer at C-4) 2 2 2
4
R R HO R R
FIGURE 7–4 Epimers. D-Glucose and two of its epimers are shown as Ketone Alcohol Hemiketal Ketal
projection formulas. Each epimer differs from D-glucose in the config-
uration at one chiral center (shaded pink). FIGURE 7–5 Formation of hemiacetals and hemiketals. An aldehyde
or ketone can react with an alcohol in a 1:1 ratio to yield a hemiacetal
or hemiketal, respectively, creating a new chiral center at the carbonyl
designated by inserting “ul” into the name of a corre- carbon. Substitution of a second alcohol molecule produces an acetal
sponding aldose; for example, D-ribulose is the ketopen- or ketal. When the second alcohol is part of another sugar molecule,
tose corresponding to the aldopentose D-ribose. The the bond produced is a glycosidic bond (p. 243).
ketohexoses are named otherwise: for example, fruc-
tose (from the Latin fructus, “fruit”; fruits are one
carbon asymmetric and producing two stereoisomers,
source of this sugar) and sorbose (from Sorbus, the
designated and (Fig. 7–6). The designation indi-
genus of mountain ash, which has berries rich in the re-
cates that the hydroxyl group at the anomeric center
lated sugar alcohol sorbitol). Two sugars that differ only
is, in a Fischer projection, on the same side as the
in the configuration around one carbon atom are called
epimers; D-glucose and D-mannose, which differ only in
the stereochemistry at C-2, are epimers, as are D-glu-
H O
cose and D-galactose (which differ at C-4) (Fig. 7–4).
1C
Some sugars occur naturally in their L form;
2
examples are L-arabinose and the L isomers of some H C OH
3
sugar derivatives that are common components of HO C H D-Glucose
glycoconjugates (Section 7.3). 4

H C OH
5
H C OH
H O
G J 6
C CH2OH
A
HOCOOH
A 6
HOOCOH CH2OH
A 5C OH
HOOCOH H H
A H
4
CH2OH C C1
OH H
L-Arabinose HO O
3
C 2
C
The Common Monosaccharides Have Cyclic Structures H OH
For simplicity, we have thus far represented the struc-

tures of aldoses and ketoses as straight-chain mole-
6 6
cules (Figs 7–3, 7–4). In fact, in aqueous solution, CH2OH CH2OH
aldotetroses and all monosaccharides with five or more 5
C O 5
C O
H H H OH
carbon atoms in the backbone occur predominantly as H H
4 4
cyclic (ring) structures in which the carbonyl group C 1C C 1C
OH H OH H
has formed a covalent bond with the oxygen of a hy- HO OH HO H
3
C 2
C 3
C 2
C
droxyl group along the chain. The formation of these
ring structures is the result of a general reaction be- H OH H OH
tween alcohols and aldehydes or ketones to form deriv- -D-Glucopyranose -D-Glucopyranose
atives called hemiacetals or hemiketals (Fig. 7–5), FIGURE 7–6 Formation of the two cyclic forms of D-glucose. Reac-
which contain an additional asymmetric carbon atom tion between the aldehyde group at C-1 and the hydroxyl group at C-5
and thus can exist in two stereoisomeric forms. For ex- forms a hemiacetal linkage, producing either of two stereoisomers, the
ample, D-glucose exists in solution as an intramolecular and anomers, which differ only in the stereochemistry around the
hemiacetal in which the free hydroxyl group at C-5 has hemiacetal carbon. The interconversion of and anomers is called
reacted with the aldehydic C-1, rendering the latter mutarotation.
hydroxyl attached at the farthest chiral center, whereas -D-glucose, and very small amounts of the linear and
indicates that these hydroxyl groups are on opposite five-membered ring (glucofuranose) forms.
sides. These six-membered ring compounds are called Ketohexoses also occur in and anomeric forms.
pyranoses because they resemble the six-membered In these compounds the hydroxyl group at C-5 (or C-6)
ring compound pyran (Fig. 7–7). The systematic names reacts with the keto group at C-2, forming a furanose (or
for the two ring forms of D-glucose are -D-glucopyranose pyranose) ring containing a hemiketal linkage (Fig. 7–5).
and -D-glucopyranose. D-Fructose readily forms the furanose ring (Fig. 7–7);
Aldoses also exist in cyclic forms having five- the more common anomer of this sugar in combined
membered rings, which, because they resemble the five- forms or in derivatives is -D-fructofuranose.
membered ring compound furan, are called furanoses. Haworth perspective formulas like those in Fig-
However, the six-membered aldopyranose ring is much ure 7–7 are commonly used to show the stereochemistry
more stable than the aldofuranose ring and predomi- of ring forms of monosaccharides. However, the six-
nates in aldohexose and aldopentose solutions. Only al- membered pyranose ring is not planar, as Haworth per-
doses having five or more carbon atoms can form spectives suggest, but tends to assume either of two
pyranose rings. “chair” conformations (Fig. 7–8). Recall from Chapter 1
Isomeric forms of monosaccharides that differ only (p. 18) that two conformations of a molecule are inter-
in their configuration about the hemiacetal or hemiketal convertible without the breakage of covalent bonds,
carbon atom are called anomers. The hemiacetal (or whereas two configurations can be interconverted only
carbonyl) carbon atom is called the anomeric carbon. by breaking a covalent bond. To interconvert and
The and anomers of D-glucose interconvert in configurations, the bond involving the ring oxygen atom
aqueous solution by a process called mutarotation would have to be broken, but interconversion of the two
(Fig. 7–6). Thus, a solution of -D-glucose and a solution chair forms does not require bond breakage. The specific
of -D-glucose eventually form identical equilibrium three-dimensional structures of the monosaccharide units
mixtures having identical optical properties. This mix- are important in determining the biological properties and
ture consists of about one-third -D-glucose, two-thirds functions of some polysaccharides, as we shall see.
Axis Axis
ax ax ax
6 CH
2OH eq
5 eq O eq
O 6 ax ax O eq
HOCH2 O 1 CH
H H 2OH
H ax eq eq
4 1 5 2 eq eq
OH H H HO eq eq
HO OH H OH ax ax ax ax
3 2 4 3
H OH OH H Two possible chair forms
(a)
-D-Glucopyranose -D-Fructofuranose
Axis
CH2OH H
O H2COH O
H OH HOCH2 O OH HO H
H
H H
OH H H HO HO
HO H H CH2OH OH
H OH
H OH OH H
-D-Glucopyranose
-D-Glucopyranose -D-Fructofuranose
(b)
FIGURE 7–8 Conformational formulas of pyranoses. (a) Two chair

HC O O
forms of the pyranose ring. Bonds to substituents and hydrogen atoms
HC CH on the ring carbons may be either axial (ax), projecting parallel to the
HC CH
C C vertical axis through the ring, or equatorial (eq), projecting roughly
H2C CH H H perpendicular to this axis. Two conformers such are these are not readily
interconvertible without breaking the ring. However, when the mole-
Pyran Furan
cule is “stretched” (by atomic force microscopy; see Box 11–1), an
FIGURE 7–7 Pyranoses and furanoses. The pyranose forms of input of about 46 kJ of energy per mole of sugar can force the inter-
D-glucose and the furanose forms of D-fructose are shown here as Ha- conversion of chair forms. Generally, substituents in the equatorial
worth perspective formulas. The edges of the ring nearest the reader positions are less sterically hindered by neighboring substituents, and
are represented by bold lines. Hydroxyl groups below the plane of the conformers with bulky substituents in equatorial positions are favored.
ring in these Haworth perspectives would appear at the right side of a Another conformation, the “boat” (not shown), is seen only in deriva-
Fischer projection (compare with Fig. 7–6). Pyran and furan are shown tives with very bulky substituents. (b) The preferred chair conformation
for comparison. of -D-glucopyranose.
Organisms Contain a Variety of Hexose Derivatives or L-mannose produces L-fucose or L-rhamnose, re-
In addition to simple hexoses such as glucose, galactose, spectively. L-Fucose is found in the complex oligosac-
and mannose, there are a number of sugar derivatives in charide components of glycoproteins and glycolipids;
which a hydroxyl group in the parent compound is re- L-rhamnose is found in plant polysaccharides.
placed with another substituent, or a carbon atom is ox- Oxidation of the carbonyl (aldehyde) carbon of glu-
idized to a carboxyl group (Fig. 7–9). In glucosamine, cose to the carboxyl level produces gluconic acid; other
galactosamine, and mannosamine, the hydroxyl at C-2 aldoses yield other aldonic acids. Oxidation of the car-
of the parent compound is replaced with an amino bon at the other end of the carbon chain—C-6 of glucose,
group. The amino group is nearly always condensed galactose, or mannose—forms the corresponding uronic
with acetic acid, as in N-acetylglucosamine. This acid: glucuronic, galacturonic, or mannuronic acid. Both
glucosamine derivative is part of many structural poly- aldonic and uronic acids form stable intramolecular es-
mers, including those of the bacterial cell wall. Bacter- ters called lactones (Fig. 7–9, lower left). In addition
ial cell walls also contain a derivative of glucosamine, to these acidic hexose derivatives, one nine-carbon
N-acetylmuramic acid, in which lactic acid (a three- acidic sugar deserves mention: N-acetylneuraminic acid
carbon carboxylic acid) is ether-linked to the oxygen (a sialic acid, but often referred to simply as “sialic acid”),
at C-3 of N-acetylglucosamine. The substitution of a a derivative of N-acetylmannosamine, is a component
hydrogen for the hydroxyl group at C-6 of L-galactose of many glycoproteins and glycolipids in animals. The
Glucose family
Amino sugars
CH2OH CH2OH CH2OH CH2OH CH2OH

O O O O O
H H OH H H OH H H OH HO H OH H H H N OH
2
OH H OH H OH H OH H OH
HO H HO H HO H H H HO H
H OH H NH2 H NH H NH2 H H
C O -D-Galactosamine -D-Mannosamine
CH3
-D-Glucose -D-Glucosamine N-Acetyl- -D-glucosamine
Deoxy sugars
CH2 O PO2
3 CH2OH CH2OH H H
O O O CH3 O O
H OH H OH H OH H CH3 H HO CH3 OH
H H H
R O C H
OH H R H R H H OH H H
HO H HO H HO H HO OH H H
COO
H OH H NH2 H NH OH H OH OH
C O
CH3
-D-Glucose 6-phosphate Muramic acid N-Acetylmuramic acid -L-Fucose -L-Rhamnose
Acidic sugars

O O CH3 O O
C CH2OH CH2OH O C H C R
O OH O O
H OH H O H HN
H H H R
C O H C OH
OH H OH H OH H H H
HO H HO O HO H OH H C OH
H OH H OH H OH OH H CH2OH
-D-Glucuronate D-Gluconate D-Glucono- -lactone N-Acetylneuraminic acid
(a sialic acid)
FIGURE 7–9 Some hexose derivatives important in biology. In amino acidic sugars contain a carboxylate group, which confers a negative
sugars, an ⎯NH2 group replaces one of the ⎯OH groups in the parent charge at neutral pH. D-Glucono--lactone results from formation of
hexose. Substitution of ⎯H for ⎯OH produces a deoxy sugar; note an ester linkage between the C-1 carboxylate group and the C-5 (also
that the deoxy sugars shown here occur in nature as the L isomers. The known as the carbon) hydroxyl group of D-gluconate.
carboxylic acid groups of the acidic sugar derivatives H O

G J
are ionized at pH 7, and the compounds are therefore 1C
A
correctly named as the carboxylates—glucuronate, 6 CH OH
2
HOCOOH
galacturonate, and so forth. 5
2
3
A
O HOOCOH
4A
In the synthesis and metabolism of carbohydrates, H H OH
3Cu 3Cu 2
the intermediates are very often not the sugars them- 4 1 HOCOOH Complex mixture of
OH H 5 A 2-,3-,4-, and
selves but their phosphorylated derivatives. Condensa- HO H HOCOOH
2 A 6-carbon acids
3
tion of phosphoric acid with one of the hydroxyl groups 6
CH2OH
H OH
of a sugar forms a phosphate ester, as in glucose -D-Glucose D-Glucose
6-phosphate (Fig. 7–9). Sugar phosphates are relatively (linear form)
stable at neutral pH and bear a negative charge. One ef-
FIGURE 7–10 Sugars as reducing agents. Oxidation of the anomeric
fect of sugar phosphorylation within cells is to trap the carbon (and probably the neighboring carbon) of glucose and other
sugar inside the cell; most cells do not have plasma sugars under alkaline conditions is the basis for Fehling’s reaction. The
membrane transporters for phosphorylated sugars. cuprous ion (Cu) produced forms a red cuprous oxide precipitate. In
Phosphorylation also activates sugars for subsequent the hemiacetal (ring) form, C-1 of glucose cannot be oxidized by
chemical transformation. Several important phosphory- complexed Cu2. However, the open-chain form is in equilibrium
lated derivatives of sugars are components of nu- with the ring form, and eventually the oxidation reaction goes to com-
cleotides (discussed in the next chapter). pletion. The reaction with Cu2 is complex, yielding a mixture of prod-
ucts and reducing 3 mol of Cu2 per mole of glucose.
Monosaccharides Are Reducing Agents
Monosaccharides can be oxidized by relatively acids. This is the basis of Fehling’s reaction, a qualitative
mild oxidizing agents such as cupric (Cu2) ion test for the presence of reducing sugar. By measuring
(Fig. 7–10). The carbonyl carbon is oxidized to a car- the amount of oxidizing agent reduced by a solution of a
boxyl group. Glucose and other sugars capable of sugar, it is also possible to estimate the concentration of
reducing cupric ion are called reducing sugars. They that sugar. For many years this test was used to detect
form enediols, which are converted to aldonic acids and and measure elevated glucose levels in blood and urine
then to a complex mixture of 2-, 3-, 4-, and 6-carbon in the diagnosis of diabetes mellitus (Box 7–1). ■
Blood Glucose Measurements in the Diagnosis and

BOX 7–1 MEDICINE
Treatment of Diabetes
Glucose is the principal fuel for the brain. When the The concentrations of glucose in blood and urine
amount of glucose reaching the brain is too low, the can be determined by a simple assay for reducing sugar,
consequences can be dire: lethargy, coma, permanent such as Fehling’s reaction, which for many years was
brain damage, and death (see Fig. 23–25). Animals used as a diagnostic test for diabetes (Fig. 7–10). Mod-
have evolved complex hormonal mechanisms to ensure ern measurements require just a drop of blood, added
that the concentration of glucose in the blood remains to a test strip containing the enzyme glucose oxidase
high enough (about 5 mM) to satisfy the brain’s needs, (Fig. 1); a simple photometer measures the color pro-
but not too high, because elevated blood glucose can duced when the H2O2 from glucose oxidation reacts with
also have serious physiological consequences. a dye, and reads out the blood glucose concentration.
Individuals with insulin-dependent diabetes melli- Because blood glucose levels change with the timing
tus do not produce sufficient insulin, the hormone that of meals and exercise, single-time measurements do not
normally serves to reduce blood glucose concentration, necessarily reflect the average blood glucose over hours
and if the diabetes is untreated their blood glucose lev- and days, so dangerous increases may go undetected.
els may rise to severalfold higher than normal. These The average glucose concentration can be assessed by
high glucose levels are believed to be at least one cause looking at its effect on hemoglobin, the oxygen-carrying
of the serious long-term consequences of untreated dia- protein in erythrocytes (p. 158). Transporters in the ery-
betes—kidney failure, cardiovascular disease, blind- throcyte membrane equilibrate intracellular and plasma
ness, and impaired wound healing—so one goal of glucose oxidase
D-Glucose O2 D-Glucono--lactone H 2 O2
therapy is to provide just enough insulin (by injection)
to keep blood glucose levels near normal. To maintain FIGURE 1 The glucose oxidase reaction, used in the measurement of
the correct balance of exercise, diet, and insulin for the blood glucose. A second enzyme, a peroxidase, catalyzes the reaction
individual, blood glucose concentration needs to be of the H2O2 with a colorless compound to produce a colored product,
measured several times a day, and the amount of insulin which is measured spectrophotometrically.
injected adjusted appropriately. (continued on next page)
Blood Glucose Measurements in the Diagnosis and

BOX 7–1 MEDICINE
Treatment of Diabetes (continued from previous page)
glucose concentrations, so hemoglobin is constantly ex- HOCH2

posed to glucose at whatever concentration is present in OH H
H
the blood. A nonenzymatic reaction occurs between glu- H
CO H2NR
cose and primary amino groups in hemoglobin (either OH H
HO
the amino-terminal Val or the e-amino groups of Lys Hemoglobin
residues; see Fig. 2). The rate of this process is propor- H OH
tional to the concentration of glucose, so the reaction Glucose
can be used as the basis for estimating the average blood 1
glucose level over weeks. The amount of glycated hemo-
globin (GHB) present at any time reflects the average
blood glucose concentration over the circulating “life- HOCH2
time” of the erythrocyte (about 120 days), although the OH H
H H
concentration in the last two weeks is the most impor- CNR
tant in setting the level of GHB. OH H
HO
The extent of hemoglobin glycation (so named
to distinguish it from glycosylation, the enzymatic H OH
transfer of glucose to a protein) is measured clinically Schiff base
2a
by extracting hemoglobin from a small sample of blood
and separating GHB from unmodified hemoglobin elec-
trophoretically, taking advantage of the charge differ-
HOCH2
ence resulting from modification of the amino OH
group(s). Normal GHB values are about 5% of total he- H H
H H
moglobin (corresponding to blood glucose of 120 mg/ CNR
OH
100 mL). In people with untreated diabetes, how- HO
ever, this value may be as high as 13%, indicating an
H OH
average blood glucose level of about 300 mg/100 mL—
dangerously high. One criterion for success in an indi- 2b
vidual program of insulin therapy (the timing,
frequency, and amount of insulin injected) is maintain-
ing GHB values at about 7%. HOCH2
In the hemoglobin glycation reaction, the first step OH
(formation of a Schiff base) is followed by a series of re- H H H
arrangements, oxidations, and dehydrations of the car- CH2NR
OH
bohydrate moiety to produce a heterogeneous mixture HO
of AGEs, advanced glycation end products. These prod- H O
ucts can leave the erythrocyte and form covalent cross- Ketoamine
links between proteins, interfering with normal protein 3
function (Fig. 2). The accumulation of relatively high
concentrations of AGEs in people with diabetes may, by
cross-linking critical proteins, cause the damage to the HOCH2 O H
CH2NR
kidneys, retinas, and cardiovascular system that charac- H HO
terize the disease. This pathogenic process is a potential H OH
target for drug action.
HO H
Glycated hemoglobin
FIGURE 2 The nonenzymatic reaction of glucose with a primary amino 4 (GHB)
group in hemoglobin begins with 1 formation of a Schiff base, which
2 undergoes the Amadori rearrangement to generate a stable product; AGEs
3 this ketoamine can further cyclize to yield GHB. 4 Subsequent 5
reactions generate advanced glycation end products (AGEs), such as
Protein cross-linking
e-N-carboxymethyllysine and methylglyoxal, compounds that 5 can
? ? ?
damage other proteins by cross-linking them, causing pathological
changes. Damage to kidneys, retinas, cardiovascular system
Disaccharides Contain a Glycosidic Bond The disaccharide maltose (Fig. 7–11) contains two
D-glucose residues joined by a glycosidic linkage be-
Disaccharides (such as maltose, lactose, and sucrose) tween C-1 (the anomeric carbon) of one glucose
consist of two monosaccharides joined covalently by an residue and C-4 of the other. Because the disaccharide
O-glycosidic bond, which is formed when a hydroxyl retains a free anomeric carbon (C-1 of the glucose
group of one sugar reacts with the anomeric carbon of residue on the right in Fig. 7–11), maltose is a reducing
the other (Fig. 7–11). This reaction represents the for- sugar. The configuration of the anomeric carbon atom
mation of an acetal from a hemiacetal (such as glucopy- in the glycosidic linkage is . The glucose residue with
ranose) and an alcohol (a hydroxyl group of the second the free anomeric carbon is capable of existing in - and
sugar molecule) (Fig. 7–5), and the resulting compound -pyranose forms.
is called a glycoside. Glycosidic bonds are readily
hydrolyzed by acid but resist cleavage by base. Thus KEY CONVENTION: To name reducing disaccharides such
disaccharides can be hydrolyzed to yield their free as maltose unambiguously, and especially to name more
monosaccharide components by boiling with dilute acid. complex oligosaccharides, several rules are followed. By
N-glycosyl bonds join the anomeric carbon of a sugar to convention, the name describes the compound written
a nitrogen atom in glycoproteins (see Fig. 7–29) and nu- with its nonreducing end to the left, and we can “build
cleotides (see Fig. 8–1). up” the name in the following order. (1) Give the config-
The oxidation of a sugar by cupric ion (the reaction uration ( or ) at the anomeric carbon joining the first
that defines a reducing sugar) occurs only with the monosaccharide unit (on the left) to the second. (2)
linear form, which exists in equilibrium with the cyclic Name the nonreducing residue; to distinguish five- and
form(s). When the anomeric carbon is involved in a gly- six-membered ring structures, insert “furano” or
cosidic bond, that sugar residue cannot take the linear “pyrano” into the name. (3) Indicate in parentheses the
form and therefore becomes a nonreducing sugar. In two carbon atoms joined by the glycosidic bond, with an
describing disaccharides or polysaccharides, the end of a arrow connecting the two numbers; for example, (1n4)
chain with a free anomeric carbon (one not involved in a shows that C-1 of the first-named sugar residue is joined
glycosidic bond) is commonly called the reducing end. to C-4 of the second. (4) Name the second residue. If
there is a third residue, describe the second glycosidic
CH2OH CH2OH bond by the same conventions. (To shorten the descrip-
O hemiacetal O tion of complex polysaccharides, three-letter abbrevia-
H H H H H OH tions or colored symbols for the monosaccharides
are often used, as given in Table 7–1.) Following this
OH H OH H
HO OH HO H convention for naming oligosaccharides, maltose is -D-
H OH alcohol
H OH
glucopyranosyl-(1n4)-D-glucopyranose. Because most
-D-Glucose -D-Glucose
sugars encountered in this book are the D enantiomers
and the pyranose form of hexoses predominates, we
hydrolysis condensation generally use a shortened version of the formal name of
H2O H 2O
Symbols and Abbreviations for
6 CH
5
2OH
6 CH
5
2OH TABLE 7–1 Common Monosaccharides and Some
O acetal O hemiacetal of Their Derivatives
H H H H H OH
4 1 4 1
OH H OH H Abequose Abe Glucuronic acid GlcA
HO H
O Arabinose Ara Galactosamine GalN
3 2 3 2
H OH H OH Fructose Fru Glucosamine GlcN
Maltose Fucose Fuc N-Acetylgalactosamine GalNAc
-D-glucopyranosyl-(1n4)-D-glucopyranose
Galactose Gal N-Acetylglucosamine GlcNAc
FIGURE 7–11 Formation of maltose. A disaccharide is formed from Glucose Glc Iduronic acid IdoA
two monosaccharides (here, two molecules of D-glucose) when an
Mannose Man Muramic acid Mur
⎯OH (alcohol) of one glucose molecule (right) condenses with the in-
tramolecular hemiacetal of the other glucose molecule (left), with Rhamnose Rha N-Acetylmuramic acid Mur2Ac
elimination of H2O and formation of a glycosidic bond. The reversal of Ribose Rib N-Acetylneuraminic
this reaction is hydrolysis—attack by H2O on the glycosidic bond. The Xylose Xyl acid (a sialic acid) Neu5Ac
maltose molecule, shown here as an illustration, retains a reducing
hemiacetal at the C-1 not involved in the glycosidic bond. Because Note: In a commonly used convention, hexoses are represented as circles, N-acetylhex-
mutarotation interconverts the and forms of the hemiacetal, the osamines as squares, and hexosamines as squares divided diagonally. All sugars with
the “gluco” configuration are blue, those with the “galacto” configuration are yellow, and
bonds at this position are sometimes depicted with wavy lines, as “manno” sugars are green. Other substituents can be added as needed: sulfate (S),
shown here, to indicate that the structure may be either or . phosphate (P), O-acetyl (OAc), or O-methyl (Ome).
such compounds, giving the configuration of the (Fig. 7–12)—a disaccharide of D-glucose that, like su-
anomeric carbon and naming the carbons joined by crose, is a nonreducing sugar—is a major constituent of
the glycosidic bond. In this abbreviated nomenclature, the circulating fluid (hemolymph) of insects, serving as
maltose is Glc(1n4)Glc. ■ an energy-storage compound. Fungi also contain tre-
halose and are used as a commercial source of this sugar.
The disaccharide lactose (Fig. 7–12), which yields
D-galactose and D-glucose on hydrolysis, occurs naturally SUMMARY 7.1 Monosaccharides and
in milk. The anomeric carbon of the glucose residue is
available for oxidation, and thus lactose is a reducing di-
Disaccharides
saccharide. Its abbreviated name is Gal(1n4)Glc. ■ Sugars (also called saccharides) are compounds
Sucrose (table sugar) is a disaccharide of glucose and containing an aldehyde or ketone group and two or
fructose. It is formed by plants but not by animals. In more hydroxyl groups.
contrast to maltose and lactose, sucrose contains no free ■ Monosaccharides generally contain several chiral
anomeric carbon atom; the anomeric carbons of both carbons and therefore exist in a variety of
monosaccharide units are involved in the glycosidic bond stereochemical forms, which may be represented
(Fig. 7–12). Sucrose is therefore a nonreducing sugar. on paper as Fischer projections. Epimers are sugars
In the abbreviated nomenclature, a double-headed that differ in configuration at only one carbon atom.
arrow connects the symbols specifying the anomeric
carbons and their configurations. For example, the ab- ■ Monosaccharides commonly form internal
breviated name of sucrose is either Glc(1m n2)Fru or hemiacetals or hemiketals, in which the aldehyde
Fru(2m n1)Glc. Sucrose is a major intermediate prod- or ketone group joins with a hydroxyl group of the
uct of photosynthesis; in many plants it is the principal same molecule, creating a cyclic structure; this can
form in which sugar is transported from the leaves to be represented as a Haworth perspective formula.
other parts of the plant body. Trehalose, Glc(1m n1)Glc The carbon atom originally found in the aldehyde or
ketone group (the anomeric carbon) can assume
either of two configurations, and , which are
6 CH 6 CH interconvertible by mutarotation. In the linear form,
2OH 2OH
O O which is in equilibrium with the cyclic forms, the
5 5
HO H H H OH anomeric carbon is easily oxidized.
4 1 O 4 1
OH H OH H ■ A hydroxyl group of one monosaccharide can add to
H H H
the anomeric carbon of a second monosaccharide to
3 2 3 2
H OH H OH form an acetal. In this disaccharide, the glycosidic
Lactose ( form) bond protects the anomeric carbon from oxidation.
-D-galactopyranosyl-(1n4)- -D-glucopyranose
Gal( 1n4)Glc
■ Oligosaccharides are short polymers of several
monosaccharides joined by glycosidic bonds. At
6 CH
2OH 1
one end of the chain, the reducing end, is a
5
O HOCH2 monosaccharide unit with its anomeric carbon
H H O H
H not involved in a glycosidic bond.
4 1 2 5
OH H H HO
HO CH2OH ■ The common nomenclature for di- or oligosaccharides
O 6
3 2 3 4 specifies the order of monosaccharide units, the
H OH OH H configuration at each anomeric carbon, and the
Sucrose carbon atoms involved in the glycosidic linkage(s).
-D-fructofuranosyl -D-glucopyranoside
Fru(2 n 1)Glc Glc( 1n2
n )Fru
6 CH
2OH H
7.2 Polysaccharides
O O 5 Most carbohydrates found in nature occur as polysac-
5
H H HOCH2 OH
H 6
charides, polymers of medium to high molecular weight.
4 1 O 1 4
OH H OH H Polysaccharides, also called glycans, differ from each
HO H H
other in the identity of their recurring monosaccharide
3 2 2 3
H OH H OH units, in the length of their chains, in the types of bonds
Trehalose linking the units, and in the degree of branching.
-D-glucopyranosyl -D-glucopyranoside Homopolysaccharides contain only a single monomeric
Glc( 1n1
n )Glc
species; heteropolysaccharides contain two or more
FIGURE 7–12 Some common disaccharides. Like maltose in Figure different kinds (Fig. 7–13). Some homopolysaccharides
7–11, these are shown as Haworth perspectives. The common name, serve as storage forms of monosaccharides that are used
full systematic name, and abbreviation are given for each disaccharide. as fuels; starch and glycogen are homopolysaccharides of
Formal nomenclature for sucrose names glucose as the parent glyco- this type. Other homopolysaccharides (cellulose and
side, although it is typically depicted as shown, with glucose on the left. chitin, for example) serve as structural elements in plant
7.2 Polysaccharides 245
Homopolysaccharides Heteropolysaccharides space is occupied by several types of heteropolysaccha-

Unbranched Branched Two Multiple rides, which form a matrix that holds individual cells to-
monomer monomer gether and provides protection, shape, and support to
types, types, cells, tissues, and organs.
unbranched branched
Unlike proteins, polysaccharides generally do not
have defining molecular weights. This difference is a
consequence of the mechanisms of assembly of the two
types of polymer. As we shall see in Chapter 27, proteins
are synthesized on a template (messenger RNA) of de-
fined sequence and length, by enzymes that follow the
template exactly. For polysaccharide synthesis there is
no template; rather, the program for polysaccharide
synthesis is intrinsic to the enzymes that catalyze the
polymerization of the monomeric units, and there is no
specific stopping point in the synthetic process.
Some Homopolysaccharides Are Stored Forms of Fuel

The most important storage polysaccharides are starch
FIGURE 7–13 Homo- and heteropolysaccharides. Polysaccharides in plant cells and glycogen in animal cells. Both polysac-
may be composed of one, two, or several different monosaccharides, charides occur intracellularly as large clusters or gran-
in straight or branched chains of varying length. ules. Starch and glycogen molecules are heavily
hydrated, because they have many exposed hydroxyl
cell walls and animal exoskeletons. Heteropolysaccha- groups available to hydrogen-bond with water. Most
rides provide extracellular support for organisms of all plant cells have the ability to form starch (see Fig. 20–2),
kingdoms. For example, the rigid layer of the bacterial and starch storage is especially abundant in tubers
cell envelope (the peptidoglycan) is composed in part of (underground stems), such as potatoes, and in seeds.
a heteropolysaccharide built from two alternating mono- Starch contains two types of glucose polymer, amy-
saccharide units. In animal tissues, the extracellular lose and amylopectin (Fig. 7–14). The former consists
6 CH
2OH CH2OH CH2OH CH2OH
5 O O O O
H H H H H H H H H H
Nonreducing H H Reducing
4 1 4 1 4 1 4 1
end OH H OH H OH H OH H end
O O O O
3 2
H OH H OH H OH H OH
(a) Amylose
6 CH
2OH
O
H H H
4 1
OH H
O ( 1n6)
branch Amylose
Branch H OH point
O
A Reducing
6 CH
2
ends
O
H H Nonreducing
H ends
4 1
OH H Amylopectin
O O
Main H OH
chain
(b) (c)
FIGURE 7–14 Glycogen and starch. (a) A short segment of amylose, a amylose and amylopectin like that believed to occur in starch granules.
linear polymer of D-glucose residues in (1→4) linkage. A single chain Strands of amylopectin (red) form double-helical structures with each
can contain several thousand glucose residues. Amylopectin has other or with amylose strands (blue). Glucose residues at the nonreduc-
stretches of similarly linked residues between branch points. Glycogen ing ends of the outer branches are removed enzymatically during the
has the same basic structure, but has more branching than amylopectin. mobilization of starch for energy production. Glycogen has a similar
(b) An (1→6) branch point of glycogen or amylopectin. (c) A cluster of structure but is more highly branched and more compact.
of long, unbranched chains of D-glucose residues con- Some Homopolysaccharides Serve Structural Roles
nected by (1n4) linkages (as in maltose). Such chains
vary in molecular weight from a few thousand to more Cellulose, a fibrous, tough, water-insoluble substance, is
than a million. Amylopectin also has a high molecular found in the cell walls of plants, particularly in stalks,
weight (up to 200 million) but unlike amylose is highly stems, trunks, and all the woody portions of the plant
branched. The glycosidic linkages joining successive body. Cellulose constitutes much of the mass of wood,
glucose residues in amylopectin chains are (1n4); the and cotton is almost pure cellulose. Like amylose, the
branch points (occurring every 24 to 30 residues) are cellulose molecule is a linear, unbranched homopolysac-
(1n6) linkages. charide, consisting of 10,000 to 15,000 D-glucose units.
Glycogen is the main storage polysaccharide of But there is a very important difference: in cellulose the
animal cells. Like amylopectin, glycogen is a polymer of glucose residues have the configuration (Fig. 7–15),
(1n4)-linked subunits of glucose, with (1n6)-linked whereas in amylose the glucose is in the configuration.
branches, but glycogen is more extensively branched The glucose residues in cellulose are linked by (1n4)
(on average, every 8 to 12 residues) and more compact glycosidic bonds, in contrast to the (1n4) bonds of
than starch. Glycogen is especially abundant in the liver, amylose. This difference gives cellulose and amylose
where it may constitute as much as 7% of the wet very different structures and physical properties.
weight; it is also present in skeletal muscle. In hepato- Glycogen and starch ingested in the diet are hy-
cytes glycogen is found in large granules, which are drolyzed by -amylases and glycosidases, enzymes in
themselves clusters of smaller granules composed of saliva and the intestine that break (1n4) glycosidic
single, highly branched glycogen molecules with an bonds between glucose units. Most animals cannot use
average molecular weight of several million. Such glyco- cellulose as a fuel source, because they lack an enzyme
gen granules also contain, in tightly bound form, the to hydrolyze the (1n4) linkages. Termites readily di-
enzymes responsible for the synthesis and degradation gest cellulose (and therefore wood), but only because
of glycogen. their intestinal tract harbors a symbiotic microorganism,
Because each branch in glycogen ends with a nonre-
ducing sugar unit, a glycogen molecule with n branches
has n 1 nonreducing ends, but only one reducing end. HO
OH OH
O
6
When glycogen is used as an energy source, glucose units O
4
5 2
are removed one at a time from the nonreducing ends. O O
Degradative enzymes that act only at nonreducing ends O HO OH 1
3
can work simultaneously on the many branches, speeding OH
(1n4)-linked D-glucose units
the conversion of the polymer to monosaccharides.
Why not store glucose in its monomeric form? It has (a)
been calculated that hepatocytes store glycogen equiva-
lent to a glucose concentration of 0.4 M. The actual 6
concentration of glycogen, which is insoluble and con-
tributes little to the osmolarity of the cytosol, is about 5 1
0.01 M. If the cytosol contained 0.4 M glucose, the 4
osmolarity would be threateningly elevated, leading to 3

2
osmotic entry of water that might rupture the cell (see

Fig. 2–12). Furthermore, with an intracellular glucose
concentration of 0.4 M and an external concentration of
about 5 mM (the concentration in the blood of a mam-
mal), the free-energy change for glucose uptake into
cells against this very high concentration gradient would
be prohibitively large.
Dextrans are bacterial and yeast polysaccharides
made up of (1n6)-linked poly-D-glucose; all have
(1n3) branches, and some also have (1n2) or (b)
(1n4) branches. Dental plaque, formed by bacteria FIGURE 7–15 Cellulose. (a) Two units of a cellulose chain; the D-glu-
growing on the surface of teeth, is rich in dextrans. Syn- cose residues are in (1→4) linkage. The rigid chair structures can ro-
thetic dextrans are used in several commercial products tate relative to one another. (b) Scale drawing of segments of two
(for example, Sephadex) that serve in the fractionation parallel cellulose chains, showing the conformation of the D-glucose
of proteins by size-exclusion chromatography (see residues and the hydrogen-bond cross-links. In the hexose unit at the
Fig. 3–17b). The dextrans in these products are chemi- lower left, all hydrogen atoms are shown; in the other three hexose
cally cross-linked to form insoluble materials of various units, the hydrogens attached to carbon have been omitted for clarity,
porosities, admitting macromolecules of various sizes. as they do not participate in hydrogen bonding.
FIGURE 7–16 Cellulose breakdown by wood fungi. A wood fungus

growing on an oak log. All wood fungi have the enzyme cellulase,
which breaks the (1→4) glycosidic bonds in cellulose, so that wood
is a source of metabolizable sugar (glucose) for the fungus. The only
vertebrates able to use cellulose as food are cattle and other ruminants
(sheep, goats, camels, giraffes). The extra stomach compartment
(rumen) of a ruminant teems with bacteria and protists that secrete
cellulase.
CH3 CH3
A A
CPO CPO
A A
6 CH
2OH H NH CH2OH H NH
3 2
5
O O O O
H H OH H H H H OH H H
4 1 4 1
OH H H OH H H
O H H O H H
5 O O
3 2
H NH CH2OH H NH CH2OH
A 6 A
CPO CPO
A A
(a) (a) CH3 CH3
FIGURE 7–17 Chitin. (a) A short segment of chitin, a homopolymer of

N-acetyl-D-glucosamine units in (1→4) linkage. (b) A spotted June
beetle (Pelidnota punctata), showing its surface armor (exoskeleton)
of chitin.
Steric Factors and Hydrogen Bonding Influence

Homopolysaccharide Folding
The folding of polysaccharides in three dimensions fol-
lows the same principles as those governing polypeptide
structure: subunits with a more-or-less rigid structure
(b) dictated by covalent bonds form three-dimensional
macromolecular structures that are stabilized by weak
interactions within or between molecules: hydrogen
Trichonympha, that secretes cellulase, which hy- bonds and hydrophobic and van der Waals interactions,
drolyzes the (1n4) linkages. Wood-rot fungi and bac- and, for polymers with charged subunits, electrostatic
teria also produce cellulase (Fig. 7–16). interactions. Because polysaccharides have so many
Chitin is a linear homopolysaccharide composed hydroxyl groups, hydrogen bonding has an especially
of N-acetylglucosamine residues in ( 1n4) linkage important influence on their structure. Glycogen, starch,
(Fig. 7–17). The only chemical difference from cellulose and cellulose are composed of pyranoside subunits
is the replacement of the hydroxyl group at C-2 with an (having six-membered rings), as are the oligosaccha-
acetylated amino group. Chitin forms extended fibers rides of glycoproteins and glycolipids to be discussed
similar to those of cellulose, and like cellulose cannot later. Such molecules can be represented as a series of
be digested by vertebrates. Chitin is the principal com- rigid pyranose rings connected by an oxygen atom
ponent of the hard exoskeletons of nearly a million bridging two carbon atoms (the glycosidic bond). There
species of arthropods—insects, lobsters, and crabs, for is, in principle, free rotation about both COO bonds
example—and is probably the second most abundant linking the residues (Fig. 7–15a), but as in polypeptides
polysaccharide, next to cellulose, in nature; an esti- (see Figs 4–2, 4–8), rotation about each bond is lim-
mated 1 billion tons of chitin are produced each year in ited by steric hindrance by substituents. The three-
the biosphere! dimensional structures of these molecules can be
described in terms of the dihedral angles, and , about CH2OH O H O OH

O 4 1
the glycosidic bond (Fig. 7–18), analogous to angles
and made by the peptide bond (see Fig. 4–2). 1 O 4
HO HO O
The bulkiness of the pyranose ring and its sub- CH2OH
stituents, and electronic effects at the anomeric carbon, Cellulose
place constraints on the angles and ; thus certain (1 4)Glc repeats
conformations are much more stable than others, as can O
be shown on a map of energy as a function of and 1 4
CH2OH CH2OH O
(Fig. 7–19). 4 O
The most stable three-dimensional structure for the
O O 1
(1n4)-linked chains of starch and glycogen is a tightly HO
HO H O
coiled helix (Fig. 7–20), stabilized by interchain hydro-
gen bonds. In amylose (with no branches) this structure H
is regular enough to allow crystallization and thus deter- Amylose
mination of the structure by x-ray diffraction. The aver- (1 4)Glc repeats
age plane of each residue along the amylose chain forms
a 60 angle with the average plane of the preceding O O
residue, so the helical structure has six residues per
6 1
CH2 O
turn. For amylose, the core of the helix is of precisely O C 1
OH 6
the right dimensions to accommodate iodine as complex HO 5
ions (I3 and I5 ), giving an intensely blue complex. This HO
HO HO
interaction is a common qualitative test for amylose.
For cellulose, the most stable conformation is that in HO
which each chair is turned 180 relative to its neighbors, Dextran
(1 6)Glc repeats (with (1 3) branches, not shown)
yielding a straight, extended chain. All ⎯OH groups are
available for hydrogen bonding with neighboring chains. FIGURE 7–18 Conformation at the glycosidic bonds of cellulose, amy-
With several chains lying side by side, a stabilizing network lose, and dextran. The polymers are depicted as rigid pyranose rings
of interchain and intrachain hydrogen bonds produces joined by glycosidic bonds, with free rotation about these bonds. Note
that in dextran there is also free rotation about the bond between C-5
straight, stable supramolecular fibers of great tensile
and C-6 (torsion angle (omega)).
strength (Fig. 7–15b). This property of cellulose has made
it a useful substance to civilizations for millennia. Many
manufactured products, including papyrus, paper, card- these materials is low because extensive interchain hydro-
board, rayon, insulating tiles, and a variety of other useful gen bonding between cellulose molecules satisfies their
materials, are derived from cellulose. The water content of capacity for hydrogen-bond formation.
, 30,40
(a) (b) , 170,170
FIGURE 7–19 A map of favored conformations for oligosaccharides and energy state, the result is a map of preferred conformations. This is anal-
polysaccharides. The torsion angles and (see Fig. 7–18), which de- ogous to the Ramachandran plot for peptides (see Figs 4–3, 4–8).
fine the spatial relationship between adjacent rings, can in principle (b) Two energetic extremes for the disaccharide Gal(1n3)Gal; these
have any value from 0 to 360. In fact, some of the torsion angles would values fall on the energy diagram (a) as shown by the red and blue dots.
give conformations that are sterically hindered, whereas others give con- The red dot indicates the least favored conformation, the blue dot the
formations that maximize hydrogen bonding. (a) When the relative en- most favored conformation. The known conformations of the three poly-
ergy () is plotted for each value of and , with isoenergy (“same saccharides shown in Figure 7–18 have been determined by x-ray crys-
energy”) contours drawn at intervals of 1 kcal/mol above the minimum tallography, and all fall within the lowest-energy regions of the map.
HO OH O
O HO 6
6 CH2 1
O 4 CH2OH O 3 O
CH2OH 2
5 2
OSO
3
O O 5
OH 4
O
3 1
CH2OH Agarose
HO 3)D-Gal(1 4)3,6-anhydro-L-Gal2S(1 repeating units
FIGURE 7–21 Agarose. The repeating unit consists of D-galactose

(1→4)-linked to 3,6-anhydro-L-galactose (in which an ether bridge
O
connects C-3 and C-6). These units are joined by (1→3) glycosidic
HO links to form a polymer 600 to 700 residues long. A small fraction of the
3,6-anhydrogalactose residues have a sulfate ester at C-2 (as shown here).
(1n4)-linked
D-glucose units
(a) (b) useful in the biochemistry laboratory. When a suspen-

sion of agarose in water is heated and cooled, the
FIGURE 7–20 Starch (amylose). (a) In the most stable conformation, with agarose forms a double helix: two molecules in parallel
adjacent rigid chairs, the polysaccharide chain is curved, rather than lin- orientation twist together with a helix repeat of three
ear as in cellulose (see Fig. 7–15). (b) A model of a segment of amylose; residues; water molecules are trapped in the central
for clarity, the hydroxyl groups have been omitted from all but one of the cavity. These structures in turn associate with each
glucose residues. Compare the two residues shaded in pink with the other to form a gel—a three-dimensional matrix that
chemical structures in (a). The conformation of (1→4) linkages in amy-
traps large amounts of water. Agarose gels are used as
lose, amylopectin, and glycogen causes these polymers to assume tightly
inert supports for the electrophoretic separation of
coiled helical structures. These compact structures produce the dense
nucleic acids, an essential part of the DNA sequencing
granules of stored starch or glycogen seen in many cells (see Fig. 20–2).
process (p. 292). Agar is also used to form a surface for
the growth of bacterial colonies. Another commercial
Bacterial and Algal Cell Walls Contain use of agar is for the capsules in which some vitamins
Structural Heteropolysaccharides and drugs are packaged; the dried agar material dis-
solves readily in the stomach and is metabolically inert.
The rigid component of bacterial cell walls (peptidogly-
can) is a heteropolymer of alternating (1n4)-linked Glycosaminoglycans Are Heteropolysaccharides
N-acetylglucosamine and N-acetylmuramic acid residues
of the Extracellular Matrix
(see Fig. 20–31). The linear polymers lie side by side in
the cell wall, cross-linked by short peptides, the exact The extracellular space in the tissues of multicellular
structure of which depends on the bacterial species. The animals is filled with a gel-like material, the extracellu-
peptide cross-links weld the polysaccharide chains into a lar matrix (ECM), also called ground substance,
strong sheath that envelops the entire cell and prevents which holds the cells together and provides a porous
cellular swelling and lysis due to the osmotic entry of pathway for the diffusion of nutrients and oxygen
water. The enzyme lysozyme kills bacteria by hydrolyzing to individual cells. The reticular ECM that surrounds fi-
the (1n4) glycosidic bond between N-acetylglucosa- broblasts and other connective tissue cells is composed
mine and N-acetylmuramic acid (see Fig. 6–24). of an interlocking meshwork of heteropolysaccharides
Lysozyme is notably present in tears, presumably as a de- and fibrous proteins such as fibrillar collagens, elastin,
fense against bacterial infections of the eye. It is also pro- and fibronectin. Basement membrane is a specialized
duced by certain bacterial viruses to ensure their release ECM that underlies epithelial cells; it consists of special-
from the host bacterial cell, an essential step of the viral ized collagens, laminin, and heteropolysaccharides.
infection cycle. Penicillin and related antibiotics kill bacte- These heteropolysaccharides, the glycosaminogly-
ria by preventing synthesis of the cross-links, leaving the cans, are a family of linear polymers composed of
cell wall too weak to resist osmotic lysis (see pp. 216–217). repeating disaccharide units (Fig. 7–22). They are
Certain marine red algae, including some of the sea- unique to animals and bacteria and are not found in
weeds, have cell walls that contain agar, a mixture of plants. One of the two monosaccharides is always either
sulfated heteropolysaccharides made up of D-galactose N-acetylglucosamine or N-acetylgalactosamine; the
and an L-galactose derivative ether-linked between C-3 other is in most cases a uronic acid, usually D-glucuronic
and C-6. Agar is a complex mixture of polysaccharides, or L-iduronic acid. Some glycosaminoglycans contain es-
all with the same backbone structure, but substituted terified sulfate groups. The combination of sulfate
to varying degrees with sulfate and pyruvate. Agarose groups and the carboxylate groups of the uronic acid
(Mr 150,000) is the agar component with the fewest residues gives glycosaminoglycans a very high density of
charged groups (sulfates, pyruvates) (Fig. 7–21). The negative charge. To minimize the repulsive forces among
remarkable gel-forming property of agarose makes it neighboring charged groups, these molecules assume an
Glycosaminoglycan Repeating disaccharide FIGURE 7–22 Repeating units of some common glycosaminoglycans
Number of of extracellular matrix. The molecules are copolymers of alternating
disaccharides CH2OH uronic acid and amino sugar residues (keratan sulfate is the exception),
per chain
O with sulfate esters in any of several positions, except in hyaluronan. The
H H O ionized carboxylate and sulfate groups (red in the perspective formulas)
COO H
HO H give these polymers their characteristic high negative charge. Therapeu-
O
Hyaluronan H O ( 1n4) tic heparin contains primarily iduronic acid (IdoA) and a smaller pro-
H
50,000 H NH portion of glucuronic acid (GlcA, not shown), and is generally highly
OH H A
H CP O sulfated and heterogeneous in length. The space-filling model shows a
( 1n3) A heparin segment as its solution structure, as determined by NMR spec-
H OH CH3
troscopy (PDB ID 1HPN). The carbons in the iduronic acid sulfate are
GlcA GlcNAc colored blue; those in glucosamine sulfate are green. Oxygen and
sulfur atoms are shown in their standard colors of red and yellow,
CH2OH
respectively. The hydrogen atoms are not shown (for clarity). Heparan

O
O3SO H sulfate (not shown) is similar to heparin but has a higher proportion of
O
GlcA and fewer sulfate groups, arranged in a less regular pattern.
COO H
O H H
Chondroitin H O ( 1n4)
4-sulfate H
H NH The glycosaminoglycan hyaluronan (hyaluronic
20–60 OH H A
H CP O acid) contains alternating residues of D-glucuronic acid
( 1n3) A
H OH CH3 and N-acetylglucosamine (Fig. 7–22). With up to 50,000
repeats of the basic disaccharide unit, hyaluronan has a
GlcA GalNAc4S
molecular weight of several million; it forms clear,
CH2OSO
3 highly viscous solutions that serve as lubricants in the
CH2OH O
O
synovial fluid of joints and give the vitreous humor of
H H
O the vertebrate eye its jellylike consistency (the Greek
Keratan HO H OH H hyalos means “glass”; hyaluronan can have a glassy or
sulfate O H
H ( 1n3) translucent appearance). Hyaluronan is also a compo-
25 H H H NH nent of the extracellular matrix of cartilage and ten-
( 1n4) A
H OH CP O dons, to which it contributes tensile strength and
A elasticity as a result of its strong interactions with other
CH3
components of the matrix. Hyaluronidase, an enzyme
Gal GlcNAc6S
secreted by some pathogenic bacteria, can hydrolyze
CH2OSO3
the glycosidic linkages of hyaluronan, rendering tissues
H O more susceptible to bacterial invasion. In many species,
H H H a similar enzyme in sperm hydrolyzes an outer gly-
O H
H ( 1n4) cosaminoglycan coat around the ovum, allowing sperm
COO OSO
3
Heparin O O penetration.
OH H
15–90 H
H NH SO
3 Other glycosaminoglycans differ from hyaluronan in
H OSO
3
three respects: they are generally much shorter poly-
( 1n4)
IdoA2S GlcNS3S6S mers, they are covalently linked to specific proteins
(proteoglycans), and one or both monomeric units
differ from those of hyaluronan. Chondroitin sulfate
(Greek chondros, “cartilage”) contributes to the tensile
strength of cartilage, tendons, ligaments, and the walls
of the aorta. Dermatan sulfate (Greek derma, “skin”)
contributes to the pliability of skin and is also present in
Heparin segment blood vessels and heart valves. In this polymer, many of
the glucuronate residues present in chondroitin sulfate
extended conformation in solution, forming a rodlike he- are replaced by their 5-epimer, L-iduronate.
lix in which the negatively charged carboxylate groups
occur on alternate sides of the helix (as shown for he-
parin in Fig. 7–22). The extended rod form also provides H COO
maximum separation between the negatively charged O O
H OH OH
sulfate groups. The specific patterns of sulfated and non- COO H
sulfated sugar residues in glycosaminoglycans provide OH H OH H
HO H HO H
for specific recognition by a variety of protein ligands
that bind electrostatically to these molecules. The sul- H OH H OH
fated glycosaminoglycans are attached to extracellular -L-Iduronate -D-Glucuronate
proteins to form proteoglycans (Section 7.3). (IdoA) (GlcA)
Keratan sulfates (Greek keras, “horn”) have no uronic

acid and their sulfate content is variable. They are present
in cornea, cartilage, bone, and a variety of horny structures
formed of dead cells: horn, hair, hoofs, nails, and claws. He-
paran sulfate (Greek hepar, “liver”) is produced by all an-
imal cells and contains variable arrangements of sulfated
and nonsulfated sugars. The sulfated segments of the chain
allow it to interact with a large number of proteins, includ-
ing growth factors and ECM components, as well as various
enzymes and factors present in plasma. Heparin is a frac-
tionated form of heparan sulfate derived mostly from
mast cells (a type of leukocyte). Heparin is a therapeutic
agent used to inhibit coagulation through its capacity to
bind the protease inhibitor antithrombin. Heparin binding FIGURE 7–23 Interaction between a glycosaminoglycan and its bind-
causes antithrombin to bind to and inhibit thrombin, a pro- ing protein. Fibroblast growth factor 1 (FGF1), its cell surface receptor
tease essential to blood clotting. The interaction is strongly (FGFR), and a short segment of a glycosaminoglycan (heparin) were
electrostatic; heparin has the highest negative charge den- co-crystallized to yield the structure shown here (PDB ID 1E0O). The
sity of any known biological macromolecule (Fig. 7–23). proteins are represented as surface contour images, with color to rep-
Purified heparin is routinely added to blood samples resent surface electrostatic potential: red, predominantly negative
obtained for clinical analysis, and to blood donated for charge; blue, predominantly positive charge. Heparin is shown in a
ball-and-stick representation, with the negative charges (⎯SO3– and
transfusion, to prevent clotting.
⎯COO) attracted to the positive (blue) surface of the FGF1 protein.
Table 7–2 summarizes the composition, properties,
Heparin was used in this experiment, but the glycosaminoglycan that
roles, and occurrence of the polysaccharides described
binds FGF1 in vivo is heparan sulfate on the cell surface.
in Section 7.2.
TABLE 7–2 Structures and Roles of Some Polysaccharides

Size (number of
monosaccharide
Polymer Type* Repeating unit† units) Roles/significance
Starch Energy storage: in plants

Amylose Homo- (1n4)Glc, linear 50–5,000
Amylopectin Homo- (1n4)Glc, with Up to 106
(1n6)Glc
branches every
24–30 residues
Glycogen Homo- (1n4)Glc, with Up to 50,000 Energy storage: in bacteria and animal cells
(1n6)Glc
branches every
8–12 residues
Cellulose Homo- ( 1n4)Glc Up to 15,000 Structural: in plants, gives rigidity and
strength to cell walls
Chitin Homo- ( 1n4)GlcNAc Very large Structural: in insects, spiders, crustaceans,
gives rigidity and strength to exoskeletons
Dextran Homo- (1n6)Glc, with Wide range Structural: in bacteria, extracellular adhesive
(1n3) branches
Peptidoglycan Hetero-; 4)Mur2Ac(1n4) Very large Structural: in bacteria, gives rigidity and
peptides GlcNAc(1 strength to cell envelope
attached
Agarose Hetero- 3)D-Gal(1n4)3,6- 1,000 Structural: in algae, cell wall material
anhydro-L-Gal(1
Hyaluronan (a Hetero-; 4)GlcA( 1n3) Up to 100,000 Structural: in vertebrates, extracellular matrix
glycosamino- acidic GlcNAc(1 of skin and connective tissue; viscosity
glycan) and lubrication in joints
*Each polymer is classified as a homopolysaccharide (homo-) or heteropolysaccharide (hetero-).

†
The abbreviated names for the peptidoglycan, agarose, and hyaluronan repeating units indicate that the polymer contains repeats of this disaccha-
ride unit. For example, in peptidoglycan, the GlcNAc of one disaccharide unit is (1→4)-linked to the first residue of the next disaccharide unit.
SUMMARY 7.2 Polysaccharides molecules (growth factors, for example) or extracellular

parasites (bacteria or viruses). On almost every eukary-
■ Polysaccharides (glycans) serve as stored fuel otic cell, specific oligosaccharide chains attached to
and as structural components of cell walls and components of the plasma membrane form a carbohy-
extracellular matrix. drate layer (the glycocalyx), several nanometers thick,
■ The homopolysaccharides starch and glycogen are that serves as an information-rich surface that a cell
stored fuels in plant, animal, and bacterial cells. shows to its surroundings. These oligosaccharides are
They consist of D-glucose with (1n4) linkages, central players in cell-cell recognition and adhesion, cell
and both contain some branches. migration during development, blood clotting, the im-
■ The homopolysaccharides cellulose, chitin, and mune response, wound healing, and other cellular
dextran serve structural roles. Cellulose, composed processes. In most of these cases, the informational car-
of (1n4)-linked D-glucose residues, lends strength bohydrate is covalently joined to a protein or a lipid to
and rigidity to plant cell walls. Chitin, a polymer of form a glycoconjugate, which is the biologically active
(1n4)-linked N-acetylglucosamine, strengthens molecule.
the exoskeletons of arthropods. Dextran forms an Proteoglycans are macromolecules of the cell
adhesive coat around certain bacteria. surface or extracellular matrix in which one or more
sulfated glycosaminoglycan chains are joined covalently
■ Homopolysaccharides fold in three dimensions. The to a membrane protein or a secreted protein. The gly-
chair form of the pyranose ring is essentially rigid, cosaminoglycan chain can bind to extracellular proteins
so the conformation of the polymers is determined through electrostatic interactions with the negatively
by rotation about the bonds from the rings to the charged groups on the polysaccharide. Proteoglycans
oxygen atom in the glycosidic linkage. Starch and are major components of all extracellular matrices.
glycogen form helical structures with intrachain Glycoproteins have one or several oligosaccha-
hydrogen bonding; cellulose and chitin form long, rides of varying complexity joined covalently to a pro-
straight strands that interact with neighboring tein. They are usually found on the outer face of the
strands. plasma membrane (as part of the glycocalyx), in the
■ Bacterial and algal cell walls are strengthened by extracellular matrix, and in the blood. Inside cells they
heteropolysaccharides—peptidoglycan in bacteria, are found in specific organelles such as Golgi complexes,
agar in red algae. The repeating disaccharide in secretory granules, and lysosomes. The oligosaccharide
peptidoglycan is GlcNAc(1n4)Mur2Ac; in sugar, portions of glycoproteins are very heterogeneous and,
it is D-Gal(1n4)3,6-anhydro-L-Gal. like glycosaminoglycans, they are rich in information,
■ Glycosaminoglycans are extracellular forming highly specific sites for recognition and high-
heteropolysaccharides in which one of the two affinity binding by carbohydrate-binding proteins called
monosaccharide units is a uronic acid (keratan lectins. Some cytosolic and nuclear proteins can be
sulfate is an exception) and the other an N-acetylated glycosylated as well.
amino sugar. Sulfate esters on some of the hydroxyl Glycolipids are membrane sphingolipids in which
groups and on the amino group of some glucosamine the hydrophilic head groups are oligosaccharides. As in
residues in heparin and in heparan sulfate give glycoproteins, the oligosaccharides act as specific sites
these polymers a high density of negative charge, for recognition by lectins. The brain and neurons are
forcing them to assume extended conformations. rich in glycolipids, which help in nerve conduction and
These polymers (hyaluronan, chondroitin sulfate, myelin formation. Glycolipids also play a role in signal
dermatan sulfate, and keratan sulfate) provide transduction in cells.
viscosity, adhesiveness, and tensile strength to the
extracellular matrix. Proteoglycans Are Glycosaminoglycan-Containing
Macromolecules of the Cell Surface and
7.3 Glycoconjugates: Proteoglycans, Extracellular Matrix
Mammalian cells can produce 40 types of proteoglycans.
Glycoproteins, and Glycolipids These molecules act as tissue organizers, and they influ-
In addition to their important roles as stored fuels ence various cellular activities, such as growth factor
(starch, glycogen, dextran) and as structural materials activation and adhesion. The basic proteoglycan unit con-
(cellulose, chitin, peptidoglycans), polysaccharides and sists of a “core protein” with covalently attached gly-
oligosaccharides are information carriers. Some provide cosaminoglycan(s). The point of attachment is a Ser
communication between cells and their extracellular residue, to which the glycosaminoglycan is joined through
surroundings; others label proteins for transport to and a tetrasaccharide bridge (Fig. 7–24). The Ser residue is
localization in specific organelles, or for destruction generally in the sequence –Ser–Gly–X–Gly– (where X
when the protein is malformed or superfluous; and oth- is any amino acid residue), although not every protein
ers serve as recognition sites for extracellular signal with this sequence has an attached glycosaminoglycan.
7.3 Glycoconjugates: Proteoglycans, Glycoproteins, and Glycolipids 253
Carboxyl terminus (a)
S S
Gly
Gly Syndecan Glypican

1 3 1 4 1 3 1 3 1 4 Globular
GlcA GalNAc4Sn GlcA Gal Gal Xyl Ser Heparan sulfate +NH
domain
Chondroitin sulfate 3 S
Core protein H3N+ S
Amino terminus Chondroitin sulfate Core protein COO–
FIGURE 7–24 Proteoglycan structure, showing the tetrasaccharide GPI anchor

Outside Cleavage site
bridge. A typical tetrasaccharide linker (blue) connects a glycosamino-
glycan—in this case chondroitin 4-sulfate (orange)—to a Ser residue
(pink) in the core protein. The xylose residue at the reducing end of Membrane
the linker is joined by its anomeric carbon to the hydroxyl of the
Ser residue. Inside COO–
Many proteoglycans are secreted into the extracellular (b) Heparan sulfate
matrix, but some are integral membrane proteins (see GlcNAc
Fig. 11–6). For example, the sheet-like extracellular ma- GlcA
trix (basal lamina) that separates organized groups of GlcNS
NS NA domain
cells from other groups contains a family of core proteins IdoA NS domain
(Mr 20,000 to 40,000), each with several covalently at- 2S 2-O-sulfate
tached heparan sulfate chains. There are two major fam- 6S 6-O-sulfate
6S 6S 6S 6S
ilies of membrane heparan sulfate proteoglycans.
Syndecans have a single transmembrane domain and an NS 2S NS 2S NS 2S NS 2S NS 2S NS 2S
extracellular domain bearing three to five chains of he- FIGURE 7–25 Two families of membrane proteoglycans. (a) Schematic
paran sulfate and in some cases chondroitin sulfate diagrams of a syndecan and a glypican in the plasma membrane. Syn-
(Fig. 7–25a). Glypicans are attached to the membrane decans are held in the membrane by hydrophobic interactions be-
by a lipid anchor, a derivative of the membrane lipid tween a sequence of nonpolar amino acid residues and plasma
phosphatidylinositol (Chapter 11). Both syndecans and membrane lipids; they can be released by a single proteolytic cut near
glypicans can be shed into the extracellular space. A pro- the membrane surface. In a typical syndecan, the extracellular amino-
tease in the ECM that cuts close to the membrane sur- terminal domain is covalently attached (by tetrasaccharide linkers such
face releases syndecan ectodomains (those domains as those in Fig. 7–24) to three heparan sulfate chains and two chon-
outside the plasma membrane), and a phospholipase droitin sulfate chains. Glypicans are held in the membrane by a
that breaks the connection to the membrane lipid covalently attached membrane lipid (GPI anchor; see Chapter 11), and
releases glypicans. Numerous chondroitin sulfate and are shed if the lipid-protein bond is cleaved by a phospholipase. All
dermatan sulfate proteoglycans also exist, some as glypicans have 14 conserved Cys residues, which form disulfide bonds
membrane-bound entities, others as secreted products to stabilize the protein moiety, and either two or three glycosamino-
in the ECM. glycan chains attached near the carboxyl terminus, close to the mem-
The glycosaminoglycan chains can bind to a variety brane surface. (b) Along a heparan sulfate chain, regions rich in
of extracellular ligands and thereby modulate the lig- sulfated sugars, the NS domains (green), alternate with regions with
chiefly unmodified residues of GlcNAc and GlcA, the NA domains
ands’ interaction with specific receptors of the cell sur-
(gray). One of the NS domains is shown in more detail, revealing a
face. Detailed studies of heparan sulfate demonstrate a
high density of modified residues: GlcNS (N-sulfoglucosamine), with a
domain structure that is not random; some domains
sulfate ester at C-6; and both GlcA and IdoA, with a sulfate ester at
(typically 3 to 8 disaccharide units long) differ from
C-2. The exact pattern of sulfation in the NS domain differs among
neighboring domains in sequence and in ability to bind to
proteoglycans.
specific proteins. Highly sulfated domains (called NS
domains) alternate with domains having unmodified
GlcNAc and GlcA residues (N-acetylated, or NA, do- can display different heparan sulfate structures when
mains) (Fig. 7–25b). The exact pattern of sulfation in the synthesized in different cell types.
NS domain depends on the particular proteoglycan; The NS domains bind specifically to extracellular
given the number of possible modifications of the proteins and signaling molecules to alter their activities.
GlcNAc–IdoA dimer, at least 32 different disaccharide The change in activity may result from a conformational
units are possible. Furthermore, the same core protein change in the protein that is induced by the binding
(a) Conformational activation (b) Enhanced protein-protein interaction

Factor Xa Thrombin
AT Heparan
sulfate
NS domain
A conformational change induced in the protein Binding of AT and thrombin to two adjacent
antithrombin (AT) on binding a specific NS domains brings the two proteins into close
pentasaccharide NS domain allows its interaction proximity, favoring their interaction, which inhibits
with blood clotting factor Xa, preventing clotting. blood clotting.
(c) Coreceptor for extracellular ligands (d) Cell surface localization/concentration

FGF (ligand) Lipoprotein lipase
NS domain
NS domain
FGF receptor dimer
Membrane Membrane
NS domains interact with both the fibroblast growth The high density of negative charges in heparan sulfate
factor (FGF) and its receptor, bringing the oligomeric attracts positively charged lipoprotein lipase
complex together and increasing the effectiveness of molecules and holds them by electrostatic and
a low concentration of FGF. sequence-specific interactions with NS domains.
FIGURE 7–26 Four types of protein interactions with NS domains of heparan sulfate.
(Fig. 7–26a), or it may be due to the ability of adjacent proteoglycans containing heparan sulfates and chon-
domains of heparan sulfate to bind to two different droitin sulfate, which provide directional cues for axon
proteins, bringing them into close proximity and en- outgrowth.
hancing protein-protein interactions (Fig. 7–26b). A Some proteoglycans can form proteoglycan ag-
third general mechanism of action is the binding of ex- gregates, enormous supramolecular assemblies of
tracellular signal molecules (growth factors, for exam- many core proteins all bound to a single molecule of
ple) to heparan sulfate, which increases their local hyaluronan. Aggrecan core protein (Mr ~250,000) has
concentrations and enhances their interaction with multiple chains of chondroitin sulfate and keratan sul-
growth factor receptors in the cell surface; in this case, fate, joined to Ser residues in the core protein through
the heparan sulfate acts as a coreceptor (Fig. 7–26c). trisaccharide linkers, to give an aggrecan monomer of
For example, fibroblast growth factor (FGF), an extra- Mr ~2 106. When a hundred or more of these “deco-
cellular protein signal that stimulates cell division, first rated” core proteins bind a single, extended molecule of
binds to heparan sulfate moieties of syndecan molecules hyaluronate (Fig. 7–27), the resulting proteoglycan
in the target cell’s plasma membrane. Syndecan pres- aggregate (Mr
2 108) and its associated water of hy-
ents FGF to the FGF plasma membrane receptor, and dration occupy a volume about equal to that of a bacter-
only then can FGF interact productively with its recep- ial cell! Aggrecan interacts strongly with collagen in the
tor to trigger cell division. Finally, in another type of extracellular matrix of cartilage, contributing to the de-
mechanism, the NS domains interact—electrostatically velopment, tensile strength, and resiliency of this
and otherwise—with a variety of soluble molecules out- connective tissue.
side the cell, maintaining high local concentrations at Interwoven with these enormous extracellular pro-
the cell surface (Fig. 7–26d). teoglycans are fibrous matrix proteins such as collagen,
The importance of correctly synthesizing sulfated elastin, and fibronectin, forming a cross-linked mesh-
domains in heparan sulfate is demonstrated in mutant work that gives the whole extracellular matrix strength
(“knockout”) mice lacking the enzyme that sulfates the and resilience. Some of these proteins are multiadhe-
C-2 hydroxyl of IdoA. These animals are born without sive, a single protein having binding sites for several dif-
kidneys and with very severe developmental abnormali- ferent matrix molecules. Fibronectin, for example, has
ties of the skeleton and eyes. Other studies demonstrate separate domains that bind fibrin, heparan sulfate, colla-
that membrane proteoglycans are important in lipopro- gen, and a family of plasma membrane proteins called
tein clearance in the liver. There is growing evidence integrins that mediate signaling between the cell inte-
that the path taken by developing axons in the nervous rior and the extracellular matrix (see Fig. 12–28). The
system, and thus the wiring circuitry, is influenced by overall picture of cell-matrix interactions that emerges
7.3 Glycoconjugates: Proteoglycans, Glycoproteins, and Glycolipids 255
Actin filaments
Hyaluronan
(up to 50,000 Integrin
repeating
disaccharides)
Aggrecan
core protein
Proteoglycan
Chondroitin Fibronectin
sulfate
Link
Keratan proteins
sulfate
Cross-linked
fibers of
collagen
Plasma membrane
FIGURE 7–28 Interactions between cells and the extracellular matrix.
FIGURE 7–27 Proteoglycan aggregate of the extracellular matrix.
The association between cells and the proteoglycan of the extracellu-
Schematic drawing of a proteoglycan with many aggrecan molecules.
lar matrix is mediated by a membrane protein (integrin) and by an ex-
One very long molecule of hyaluronan is associated noncovalently with
tracellular protein (fibronectin in this example) with binding sites for
about 100 molecules of the core protein aggrecan. Each aggrecan mol-
both integrin and the proteoglycan. Note the close association of col-
ecule contains many covalently bound chondroitin sulfate and keratan
lagen fibers with the fibronectin and proteoglycan.
sulfate chains. Link proteins at the junction between each core protein
and the hyaluronan backbone mediate the core protein–hyaluronan in-
teraction. The micrograph shows a single molecule of aggrecan, viewed Glycoproteins Have Covalently Attached Oligosaccharides
with the atomic force microscope (see Box 11–1).
Glycoproteins are carbohydrate-protein conjugates in
which the glycans are smaller, branched, and more
(Fig. 7–28) shows an array of interactions between cel- structurally diverse than the glycosaminoglycans of
lular and extracellular molecules. These interactions proteoglycans. The carbohydrate is attached at its
serve not merely to anchor cells to the extracellular anomeric carbon through a glycosidic link to the ⎯OH
matrix but also to provide paths that direct the migration of a Ser or Thr residue (O-linked), or through an N-gly-
of cells in developing tissue and to convey information cosyl link to the amide nitrogen of an Asn residue (N-
in both directions across the plasma membrane. linked) (Fig. 7–29). Some glycoproteins have a single
(a) O-linked (b) N-linked
O
CH2 HOCH2 O C O
O O
HO H H H H NH C CH2 CH
C O
OH H OH H NH
H O CH2 CH O H
FIGURE 7–29 Oligosaccharide linkages in glycopro-
H NH
NH
H NH
teins. (a) O-linked oligosaccharides have a glyco-
C O C O
sidic bond to the hydroxyl group of Ser or Thr residues
(pink), illustrated here with GalNAc as the sugar at the CH3 CH3
GalNAc Ser GlcNAc Asn
reducing end of the oligosaccharide. One simple
chain and one complex chain are shown. (b) N-linked Examples: Examples:
oligosaccharides have an N-glycosyl bond to the
Ser/Thr
amide nitrogen of an Asn residue (green), illustrated

Asn
Asn
here with GlcNAc as the terminal sugar. Three com-

mon types of oligosaccharide chains that are N-linked
GlcNAc
in glycoproteins are shown. A complete description of
Man
Ser/ Thr
oligosaccharide structure requires specification of the Gal

Asn
position and stereochemistry ( or ) of each glyco- Neu5Ac

sidic linkage. GalNAc
oligosaccharide chain, but many have more than one; Many of the proteins secreted by eukaryotic cells
the carbohydrate may constitute from 1% to 70% or are glycoproteins, including most of the proteins of
more of the glycoprotein by mass. Mucins are secreted blood. For example, immunoglobulins (antibodies) and
or membrane glycoproteins that can contain large num- certain hormones, such as follicle-stimulating hormone,
bers of O-linked oligosaccharide chains. Mucins are luteinizing hormone, and thyroid-stimulating hormone,
present in most secretions; they give mucus its charac- are glycoproteins. Many milk proteins, including lactal-
teristic slipperiness. About half of all proteins of mam- bumin, and some of the proteins secreted by the pan-
mals are glycosylated, and about 1% of all mammalian creas (such as ribonuclease) are glycosylated, as are
genes encode enzymes involved in the synthesis and most of the proteins contained in lysosomes.
attachment of these oligosaccharide chains. Sequences The biological advantages of adding oligosaccha-
for the attachment of O-linked chains tend to be rich in rides to proteins are slowly being uncovered. The very
Gly, Val, and Pro residues. In contrast the attachment of hydrophilic clusters of carbohydrate alter the polarity
N-linked chains depends on the consensus sequence and solubility of the proteins with which they are conju-
N–{P}–[ST] (see Box 3–3 for the conventions on repre- gated. Oligosaccharide chains that are attached to newly
senting consensus sequences). As with proteoglycans, synthesized proteins in the endoplasmic reticulum (ER)
not all potential sites are used. and elaborated in the Golgi complex serve as destination
One class of glycoproteins found in the cytoplasm labels and also act in protein quality control, targeting
and the nucleus is unique in that the glycosylated posi- misfolded proteins for degradation (see Fig. 27–39).
tions in the protein carry only single residues of When numerous negatively charged oligosaccharide
N-acetylglucosamine, in O-glycosidic linkage to the chains are clustered in a single region of a protein, the
hydroxyl group of Ser side chains. This modification charge repulsion among them favors the formation of an
is reversible and often occurs on the same Ser residues extended, rodlike structure in that region. The bulki-
that are phosphorylated at some stage in the protein’s ness and negative charge of oligosaccharide chains also
activity. The two modifications are mutually exclusive, protect some proteins from attack by proteolytic en-
and this type of glycosylation may prove to be important zymes. Beyond these global physical effects on protein
in the regulation of protein activity. We discuss it in the structure, there are also more specific biological effects
context of protein phosphorylation in Chapter 12. of oligosaccharide chains in glycoproteins (Section 7.4).
As we shall see in Chapter 11, the external surface The importance of normal protein glycosylation is clear
of the plasma membrane has many membrane glycopro- from the finding of at least 18 different genetic disorders
teins with arrays of covalently attached oligosaccharides of glycosylation in humans, all causing severely defec-
of varying complexity. The first well-characterized mem- tive physical or mental development; some of these dis-
brane glycoprotein was glycophorin A of the erythrocyte orders are fatal.
membrane (see Fig. 11–7). It contains 60% carbohy-
drate by mass, in the form of 16 oligosaccharide chains Glycolipids and Lipopolysaccharides
(totaling 60 to 70 monosaccharide residues) covalently
attached to amino acid residues near the amino termi-
Are Membrane Components
nus of the polypeptide chain. Fifteen of the oligosaccha- Glycoproteins are not the only cellular components that
ride chains are O-linked to Ser or Thr residues, and one bear complex oligosaccharide chains; some lipids, too,
is N-linked to an Asn residue. have covalently bound oligosaccharides. Gangliosides
Glycomics is the systematic characterization of all are membrane lipids of eukaryotic cells in which the po-
of the carbohydrate components of a given cell or tissue, lar head group, the part of the lipid that forms the outer
including those attached to proteins and to lipids. For surface of the membrane, is a complex oligosaccharide
glycoproteins, this also means determining which pro- containing a sialic acid (Fig. 7–9) and other monosac-
teins are glycosylated and where in the amino acid se- charide residues. Some of the oligosaccharide moieties
quence each oligosaccharide is attached. This is a of gangliosides, such as those that determine human
challenging undertaking, but worthwhile because of the blood groups (see Fig. 10–15), are identical with those
potential insights it offers into normal patterns of glyco- found in certain glycoproteins, which therefore also
sylation and the ways in which they are altered during contribute to blood group type. Like the oligosaccharide
development or in genetic diseases or cancer. Current moieties of glycoproteins, those of membrane lipids are
methods of characterizing the whole carbohydrate com- generally, perhaps always, found on the outer face of the
plement of cells depend heavily on sophisticated appli- plasma membrane.
cation of mass spectroscopy (see Fig. 7–37). Lipopolysaccharides are the dominant surface
The structures of a large number of O- and N-linked feature of the outer membrane of gram-negative
oligosaccharides from a variety of glycoproteins are bacteria such as Escherichia coli and Salmonella
known; Figure 7–29 shows a few typical examples. We typhimurium. These molecules are prime targets of
consider the mechanisms by which specific proteins ac- the antibodies produced by the vertebrate immune sys-
quire specific oligosaccharide moieties in Chapter 27. tem in response to bacterial infection and are therefore
7.4 Carbohydrates as Informational Molecules: The Sugar Code 257
A SUMMARY 7.3 Glycoconjugates:

R
n10
Proteoglycans, Glycoproteins,
R
A
O-Specific and Glycolipids
chain
GlcNAc ■ Proteoglycans are glycoconjugates in which one
Man
Glc R
or more large glycans, called sulfated
Gal glycosaminoglycans (heparan sulfate, chondroitin
A AbeOAc
sulfate, dermatan sulfate, or keratan sulfate) are
R Rha
covalently attached to a core protein. Bound to
K Kdo Core
H Hep
H H the outside of the plasma membrane by a
H
transmembrane peptide or a covalently attached
K K K
lipid, proteoglycans provide points of adhesion,
O O recognition, and information transfer between cells,
O O O O

O O HO O or between the cell and the extracellular matrix.
P P
HO
O O ■ Glycoproteins contain oligosaccharides covalently
NH HN OH
O linked to Asp or Ser/Thr residues. The glycans
O O O O are typically branched and smaller than
O O OH OH
glycosaminoglycans. Many cell surface or
O O
extracellular proteins are glycoproteins, as are
most secreted proteins. The covalently attached
Lipid A
oligosaccharides influence the folding and stability
of the proteins, provide critical information about
the targeting of newly synthesized proteins, and
allow for specific recognition by other proteins.
■ Glycomics is the determination of the full
complement of sugar-containing molecules in a cell
or tissue, and the determination of the function of
each such molecule.
■ Glycolipids in plants and animals and lipopoly-
FIGURE 7–30 Bacterial lipopolysaccharides. Schematic diagram of the
saccharides in bacteria are components of the cell
lipopolysaccharide of the outer membrane of Salmonella typhimurium.
envelope with covalently attached oligosaccharide
Kdo is 3-deoxy-D-manno-octulosonic acid (previously called ke-
chains exposed on the cell’s outer surface.
todeoxyoctonic acid); Hep is L-glycero-D-manno-heptose; AbeOAc is
abequose (a 3,6-dideoxyhexose) acetylated on one of its hydroxyls.
There are six fatty acid residues in the lipid A portion of the molecule.
Different bacterial species have subtly different lipopolysaccharide
7.4 Carbohydrates as Informational
structures, but they have in common a lipid region (lipid A), a core Molecules:The Sugar Code
oligosaccharide also known as endotoxin, and an “O-specific” chain,
Glycobiology, the study of the structure and function of
which is the principal determinant of the serotype (immunological
glycoconjugates, is one of the most active and exciting
reactivity) of the bacterium. The outer membranes of the gram-negative
areas of biochemistry and cell biology. As is becoming
bacteria S. typhimurium and E. coli contain so many lipopolysaccharide
molecules that the cell surface is virtually covered with O-specific
increasingly clear, cells use specific oligosaccharides to
chains.
encode important information about intracellular tar-
geting of proteins, cell-cell interactions, cell differentia-
tion and tissue development, and extracellular signals.
important determinants of the serotype of bacterial Our discussion uses just a few examples to illustrate the
strains (serotypes are strains that are distinguished on diversity of structure and the range of biological activity
the basis of antigenic properties). The lipopolysaccha- of the glycoconjugates. In Chapter 20 we discuss the
rides of S. typhimurium contain six fatty acids bound biosynthesis of polysaccharides, including peptidogly-
to two glucosamine residues, one of which is the point of can; and in Chapter 27, the assembly of oligosaccharide
attachment for a complex oligosaccharide (Fig. 7–30). chains on glycoproteins.
E. coli has similar but unique lipopolysaccharides. The Improved methods for the analysis of oligosaccha-
lipid A portion of the lipopolysaccharides of some bacte- ride and polysaccharide structure have revealed remark-
ria is called endotoxin; its toxicity to humans and other able complexity and diversity in the oligosaccharides of
animals is responsible for the dangerously lowered glycoproteins and glycolipids. Consider the oligosaccha-
blood pressure that occurs in toxic shock syndrome re- ride chains in Figure 7–29, typical of those found in
sulting from gram-negative bacterial infections. ■ many glycoproteins. The most complex of those shown
contains 14 monosaccharide residues of four different deterrents to insects and other predators. In the labora-
kinds, variously linked as (1n2), (1n3), (1n4), (1n6), tory, purified plant lectins are useful reagents for detect-
(2n3), and (2n6), some with the and some with the ing and separating glycans and glycoproteins with
configuration. Branched structures, not found in nu- different oligosaccharide moieties. Here we discuss just a
cleic acids or proteins, are common in oligosaccharides. few examples of the roles of lectins in animal cells.
With the reasonable assumption that 20 different mono- Some peptide hormones that circulate in the blood
saccharide subunits are available for construction of have oligosaccharide moieties that strongly influence
oligosaccharides, we can calculate that many billions of their circulatory half-life. Luteinizing hormone and thy-
different hexameric oligosaccharides are possible; this rotropin (polypeptide hormones produced in the adre-
compares with 6.4 107 (206) different hexapeptides nal cortex) have N-linked oligosaccharides that end
possible with the 20 common amino acids, and 4,096 (46 ) with the disaccharide GalNAc4S(1n4)GlcNAc, which
different hexanucleotides with the four nucleotide sub- is recognized by a lectin (receptor) of hepatocytes.
units. If we also allow for variations in oligosaccharides (GalNAc4S is N-acetylgalactosamine sulfated on the
resulting from sulfation of one or more residues, the ⎯ OH group at C-4.) Receptor-hormone interaction me-
number of possible oligosaccharides increases by two diates the uptake and destruction of luteinizing hor-
orders of magnitude. In reality, only a subset of possible mone and thyrotropin, reducing their concentration in
combinations is found, given the restrictions imposed by the blood. Thus the blood levels of these hormones un-
the biosynthetic enzymes and the availability of precur- dergo a periodic rise (due to pulsatile secretion by the
sors. Nevertheless, the enormously rich structural infor- adrenal cortex) and fall (due to continual destruction
mation in glycans does not merely rival but far surpasses by hepatocytes).
that of nucleic acids in the density of information con- The residues of Neu5Ac (a sialic acid) situated at
tained in a molecule of modest size. Each of the oligosac- the ends of the oligosaccharide chains of many plasma
charides represented in Figure 7–29 presents a unique, glycoproteins (Fig. 7–29) protect those proteins from
three-dimensional face—a word in the sugar code— uptake and degradation in the liver. For example, ceru-
readable by the proteins that interact with it. loplasmin, a copper-containing serum glycoprotein, has
several oligosaccharide chains ending in Neu5Ac. The
Lectins Are Proteins That Read the Sugar Code mechanism that removes sialic acid residues from serum
glycoproteins is unclear. It may be due to the activity of
and Mediate Many Biological Processes the enzyme sialidase (also called neuraminidase) pro-
Lectins, found in all organisms, are proteins that bind duced by invading organisms or to a steady, slow release
carbohydrates with high specificity and with moderate to by extracellular enzymes. The plasma membrane of he-
high affinity (Table 7–3). Lectins serve in a wide variety patocytes has lectin molecules (asialoglycoprotein re-
of cell-cell recognition, signaling, and adhesion processes ceptors; “asialo-” indicating “without sialic acid”) that
and in intracellular targeting of newly synthesized pro- specifically bind oligosaccharide chains with galactose
teins. Plant lectins, abundant in seeds, probably serve as residues no longer “protected” by a terminal Neu5Ac
TABLE 7–3 Some Lectins and the Oligosaccharide Ligands They Bind
Lectin source and lectin Abbreviation Ligand(s)
Plant
Concanavalin A ConA Manl—OCH3
Griffonia simplicifolia lectin 4 GS4 Lewis b (Leb) tetrasaccharide
Wheat germ agglutinin WGA Neu5Ac(2n3)Gal(1n4)Glc
GlcNAc(1n4)GlcNAc
Ricin Gal(1n4)Glc
Animal
Galectin-1 Gal(1n4)Glc
Mannose-binding protein A MBP-A High-mannose octasaccharide
Viral
Influenza virus hemagglutinin HA Neu5Ac(2n6)Gal(1n4)Glc
Polyoma virus protein 1 VP1 Neu5Ac(2n3)Gal(1n4)Glc
Bacterial
Enterotoxin LT Gal
Cholera toxin CT GM1 pentasaccharide
Source: Weiss, W.I. & Drickamer, K. (1996) Structural basis of lectin-carbohydrate recognition. Annu. Rev. Biochem. 65, 441–473.
residue. Receptor-ceruloplasmin interaction triggers en- Glycoprotein ligand Glycoprotein ligand

docytosis and destruction of the ceruloplasmin. for integrin for P-selectin
Integrin
OH P-selectin
HOH2C H
C Free
H COO Capillary neutrophil
H C endothelial
OH cell
HO O
Rolling
HN H
OH
H 3C C H
O
N-Acetylneuraminic acid (Neu5Ac) Adhesion
(a sialic acid)
Site of
A similar mechanism is apparently responsible for re- inflammation
moving “old” erythrocytes from the mammalian blood-
Extravasation
stream. Newly synthesized erythrocytes have several
membrane glycoproteins with oligosaccharide chains that
end in Neu5Ac. When the sialic acid residues are removed Blood
by withdrawing a sample of blood from experimental ani- flow
mals, treating it with sialidase in vitro, and reintroducing it
into the circulation, the treated erythrocytes disappear
from the bloodstream within a few hours; erythrocytes FIGURE 7–31 Role of lectin-ligand interactions in lymphocyte move-
with intact oligosaccharides (withdrawn and reintroduced ment to the site of an infection or injury. A neutrophil circulating
without sialidase treatment) continue to circulate for days. through a capillary is slowed by transient interactions between P-selectin
molecules in the plasma membrane of the capillary endothelial cells
Cell surface lectins are important in the develop-
and glycoprotein ligands for P-selectin on the neutrophil surface. As it
ment of some human diseases—both human lectins
interacts with successive P-selectin molecules, the neutrophil rolls
and the lectins of infectious agents. Selectins are a family
along the capillary surface. Near a site of inflammation, stronger inter-
of plasma membrane lectins that mediate cell-cell recogni-
actions between integrin in the capillary surface and its ligand in the
tion and adhesion in a wide range of cellular processes.
neutrophil surface lead to tight adhesion. The neutrophil stops rolling
One such process is the movement of immune cells (neu- and, under the influence of signals sent out from the site of inflamma-
trophils) through the capillary wall, from blood to tissues, tion, begins extravasation—escape through the capillary wall—as it
at sites of infection or inflammation (Fig. 7–31). At an moves toward the site of inflammation.
infection site, P-selectin on the surface of capillary
endothelial cells interacts with a specific oligosaccharide Lex portion of sialoglycoproteins or that alter the
of the glycoproteins of circulating neutrophils. This inter- biosynthesis of the oligosaccharide might prove effective
action slows the neutrophils as they adhere to and roll as selectin-specific drugs for treating chronic inflamma-
along the endothelial lining of the capillaries. A second tion or metastatic disease.
interaction, between integrin molecules (p. 455) in the Several animal viruses, including the influenza virus,
neutrophil plasma membrane and an adhesion protein on attach to their host cells through interactions with
the endothelial cell surface, now stops the neutrophil and oligosaccharides displayed on the host cell surface. The
allows it to move through the capillary wall into the lectin of the influenza virus, known as the HA (hemagglu-
infected tissues to initiate the immune attack. Two other tinin) protein, is essential for viral entry and infection. Af-
selectins participate in this “lymphocyte homing”: E- ter the virus has entered a host cell and has been
selectin on the endothelial cell and L-selectin on the neu- replicated, the newly synthesized viral particles bud out of
trophil bind their cognate oligosaccharides on the the cell, wrapped in a portion of its plasma membrane. A vi-
neutrophil and endothelial cell, respectively. ral sialidase (neuraminidase) trims the terminal sialic acid
Human selectins mediate the inflammatory re- residue from the host cell’s oligosaccharides, releasing the
sponses in rheumatoid arthritis, asthma, psoriasis, mul- viral particles from their interaction with the cell and pre-
tiple sclerosis, and the rejection of transplanted organs, venting their aggregation with one another. Another
and thus there is great interest in developing drugs that round of infection can now begin. The antiviral drugs os-
inhibit selectin-mediated cell adhesion. Many carcino- eltamivir (Tamiflu) and zanamivir (Relenza) (next page)
mas express an antigen normally present only in fetal are used clinically in the treatment of influenza. These
cells (sialyl Lewis x, or sialyl Lex) that, when shed into drugs are sugar analogs; they inhibit the viral sialidase by
the circulation, facilitates tumor cell survival and metas- competing with the host cell’s oligosaccharides for binding.
tasis. Carbohydrate derivatives that mimic the sialyl This prevents the release of viruses from the infected cell
and also causes viral particles to aggregate, both of which

block another cycle of infection.
NH2 NH
O
O NH2
HN NH
O
O
O HN COOH
O O
Barry J. Marshall J. Robin Warren
HO OH
Oseltamivir Zanamivir Some of the most devastating of the human parasitic
(Tamiflu) (Relenza) diseases, widespread in much of the developing world,
are caused by eukaryotic microorganisms that display
Lectins on the surface of the herpes simplex viruses unusual surface oligosaccharides, which in some cases
HSV-1 and HSV-2 (the causative agents of oral and gen- are known to be protective for the parasites. These or-
ital herpes, respectively) bind specifically to heparan ganisms include the trypanosomes, responsible for
sulfate on the host cell surface as a first step in the in- African sleeping sickness and Chagas disease; Plasmo-
fection cycle; infection requires precisely the right pat- dium falciparum, the malaria parasite; and Entamoeba
tern of sulfation on this polymer. Analogs of heparan histolytica, the causative agent of amoebic dysentery.
sulfate that mimic its interaction with the viruses are be- The prospect of finding drugs that interfere with the syn-
ing investigated as possible antiviral drugs, interfering thesis of these unusual oligosaccharide chains, and
with interactions between virus and cell. therefore with the replication of the parasites, has in-
Some microbial pathogens have lectins that mediate spired much recent work on the biosynthetic pathways
bacterial adhesion to host cells or the entry of toxin into of these oligosaccharides.
cells. For example, Helicobacter pylori—shown by The cholera toxin molecule (produced by the bac-
Barry J. Marshall and J. Robin Warren in the 1980s to terium Vibrio cholerae) triggers diarrhea after entering
be responsible for most gastric ulcers—adheres to the intestinal cells responsible for water absorption from
inner surface of the stomach as bacterial membrane the intestine. The toxin attaches to its target cell
lectins interact with specific oligosaccharides of mem- through the oligosaccharide moiety of ganglioside GM1,
brane glycoproteins of the gastric epithelial cells a membrane phospholipid (for the structure of GM1 see
(Fig. 7–32). Among the binding sites recognized by H. Box 10–2, Fig. 1), on the surface of intestinal epithelial
pylori is the oligosaccharide Lewis b (Leb), when it is cells. Similarly, the pertussis toxin produced by Borde-
part of the type O blood group determinant. This obser- tella pertussis, the bacterium that causes whooping
vation helps to explain the severalfold greater incidence cough, enters target cells only after interacting with a
of gastric ulcers in people of blood type O than in those host cell oligosaccharide (or perhaps several oligosac-
of type A or B. Chemically synthesized analogs of the Leb charides) bearing a terminal sialic acid residue. Under-
oligosaccharide may prove useful in treating this type of standing the details of the oligosaccharide-binding sites
ulcer. Administered orally, they could prevent bacterial of these toxins (lectins) may allow the development of
adhesion (and thus infection) by competing with the genetically engineered toxin analogs for use in vaccines.
gastric glycoproteins for binding to the bacterial lectin. Toxin analogs engineered to lack the carbohydrate bind-
ing site would be harmless because they could not bind
to and enter cells, but they might elicit an immune re-
sponse that would protect against later exposure to the
natural toxin. It is also possible to imagine drugs that
would act by mimicking cell surface oligosaccharides,
binding to the bacterial lectins or toxins and preventing
their productive binding to cell surfaces.
Lectins also act intracellularly. An oligosaccharide
containing mannose 6-phosphate marks newly synthe-
sized proteins in the Golgi complex for transfer to the
lysosome (see Fig. 27–39). A common structural feature
on the surface of these glycoproteins, the signal patch,
is recognized by an enzyme that phosphorylates (in a
FIGURE 7–32 An ulcer in the making. Helicobacter pylori cells adher- two-step process) a mannose residue at the terminus
ing to the gastric surface. This bacterium causes ulcers by interactions of an oligosaccharide chain. The resulting mannose
between a bacterial surface lectin and the Leb oligosaccharide (a blood 6-phosphate residue is then recognized by the cation-
group antigen) of the gastric epithelium. dependent mannose 6-phosphate receptor, a membrane-
associated lectin with its mannose phosphate binding Lectin-Carbohydrate Interactions Are Highly Specific
site on the lumenal side of the Golgi complex. When a and Often Polyvalent
section of the Golgi complex containing this receptor
buds off to form a transport vesicle, proteins containing In all the functions of lectins described above, and in many
mannose phosphate residues are dragged into the form- more known to involve lectin-oligosaccharide interactions,
ing bud by interaction of their mannose phosphates with it is essential that the oligosaccharide have a unique struc-
the receptor; the vesicle then moves to and fuses with a ture, so that recognition by the lectin is highly specific.
lysosome, depositing its cargo therein. Many, perhaps The high density of information in oligosaccharides pro-
all, of the degradative enzymes (hydrolases) of the lyso- vides a sugar code with an essentially unlimited number of
some are targeted and delivered by this mechanism. unique “words” small enough to be read by a single pro-
Some of the mannose 6-phosphate receptors can cap- tein. In their carbohydrate-binding sites, lectins have a
ture enzymes containing the mannose 6-phosphate subtle molecular complementarity that allows interaction
residue and direct them to the lysosome. This process is only with their correct carbohydrate cognates. The result
the basis for “enzyme replacement therapy” to correct is an extraordinarily high specificity in these interactions.
lysosomal storage disorders in humans. ■ The affinity between an oligosaccharide and each carbo-
Other lectins act in other kinds of protein sorting. hydrate binding domain (CBD) of a lectin is sometimes
Any newly synthesized protein in the endoplasmic reticu- modest (micromolar to millimolar Kd values), but the ef-
lum already has a complex oligosaccharide attached, fective affinity is in many cases greatly increased by lectin
which can be bound by either of two ER lectins that are multivalency, in which a single lectin molecule has multi-
also chaperones: calnexin (membrane-bound) or cal- ple CBDs. In a cluster of oligosaccharides—as is com-
reticulin (soluble). These lectins link the new protein monly found on a membrane surface, for example—each
with an enzyme that brings about rapid disulfide ex- oligosaccharide can engage one of the lectin’s CBDs,
change as the protein tries various ways to fold, leading strengthening the interaction. When cells express multi-
eventually to the native conformation. At this point, en- ple receptors, the avidity of the interaction can be very
zymes in the ER trim the oligosaccharide moiety to a form high, enabling highly cooperative events such as cell at-
recognized by another lectin, ERGIC53, which draws the tachment and rolling (see Fig. 7–31).
folded protein (glycoprotein) into the Golgi complex for X-ray crystallographic studies of the structures of
further maturation. If a protein has not folded effectively, several lectin-carbohydrate complexes have provided
the oligosaccharide is trimmed to another form, this one rich details of the lectin-sugar interaction (Fig. 7–33). In
recognized by a lectin, EDEM, that initiates movement of humans, a family of 11 lectins that bind to oligosaccharide
the defectively folded protein into the cytosol, where it chains ending in sialic acid residues plays some important
will be degraded. Thus, protein glycosylation serves in biological roles. All of these lectins bind sialic acids at
the ER as a kind of quality control signal, allowing the cell sandwich domains like those found in immunoglobulins
to eliminate improperly folded proteins. (This process is (Igs; see this motif in the CD8 protein in Fig. 4–21), and
described in greater detail in Chapter 27.) the proteins are therefore called siglecs 1 to 11(sialic
His105
Arg135
Asn104
Glu133
Tyr45
Mn Tyr143
Asp103
Arg111 Gln66
(a) (b)
FIGURE 7–33 Details of a lectin-carbohydrate interaction. Structure bonded to Arg111 and coordinated with the manganese ion (shown
of the bovine mannose 6-phosphate receptor complexed with man- smaller than its van der Waals radius for clarity). Each hydroxyl group
nose 6-phosphate (PDB ID 1M6P). The protein is represented as a sur- of mannose is hydrogen-bonded to the protein. The His105 hydrogen-
face contour image, showing the surface as predominantly negatively bonded to a phosphate oxygen of mannose 6-phosphate may be the
charged (red) or positively charged (blue). Mannose 6-phosphate is residue that, when protonated at low pH, causes the receptor to re-
shown as a stick structure; a manganese ion is shown in violet. (b) An lease mannose 6-phosphate into the lysosome.
enlarged view of the binding site. Mannose 6-phosphate is hydrogen-
acid-recognizing Ig-superfamily lectins), or sometimes

sialoadhesins. The interaction of a siglec with sialic acid
(Neu5Ac) involves each of the ring substituents unique to H H
Neu5Ac: the acetyl group at C-5 undergoes both hydrogen- O O
Hydrophilic O
bond and van der Waals interactions with the protein; side CH2
H
the carboxyl group makes a salt bridge with a conserved H
Arg residue; and the hydroxyls of the glycerol moiety H OH
HO
hydrogen-bond with the protein. Siglecs regulate activi- OH
ties in the immune and nervous systems and in blood H H
cell development. Siglec-7, for example, by binding to a Indolyl moiety
specific ganglioside (GD3) containing two sialic acid Hydrophobic
of Trp
side
residues, suppresses the activity of NK (natural killer)
cells in the immune system, sparing cells targeted for
immune destruction from the NK killing activity. The
elevated GD3 levels in tumors such as malignant FIGURE 7–34 Hydrophobic interactions of sugar residues. Sugar units
melanoma and neuroblastoma may be a mechanism for such as galactose have a more polar side (the top of the chair as shown
evading the protective action of the immune system. here, with the ring oxygen and several hydroxyls) that is available to
The structure of the mannose 6-phosphate recep- hydrogen-bond with the lectin, and a less polar side that can have hy-
tor/lectin reveals details of its interaction with mannose drophobic interactions with nonpolar side chains in the protein, such
6-phosphate that explain the specificity of the binding as the indole ring of Trp residues.
and the role for a divalent cation in the lectin-sugar
interaction (Fig. 7–33a). His105 is hydrogen-bonded to ample, many sugars have a more polar and a less polar
one of the oxygen atoms of the phosphate (Fig. 7–33b). side (Fig. 7–34); the more polar side hydrogen-bonds
When the protein tagged with mannose 6-phosphate with the lectin, while the less polar undergoes hydropho-
reaches the lysosome (which has a lower internal pH bic interactions with nonpolar amino acid residues. The
than the Golgi complex), the receptor loses its affinity sum of all these interactions produces high-affinity bind-
for mannose 6-phosphate. Protonation of His105 may be ing and high specificity of lectins for their carbohydrates.
responsible for this change in binding. This represents a kind of information transfer that is
In addition to these very specific interactions, there clearly central in many processes within and between
are more general interactions that contribute to the cells. Figure 7–35 summarizes some of the biological in-
binding of many carbohydrates to their lectins. For ex- teractions mediated by the sugar code.
Virus Bacterium Lymphocyte
Oligosaccharide
chain
Plasma
membrane P-selectin
protein
Toxin
Glycolipid FIGURE 7–35 Roles of oligosaccharides in recognition

and adhesion at the cell surface. (a) Oligosaccharides
with unique structures (represented as strings of hexa-
(c)
gons), components of a variety of glycoproteins or gly-
(d) colipids on the outer surface of plasma membranes,
(b)
(e) interact with high specificity and affinity with lectins in
(a)
Mannose 6-phosphate the extracellular milieu. (b) Viruses that infect animal
receptor/lectin cells, such as the influenza virus, bind to cell surface
glycoproteins as the first step in infection. (c) Bacterial
(f ) toxins, such as the cholera and pertussis toxins, bind to
a surface glycolipid before entering a cell. (d) Some bac-
Enzyme teria, such as H. pylori, adhere to and then colonize or
Enzyme
Mannose infect animal cells. (e) Selectins (lectins) in the plasma
6-phosphate
membrane of certain cells mediate cell-cell interactions,
residue on
newly synthesized such as those of neutrophils with the endothelial cells of
protein the capillary wall at an infection site. (f) The mannose 6-
phosphate receptor/lectin of the trans Golgi complex
Lysosome
Trans Golgi binds to the oligosaccharide of lysosomal enzymes, tar-
geting them for transfer into the lysosome.
7.5 Working with Carbohydrates 263
SUMMARY 7.4 Carbohydrates as For analysis of the oligosaccharide moieties of

glycoproteins and glycolipids, the oligosaccharides are
Informational Molecules: released by purified enzymes—glycosidases that specif-
The Sugar Code ically cleave O- or N-linked oligosaccharides or lipases
■ Monosaccharides can be assembled into an almost that remove lipid head groups. Alternatively, O-linked
limitless variety of oligosaccharides, which differ in glycans can be released from glycoproteins by treat-
the stereochemistry and position of glycosidic ment with hydrazine.
bonds, the type and orientation of substituent The resulting mixtures of carbohydrates are re-
groups, and the number and type of branches. solved into their individual components by a variety of
Glycans are far more information-dense than methods (Fig. 7–36), including the same techniques
nucleic acids or proteins. used in protein and amino acid separation: fractional
precipitation by solvents, and ion-exchange and size-
■ Lectins, proteins with highly specific carbohydrate-
exclusion chromatography (see Fig. 3–17). Highly puri-
binding domains, are commonly found on the outer
fied lectins, attached covalently to an insoluble support,
surface of cells, where they initiate interaction with
are commonly used in affinity chromatography of carbo-
other cells. In vertebrates, oligosaccharide tags
hydrates (see Fig. 3–17c).
“read” by lectins govern the rate of degradation of
Hydrolysis of oligosaccharides and polysaccharides
certain peptide hormones, circulating proteins, and
in strong acid yields a mixture of monosaccharides,
blood cells.
which may be identified and quantified by chromato-
■ Bacterial and viral pathogens and some eukaryotic graphic techniques to yield the overall composition of
parasites adhere to their animal-cell targets the polymer.
by the binding of lectins in the pathogens to Oligosaccharide analysis relies increasingly on mass
oligosaccharides on the target cell surface. spectrometry and high-resolution NMR spectroscopy.
■ Intracellular lectins mediate intracellular protein Matrix-assisted laser desorption/ionization mass spec-
targeting to specific organelles or to the secretory trometry (MALDI MS) and tandem mass spectrometry
pathway. (MS/MS), both described in Box 3–2, are readily appli-
cable to polar compounds such as oligosaccharides.
■ X-ray crystallography of lectin-sugar complexes
MALDI MS is a very sensitive method for determining
shows the detailed complementarity between the
the mass of a molecular ion (in this case, the entire
two molecules, which accounts for the strength and
oligosaccharide chain; Fig. 7–37). MS/MS reveals the
specificity of lectin interactions with carbohydrates.
mass of the molecular ion and many of its fragments,
which are usually the result of breakage of the glycosidic
bonds. NMR analysis alone (see Box 4–5), especially for
7.5 Working with Carbohydrates oligosaccharides of moderate size, can yield much infor-
The growing appreciation of the importance of oligosac- mation about sequence, linkage position, and anomeric
charide structure in biological recognition has been the carbon configuration. For example, the structure of the
driving force behind the development of methods for an- heparin segment shown as a space-filling model in
alyzing the structure and stereochemistry of complex Figure 7–22 was obtained entirely by NMR spectroscopy.
oligosaccharides. Oligosaccharide analysis is compli- Automated procedures and commercial instruments are
cated by the fact that, unlike nucleic acids and proteins, used for the routine determination of oligosaccharide
oligosaccharides can be branched and are joined by a va- structure, but the sequencing of branched oligosaccha-
riety of linkages. The high charge density of many rides joined by more than one type of bond remains a far
oligosaccharides and polysaccharides, and the relative more formidable task than determining the linear se-
lability of the sulfate esters in glycosaminoglycans, pres- quences of proteins and nucleic acids.
ent further difficulties. Another important tool in working with carbohy-
For simple, linear polymers such as amylose, the posi- drates is chemical synthesis, which has proved to be a
tions of the glycosidic bonds are determined by the classical powerful approach to understanding the biological func-
method of exhaustive methylation: treating the intact poly- tions of glycosaminoglycans and oligosaccharides. The
saccharide with methyl iodide in a strongly basic medium to chemistry involved in such syntheses is difficult, but car-
convert all free hydroxyls to acid-stable methyl ethers, then bohydrate chemists can now synthesize short segments
hydrolyzing the methylated polysaccharide in acid. The of almost any glycosaminoglycan, with correct stereo-
only free hydroxyls present in the monosaccharide deriva- chemistry, chain length, and sulfation pattern, and
tives so produced are those that were involved in glycosidic oligosaccharides significantly more complex than those
bonds. To determine the sequence of monosaccharide shown in Figure 7–29. Solid-phase oligosaccharide syn-
residues, including any branches that are present, exogly- thesis is based on the same principles (and has the same
cosidases of known specificity are used to remove residues advantages) as peptide synthesis (see Fig. 3–29), but
one at a time from the nonreducing end(s). The known requires a set of tools unique to carbohydrate chemistry:
specificity of these exoglycosidases often allows deduction blocking groups and activating groups that allow the syn-
of the position and stereochemistry of the linkages. thesis of glycosidic linkages with the correct hydroxyl
Glycoprotein
or glycolipid
Release oligosaccharides
with endoglycosidase
Oligosaccharide
mixture
1) Ion-exchange chromatography
2) Gel filtration
3) Lectin affinity chromatography
Purified Separated
polysaccharide oligosaccharides
Exhaustive
methylation Enzymatic hydrolysis NMR and
Hydrolysis with with CH3I, with specific mass
strong acid strong base glycosidases spectrometry
Fully methylated Smaller

Monosaccharides
carbohydrate oligosaccharides
Resolution of fragments
High-performance Acid hydrolysis yields in mixture
liquid chromatography, or monosaccharides
derivatization methylated at every Each oligosaccharide
and gas-liquid —OH except those involved subjected to methylation
chromatography in glycosidic bonds or enzymatic analysis
Composition of Sequence of Sequence of

mixture Position(s) of monosaccharides; monosaccharides;
Types and amounts glycosidic position and position and
of monosaccharide bonds configuration of configuration of
units glycosidic bonds glycosidic bonds
FIGURE 7–36 Methods of carbohydrate analysis. A carbohydrate purified in the first stage of the analysis
often requires all four analytical routes for its complete characterization.
Man
100 GlcNAc
Gal
Fuc
2395.9
80
2837.4
Relative intensity (%)
2192.2 2244.2
60
2459.3
1784.0 3909.6
40
1579.9 1988.1
2285.2
2663.3 2908.4 3286.5 3460.5 4083.6
20 2489.3
3735.6
0
1500 2020 2540 3060 3580 4100
m/z
FIGURE 7–37 Separation and quantification of the oligosaccharides in Each distinct oligosaccharide produces a peak at its molecular mass, and
a group of glycoproteins. In this experiment, the mixture of proteins ex- the area under the curve reflects the quantity of that oligosaccharide. The
tracted from kidney tissue was treated to release oligosaccharides from most prominent oligosaccharide here (mass 2837.4 u) is composed of
glycoproteins, and the oligosaccharides were analyzed by matrix- 13 sugar residues; in this sample, other oligosaccharides containing as
assisted laser desorption/ionization mass spectrometry (MALDI MS). few as 7 and as many as 19 residues are also resolved by this method.
Further Reading 265
group. Highly purified enzymes (glycosyltransferases) chondroitin sulfate 250 glypican 253
should greatly aid in the preparation of pure synthetic heparan sulfate 251 glycomics 256
compounds. Synthetic approaches like this represent a proteoglycan 252 lectin 258
current area of great interest since it is difficult to purify glycoprotein 252 selectin 259
in adequate quantity defined oligosaccharides from natu- glycolipid 252 siglec 261
ral sources. Glycan microarrays of defined oligosaccha- syndecan 253 sialoadhesin 262
rides, analogous to the DNA arrays described in Chapter 9,
can be probed with fluorescently tagged lectins to de-
termine their binding specificity. Further Reading
General
SUMMARY 7.5 Working with
Collins, P.M. & Ferrier, R.J. (1995) Monosaccharides: Their
Carbohydrates Chemistry and Their Roles in Natural Products, John Wiley &
■ Establishing the complete structure of Sons, Chichester, UK.
A comprehensive text at the graduate level.
oligosaccharides and polysaccharides requires
determination of linear sequence, branching posi- Lindhorst, T.K. (2003) Essentials of Carbohydrate Chemistry
and Biochemistry, 2nd edn, Wiley-VCH, Weinheim, Germany.
tions, the configuration of each monosaccharide
Morrison, R.T. & Boyd, R.N. (1992) Organic Chemistry, 6th edn,
unit, and the positions of the glycosidic linkages—a
Prentice Hall, Upper Saddle River, NJ.
more complex problem than protein and nucleic Chapters 34 and 35 cover the structure, stereochemistry,
acid analysis. nomenclature, and chemical reactions of carbohydrates.
■ The structures of oligosaccharides and Pérez, S. & Mulloy, B. (2005) Prospects for glycoinformatics. Curr.
polysaccharides are usually determined by a Opin. Struct. Biol. 15, 517–524.
Brief introduction to some very useful materials on carbohy-
combination of methods: specific enzymatic drate structure, synthesis, chemistry, and biology on the Internet.
hydrolysis to determine stereochemistry at the
Varki, A., Cummings, R., Esko, J., Freeze, H., Hart, G., &
glycosidic bond and produce smaller fragments for Marth, J. (eds). (2002) Essentials of Glycobiology, Cold Spring
further analysis; methylation to locate glycosidic Harbor Laboratory Press, Cold Spring Harbor, NY.
bonds; and stepwise degradation to determine Structure, biosynthesis, metabolism, and function of gly-
sequence and configuration of anomeric carbons. cosaminoglycans, proteoglycans, glycoproteins, and glycolipids, all
presented at an intermediate level and very well illustrated.
■ Mass spectrometry and high-resolution NMR
spectroscopy, applicable to small samples of Glycosaminoglycans and Proteoglycans
carbohydrate, yield essential information about Bishop, J.R., Schuksz, M., & Esko, J.D. (2007) Heparan sulfate
sequence, configuration at anomeric and other proteoglycans fine-tune mammalian physiology. Nature 446,
carbons, and positions of glycosidic bonds. 1030–1037.
Bülow, H.E. & Hobert, O. (2006) The molecular diversity of gly-
■ Solid-phase synthetic methods yield defined cosaminoglycans shapes animal development. Annu. Rev. Cell Biol.
oligosaccharides that are of great value in exploring 22, 375–407.
lectin-oligosaccharide interactions and may prove Advanced review of recent studies on glycosaminoglycan de-
clinically useful. fects in human disease and of the use of model organisms to study
glycosaminoglycan biology.
Esko, J.D. & Selleck, S.B. (2002) Order out of chaos: assembly of
Key Terms ligand binding sites in heparan sulfate. Annu. Rev. Biochem. 71,
435–471.
Fears, C.Y. & Woods, A. (2006) The role of syndecans in disease
Terms in bold are defined in the glossary.
and wound healing. Matrix Biol. 25, 443–456.
Intermediate-level review.
glycoconjugate 235 anomeric carbon 239
monosaccharide 235 mutarotation 239 Gama, C.I. & Hsieh-Wilson, L.C. (2005) Chemical approaches to
deciphering the glycosaminoglycan code. Curr. Opin. Chem. Biol. 9,
oligosaccharide 235 Haworth perspective
609–619.
disaccharide 235 formulas 239 Intermediate review of the use of chemically synthesized gly-
polysaccharide 235 reducing sugar 241 cosaminoglycans in exploring the functions of these glycoconjugates.
aldose 236 hemoglobin glycation 242 Häker, U., Nybakken, K., & Perrimon, N. (2005) Heparan sul-
ketose 236 glycosidic bonds 243 phate proteoglycans: the sweet side of development. Nat. Rev. Mol.
Fischer projection reducing end 243 Cell Biol. 6, 530–541.
glycan 244 Intermediate review of the roles of proteoglycans in development.
formulas 236
epimer 238 starch 245 Holt, C.E. & Dickson, B.J. (2005) Sugar codes for axons? Neuron
46, 169–172.
hemiacetal 238 glycogen 246
Brief, intermediate-level review of the possible role of
hemiketal 238 extracellular matrix glycosaminoglycans in directing the outgrowth of axons in the
pyranose 239 (ECM) 249 developing nervous system.
furanose 239 glycosaminoglycan 249 Iozzo, R.V. (1998) Matrix proteoglycans: from molecular design to
anomers 239 hyaluronan 250 cellular function. Annu. Rev. Biochem. 67, 609–652.

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I would feel more optimistic about a bright future for man if he spent

FIGURE 7–1 Representative monosaccharides. (a) Two trioses, an aldose

The Two Families of Monosaccharides Are Aldoses

Monosaccharides Have Asymmetric Centers Fischer projection formulas

All the monosaccharides except dihydroxyacetone con- CHO CHO

different optical isomers, or enantiomers (Fig. 7–2).

Three carbons Four carbons Five carbons

In general, a molecule with n chiral centers can have

glycoconjugates (Section 7.3). 4

For simplicity, we have thus far represented the struc-

FIGURE 7–8 Conformational formulas of pyranoses. (a) Two chair

CH2OH CH2OH CH2OH CH2OH CH2OH

carboxylic acid groups of the acidic sugar derivatives H O

Blood Glucose Measurements in the Diagnosis and

Blood Glucose Measurements in the Diagnosis and

glucose concentrations, so hemoglobin is constantly ex- HOCH2

Homopolysaccharides Heteropolysaccharides space is occupied by several types of heteropolysaccha-

Some Homopolysaccharides Are Stored Forms of Fuel

osmolarity would be threateningly elevated, leading to 3

osmotic entry of water that might rupture the cell (see

FIGURE 7–16 Cellulose breakdown by wood fungi. A wood fungus

FIGURE 7–17 Chitin. (a) A short segment of chitin, a homopolymer of

Steric Factors and Hydrogen Bonding Inﬂuence

described in terms of the dihedral angles, and , about CH2OH O H O OH

(a) (b) ,  170,170

FIGURE 7–21 Agarose. The repeating unit consists of D-galactose

(a) (b) useful in the biochemistry laboratory. When a suspen-

Keratan sulfates (Greek keras, “horn”) have no uronic

TABLE 7–2 Structures and Roles of Some Polysaccharides

Starch Energy storage: in plants

*Each polymer is classiﬁed as a homopolysaccharide (homo-) or heteropolysaccharide (hetero-).

SUMMARY 7.2 Polysaccharides molecules (growth factors, for example) or extracellular

Carboxyl terminus (a)

Gly Syndecan Glypican

Amino terminus Chondroitin sulfate Core protein COO–

FIGURE 7–24 Proteoglycan structure, showing the tetrasaccharide GPI anchor

(a) Conformational activation (b) Enhanced protein-protein interaction

(c) Coreceptor for extracellular ligands (d) Cell surface localization/concentration

(a) O-linked (b) N-linked

amide nitrogen of an Asn residue (green), illustrated

here with GlcNAc as the terminal sugar. Three com-

oligosaccharide structure requires speciﬁcation of the Gal

position and stereochemistry ( or ) of each glyco- Neu5Ac

A SUMMARY 7.3 Glycoconjugates:

residue. Receptor-ceruloplasmin interaction triggers en- Glycoprotein ligand Glycoprotein ligand

and also causes viral particles to aggregate, both of which

acid-recognizing Ig-superfamily lectins), or sometimes

Virus Bacterium Lymphocyte

Glycolipid FIGURE 7–35 Roles of oligosaccharides in recognition

SUMMARY 7.4 Carbohydrates as For analysis of the oligosaccharide moieties of

Fully methylated Smaller

Composition of Sequence of Sequence of

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described in terms of the dihedral angles, and , about CH2OH O H O OH

(a) (b) , 170,170