Chapter 7A Lecture

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Transcript Chapter 7A Lecture

Chap. 7A. Carbohydrates and Glycobiology
• Monosaccharides and Disaccharides
• Polysaccharides
• Glycoconjugates: Proteoglycans, Glycoproteins,
and Glycosphingolipids
• Carbohydrates as Informational Macromolecules:
the Sugar Code
• Working with Carbohydrates
Fig. 7-34. Helicobacter pylori cells
adhering to the gastric surface.
Intro. to Carbohydrates
Carbohydrates are the most abundant biomolecules on Earth. Each
year, photosynthesis converts more than 100 billion metric tons of
CO2 and H20 into cellulose and other plant products. Carbohydrates
are polyhydroxy aldehydes and ketones, or substances that yield
such compounds on hydrolysis. Many, but not all have the empirical
formula (CH2O)n, but some also contain nitrogen, phosphorus, or
sulfur. Carbohydrates occur in four main size classes:
monosaccharides, disaccharides, oligosaccharides, and
polysaccharides. The most abundant monosaccharide in nature is Dglucose, which is also known as dextrose. A common disaccharide,
sucrose, consists of the six-carbon sugars D-glucose and Dfructose. Common polysaccharides include cellulose and starches.
Both of these are homopolymers of D-glucose units, but with
different linkages between residues. More complex carbohydrate
polymers attached to a protein or lipid moiety (glycoconjugates) are
also prevalent in nature. This chapter introduces the major classes
of carbohydrates and glycoconjugates and provides examples of
their many structural and functional roles in biology.
Intro. to Monosaccharides
Monosaccharides are colorless, crystalline solids that are very
soluble in water, but insoluble in nonpolar solvents. Most have a
sweet taste. The backbones of common monosaccharides are
unbranched carbon chains in which all the carbons are linked by
single bonds. In this open-chain form, one of the carbon atoms is
double-bonded to an oxygen atom to form a carbonyl group. Each
of the other carbons 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 called an aldose. If the carbonyl group is at
any other position (a ketone group) the monosaccharide is a
ketose. Monosaccharides with three, four, five, six, and seven
carbons in their backbones are called trioses, tetroses, pentoses,
hexoses, and heptoses. Many of the carbon atoms to which
hydroxyl groups are attached are chiral centers. This gives rise to
the many stereoisomers found in monosaccharides.
Common Monosaccharides
Common aldoses and ketoses of three-, five-, and six-carbon
lengths are shown in Fig. 7-1. The simplest monosaccharides are
the two three-carbon trioses: D-glyceraldehyde, an aldotriose;
and dihydroxyacetone, a ketotriose. The most common
monosaccharides in nature are the aldohexose D-glucose, and the
ketohexose D-fructose. The aldopentoses D-ribose and 2-deoxyD-ribose are components of nucleotides and nucleic acids.
D & L Stereoisomers
All of the monosaccharides except
dihydroxyacetone contain one or more
asymmetric (chiral) carbon atoms and thus
occur in optically active isomeric forms. The
simplest aldose, glyceraldehyde, contains one
chiral center (the middle carbon atom) and
therefore has two different optical isomers,
or enantiomers (Fig. 7-2). One of the two
enantiomers of glyceraldehyde is, by
convention, designated the D isomer and the
other is the L isomer. In general, a molecule
with n chiral centers can have 2n
stereoisomers. Glyceraldehyde has 21 = 2;
the aldohexoses with four chiral centers
have 24 = 16. The stereoisomers of
monosaccharides of each carbon-chain length
are divided into two groups that differ in the
configuration about the chiral carbon that is
most distant from the carbonyl carbon.
Those in which the configuration of this
reference carbon is the same as that of Dglyceraldehyde are designated D isomers.
Those with the same configuration as Lglyceraldehyde are L isomers. Thus of the
16 possible aldohexoses, eight are D forms
and 8 are L forms. The reason D forms
predominate in nature is unknown.
Structures of the D Monosaccharides
The structures of the D stereoisomers of all the aldoses and
ketoses having three to six carbon atoms are shown in Fig. 7-3
(next two slides). The carbons of a sugar are numbered beginning
at the end of the chain nearest the carbonyl group. Each of the
eight aldohexoses, which differ in the stereochemistry at C-2, C3, and C-4, has its own name: D-glucose, D-mannose, D-galactose,
and so forth. The four- and five-carbon ketoses are designated by
inserting “ul” into the name of the corresponding aldose; for
example, D-ribulose is the ketopentose corresponding to the
aldopentose D-ribose. The ketohexoses are named otherwise: for
example, fructose is named from the Latin fructus, “fruit”.
Structures of the D-Aldoses
Structures of the D-Ketoses
Epimers of D-Aldohexoses
Two monosaccharides that differ only in the configuration around
one chiral carbon atom are called epimers. D-glucose and Dmannose are epimers which differ in the configuration at C-2. Dglucose and D-galactose are epimers that differ in the
configuration at C-4 (Fig. 7-4).
Common L Stereoisomers
Some sugars occur naturally in their L form. Some examples are
L-arabinose (below) and the L isomers of some sugar derivatives
that are common components of glycoconjugates.
Formation of Hemiacetals and Hemiketals
Aldotetroses and all monosaccharides with five or more carbon
atoms occur predominantly as cyclic ring structures in which the
carbonyl group has formed a covalent bond with the oxygen of a
hydroxyl group along the chain. The formation of these ring
structures is the result of a general reaction between alcohols and
aldehydes or ketones to form derivatives called hemiacetals or
hemiketals (Fig. 7-5). Actually, two molecules of an alcohol can
add to a carbonyl carbon. The product of the first reaction for an
aldose is a hemiacetal, and the product of the first reaction for a
ketose is a hemiketal. If the -OH and carbonyl groups are from
the same molecule, a five- or six-membered ring results. The
addition of the second alcohol molecule produces the full acetal or
ketal, and the bond formed is a glycosidic linkage. When the two
reacting molecules are both monosaccharides, the acetal or ketal
produced is a disaccharide.
Cyclization of D-Glucose
The reaction of the first alcohol with an
aldose or ketose creates an additional
chiral center at what was the carbonyl
carbon. Because the alcohol can add to
the carbonyl carbon by attacking either
from the “front” or the “back”, the
reaction can produce either of two
stereoisomeric configurations, denoted 
and ß. For example, D-glucose (Fig. 76) exists in solution as an intramolecular
hemiacetal in which the free hydroxyl
group at C-5 has reacted with the
aldehyde C-1, rendering the latter
carbon asymmetric and producing two
possible stereoisomers, designated 
and ß. These two isomeric forms, which
differ only in their configuration about
the hemiacetal carbon atom are called
anomers, and the carbonyl carbon is
called the anomeric carbon. The same
nomenclature is used to describe anomeric forms of hemiketals such
as formed by fructose (see below). The  and ß anomers of Dglucose interconvert via the linear form in aqueous solution by a
process called mutarotation. In solution, an equilibrium mixture
forms which consists of about one-third -D-glucopyranose, twothirds ß-D-glucopyranose, and trace amounts of the linear and fivemembered glucofuranose ring forms.
Pyranoses and Furanoses
Six-membered monosaccharide ring
compounds are called pyranoses
because they resemble pyran (Fig. 77). Five-membered monosaccharide
ring compounds are called furanoses
because they resemble furan. The
systematic names for the two ring
forms of D-glucose are therefore D-glucopyranose and ß-Dglucopyranose. Ketohexoses such as
fructose also occur as cyclic compounds
with  and ß anomeric forms. In these
compounds the hydroxyl group at C-5
(or C-6) reacts with the keto group at
C-2 forming a furanose (or pyranose,
not shown) ring containing a hemiketal
linkage. D-fructose readily forms a
furanose ring (Fig. 7-7). The more
common anomer of this sugar in
combined forms or in derivatives is ßD-fructofuranose.
Fisher Projection & Haworth Perspective
Cyclic sugar structures are more accurately represented in
Haworth perspective formulas (see below) than in Fischer
projections used for linear sugar structures. In Haworth formulas
the six-membered ring is tilted to make its plane almost
perpendicular to that of the paper. The bonds closest to the
reader are drawn thicker than those farther away. To convert
the Fisher projection formula of any linear D-hexose to a
Haworth perspective formula, draw the six-membered ring (five
carbons, and one oxygen at the upper right), number the carbons
in a clockwise direction beginning with the anomeric carbon, then
add the hydroxyl groups as follows. If a hydroxyl group is to the
right in the Fischer formula, it is placed pointing down in the
Haworth formula. If a hydroxyl group is to the left in the
Fischer formula, then it is placed pointing up in the Haworth
formula. The terminal -CH2OH group
projects upward for the D-enantiomer,
and downward for the L-enantiomer.
When the hydroxyl group on the
anomeric carbon of a D-hexose is on
the same side of the ring as C-6, the
structure is by definition ß. When it is
on the opposite side from C-6, the
structure is .
Worked Example 7-1. Conversion of
Fisher Projection to Haworth Perspective
Conformational Formulas of Pyranoses
It is important to keep in mind the
actual conformational structures of
the ring forms of monosaccharides.
For example the six-membered
pyranose ring is not actually planar,
as suggested by Haworth
representations, but instead tends to
assume either of two chair
conformations (Fig. 7-8). The
interconversion of the two chair
forms (conformers) does not require
bond breakage and does not change
the configurations of substituents
attached to any of the ring carbons.
However, it does require a
considerable input of energy. The
actual three-dimensional structures
of monosaccharide units are important
in determining the biological
properties and functions of some
polysaccharides, as shown below.
Important Hexose Derivatives (I)
In addition to simple hexoses such as glucose, galactose, and
mannose, there are many sugar derivatives in which a hydroxyl
group in the parent compound is replaced with another
substituent, or a carbon atom is oxidized to a carboxyl group. In
addition, hexoses in metabolic pathways commonly are
phosphorylated on hydroxyl groups (Fig. 7-9).
Important Hexose Derivatives (II)
In amino sugars, an -NH2 group replaces one of the -OH groups in
the parent hexose. Substitution of -H for -OH produces a deoxy
sugar, some of which occur in nature as L isomers. The acidic
sugars contain a carboxylate group, which confers a negative
charge at neutral pH. Lactones result from the formation of an
ester linkage between the C-1 carboxylate group and the C-5
hydroxyl group of the sugar. Some notable functions of hexose
derivatives in biology are 1) N-acetylglucosamine and Nacetylmuramic acid, components of the bacterial cell wall; and 2)
N-acetylneuraminic acid (sialic acid) and fucose, components of the
oligosaccharide chains of mammalian glycoproteins.
Measurement of Blood Glucose Level
Monosaccharides can be oxidized by relatively mild oxidizing
agents such as cupric (Cu2+) ion which oxidizes the carbonyl
carbon to a carboxyl group. Glucose and other sugars capable of
this reaction therefore are called reducing sugars. This reaction
(Fehling’s reaction) was used for many years to detect and
monitor glucose levels in people with diabetes mellitus. Today, an
immobilized enzyme (glucose oxidase) on a test strip is used to
catalyze the oxidation of free glucose to D-glucono--lactone
(see below). The hydrogen peroxide H2O2 produced as the second
product of this reaction subsequently reacts with a colorless
compound in the strip via the enzyme peroxidase to form a
colored product which can be quantified using a simple
Hemoglobin Glycation in Diabetes Mellitus
Glucose is a reactive molecule at high
concentrations and its modification of
tissue proteins is thought to be
responsible for the nephropathy,
neuropathy, retinopathy, and
cardiovascular diseases that are
common in diabetics. The nonenzymatic
modification of proteins (at amino
groups) by glucose is referred to as
glycation, and the structures that
result are called advanced glycation end
products (AGEs). Hemoglobin is a
protein that commonly is modified by
glucose at its N-terminal valines or the
-amino groups of its lysine residues
(Box 7-1, Fig. 1). This reaction has
little effect on hemoglobin function, but
it is highly diagnostic of a patient’s
long-term blood glucose level. In
nondiabetics, glycated hemoglobin
makes up about 5% of the total
hemoglobin level. In a poorly-controlled
diabetic, this value may be as high as
13%, indicating an average blood
glucose level of about 300 mg/dl (about
3 times the normal level). Glucoselowering drugs are prescribed to keep
glycated hemoglobin levels at about 7%.
Disaccharides (I)
A disaccharide (e.g., maltose, Fig. 710) is formed from two
monosaccharides (two D-glucose
molecules for maltose) when an -OH
alcohol group of the right D-glucose
condenses with the intramolecular
hemiacetal of the left D-glucose.
Water is eliminated, and a glycoside
with a glycosidic bond is formed. The
reversal of this reaction is hydrolysis
by attack of a water molecule on this
bond--a reaction which is readily
catalyzed using dilute acid. The
oxidation of a sugar by cupric ion
occurs only with its linear form, which
exists in equilibrium with its cyclic
forms. Thus, the anomeric carbon of the D-glucose residue on the
left can no longer react with Cu2+ because it is tied up in a
glycosidic bond. In contrast, the hemiacetal linkage in the right Dglucose molecule can open up, and react with Cu2+. For this reason,
the right end of maltose is called its reducing end. Because
mutarotation interconverts the  and ß forms of the right
hemiacetal linkage, the bonds at this position are sometimes
depicted with wavy lines to indicate that either configuration at
the anomeric carbon is possible. In maltose, the configuration of
the anomeric carbon atom in the glycosidic linkage is .
Disaccharides (II)
The convention for formally naming disaccharides (and
oligosaccharides) is as follows. 1) Start with the configuration (
or ß) at the anomeric carbon joining the first monosaccharide unit
(on the left) to the second. 2) Name the nonreducing residue at
the left; to distinguish five- and six-membered ring structures,
insert “furano” or “pyrano” into the name. 3) Indicate in
parentheses the two carbon atoms joined by the glycosidic bond,
with an arrow connecting the two numbers. In maltose, (14)
shows that C-1 of the first D-glucose unit is joined to C-4 of the
second. 4) Name the second residue. Following this convention,
maltose is -D-glucopyranosyl-(14)-D-glucopyranose. Because
most sugars in the textbook are the D enantiomers and the
pyranose form of hexoses predominates, a shortened version of
the formal name of compounds, such as maltose, can be used which
gives the configuration of the anomeric carbon and names the
carbons joined by the glycosidic bond. In this abbreviated
nomenclature, maltose is Glc(14)Glc. Symbols and abbreviations
for common monosaccharides and some of their derivatives are
listed in Table 7-1 (not covered).
Disaccharides (III)
The chemical structures and full
systematic names of the common
disaccharides, lactose (milk sugar),
sucrose (table sugar), and
trehalose (a sugar occurring in
insect hemolymph) are shown in Fig.
7-11. Lactose is composed of D
galactose and D glucose, sucrose is
composed of D fructose and D
glucose, and trehalose is composed
of two D glucose residues. Lactose
is a reducing sugar, and its
reducing end is located on the
glucose unit on the right. Sucrose
and trehalose are both nonreducing
sugars because the anomeric
carbons of both monosaccharides in
these compounds are tied up in
glycosidic linkages.
Intro. to Polysaccharides
Most carbohydrates found in nature
occur as polysaccharides, polymers of
medium to high molecular weight (Mr
>20,000). Polysaccharides, also called
glycans, differ from each other in the
identity of their recurring
monosaccharide units, in the lengths
of their chains, in the types of bonds
linking the monosaccharide units, and
in the degree of branching.
Homopolysaccharides contain only a
single monomeric species, whereas
heteropolysaccharides contain two or
more different kinds (Fig. 7-12).
Unlike proteins, polysaccharides
generally do not have defined
molecular weights. This is because
polysaccharides are not synthesized
from a template. Instead, there is no
specific stopping point for the
enzymes involved in their biosynthesis.
Starches (I)
Starch is a storage homopolysaccharide of D glucose residues that
is found in the cytoplasm of plant cells. Starch (and glycogen) is
extensively hydrated because it has many exposed hydroxyl groups
available to hydrogen-bond with water. Starches consist of two
types of polymers called amylose and amylopectin (Fig. 7-13).
Amylose (Fig. 7-13a) is a linear polymer of D glucose residues that
all are connected via (14) linkages (as in maltose). The molecular
weights of amylose chains vary from a few thousand to more than a
million. Amylopectin is a branched polymer of D glucose residues
that can weigh up to 200 million Da. The glycosidic linkages
between D glucose residues in amylopectin chains are also (14);
the branch point linkages between D glucose units, however, are
(16) linkages (Fig. 7-13b, next slide). Branch points occur about
every 24 to 30 residues.
Starches (II)
A cluster of amylose and amylopectin molecules, like that believed
to be present in the starch granules in plant cells, is shown in Fig.
7-13c (right). Strands of amylopectin (black) form double-helical
structures with each other or with amylose strands (blue).
Amylopectin has (16) branch points (red). Glucose resides at
the nonreducing ends of the outer branches are removed
enzymatically during the mobilization of starch for energy
production. Glycogen has a structure that is similar to
amylopectin, but is more highly branched and more compact.
Glycogen is the main storage polysaccharide occurring in animal
cells. Its structure is very similar to amylopectin, in that main
chain linkages between D glucose units are (14) and the linkages
at branch points are (16). Branch points occur more frequently
in glycogen (about every 8 to 12 residues) than in amylopectin.
Glycogen is especially abundant in hepatocytes of the liver where it
may constitute as much as 7% of the wet weight of the tissue.
Slightly less glycogen (about 2% by wet weight) is stored in skeletal
muscle cells. Glycogen molecules occur in large granules that can be
observed in the cytoplasm of cells by electron microscopy. A single
glycogen molecule can weigh several million Da. Like amylopectin,
glycogen molecules have many nonreducing ends at the ends of the
branches, but only one reducing end. The enzymes of glycogen
metabolism build up and break down glycogen to glucose units at the
nonreducing ends of the molecule. Simultaneous reactions at the
many nonreducing ends speed up the metabolism of the
polysaccharide. As discussed in Chap. 2, the storage of glucose
units in glycogen molecules has a much smaller osmotic effect on
cells than would the storage of an equivalent amount of glucose as
the free monosaccharide.
Cellulose is a linear homopolysaccharide composed exclusively of D
glucose units held together in (ß14) linkages (Fig. 7-14). A single
chain of cellulose can contain 10-to-15,000 residues. Due to the
presence of ß linkages, cellulose chains fold quite differently than
chains of D glucose in the starches and glycogen (see below).
Cellulose molecules are insoluble in water and form tough fibers.
Cellulose is found in the cell walls of plants, particularly in stalks,
stems, trunks, and all the woody portions of the plant body.
Cellulose constitutes much of the mass of wood, and cotton is
almost pure cellulose. Vertebrate animals lack the hydrolytic
enzymes (cellulases) that can cleave the (ß14) linkages between
glucose units in cellulose. These enzymes are produced by many
cellulolytic microorganisms. These microorganisms, such as
Trichonympha (Fig. 7-15), a symbiotic protist that resides in the
termite gut, allow the host to derive energy from the glucose units
stored in cellulose. Similarly, cellulases produced by microorganisms
living in the rumens of cattle, sheep, and goats allow these animals
to obtain energy from cellulose present in soft grasses in the diet.
Chitin is a linear homopolysaccharide composed of Nacetylglucosamine residues in (ß14) linkage (Fig. 7-16). The only
chemical difference from cellulose is the replacement of the
hydroxyl group at C-2 with an acetylated amino group. Chitin also
forms extended fibers similar to those of cellulose. Like cellulose,
chitin cannot be digested by enzymes found in vertebrates. Chitin
is the principal component of the hard exoskeletons of nearly a
million species of arthropods--insects, lobsters, and crabs, for
example--and is probably the second most abundant polysaccharide
in nature.
Folding of Homopolysaccharides
The folding of polysaccharides in three
dimensions follows the same principles
as those governing the folding of
polypeptides. Weak noncovalent
interactions, particularly hydrogen
bonds between -OH groups, are
important in stabilizing structures. In
addition, rotation about the  and 
bonds adjacent to the oxygen atoms of
glycosidic bonds between
monosaccharide units have steric
constraints as they do for the
comparable bonds on either side of the
 carbons in the polypeptide backbone
(Fig. 7-17). Analogous to polypeptides,
polysaccharides can be represented as
a series of rigid pyranose rings
connected by an oxygen atom bridging
the rings. Certain conformations are
much more stable than others, as can
be shown on a Ramachandran-like plot
of energy as a function of  and 
angles (Fig. 7-18, not covered).
Helical Structure of Starch (Amylose)
The most stable three-dimensional structure for the (14)
linked chains of starch and glycogen is a tightly coiled helix (Fig.
7-19b). The helix is stabilized by interchain hydrogen bonds. The
glucose residues in the chain are also able to form hydrogen
bonds to the surrounding solvent, which keep the polymer in
solution. The average plane of each residue along the amylose
chain forms a 60˚ angle with the average plane of the preceding
residue (Fig. 7-19a), so the helical structure has six residues per
turn. These tightly coiled helical structures produce the dense
granules of stored starch or glycogen seen in many cells.
Interactions Between Cellulose Chains
For cellulose, the most stable
conformation is that in which each chair
is turned 180˚ relative to its neighbors,
yielding a straight extended chain (Fig.
7-17, above). All -OH groups are
available for hydrogen bonding with
neighboring chains. With several chains
lying side by side, a stabilizing network
of interchain and intrachain hydrogen
bonds produces straight, stable
supramolecular fibers of great tensile
strength (Fig. 7-20). The water content
of cellulose fibers is low because
extensive interchain hydrogen bonding
between cellulose molecules satisfies
their capacity for hydrogen bond
The Extracellular Matrix
The extracellular space in the tissues of multicellular animals is
filled with a gel-like material, the extracellular matrix (ECM),
which holds cells together and provides a porous pathway for the
diffusion of nutrients and oxygen to individual cells. The ECM that
surrounds fibroblasts and other connective tissue cells is composed
of an interlocking meshwork of heteropolysaccharides and fibrous
proteins such as fibrillar collagens, elastins, and fibronectins.
These heteropolysaccharides, the glycosaminoglycans, are a family
of linear polymers composed of repeating disaccharide units (next
two slides). They are unique to animals and bacteria and are not
found in plants. One of the two monosaccharides is always either
N-acetylglucosamine or N-acetylgalactosamine. The other
monosaccharide is in most cases a uronic acid, usually D-glucuronic
acid or its 5-epimer, L-iduronic acid. Some glycosaminoglycans
contain sulfate groups attached to hydroxyl groups in ester linkage.
The combination of sulfate groups and the carboxylate groups of
the uronic acids gives glycosaminoglycans a very high density of
negative charge, and an extended rod-like structure in solution.
Glycosaminoglycans are specifically recognized by a number of
proteins that bind them via electrostatic interactions. As discussed
in the 7B lecture slide file, the sulfated glycosaminoglycans are
attached to extracellular proteins to form the proteoglycans.
Glycosaminoglycans (I)
The glycosaminoglycan hyaluronan
(hyaluronic acid) consists of alternating
residues of D-glucuronic acid and Nacetylglucosamine (Fig. 7-22). A single
hyaluronan molecule contains up to 50,000
repeats of this disaccharide unit and has a
molecular weight of several million. It
forms clear, highly viscous solutions that
serve as lubricant in the synovial fluid of
joints and give the vitreous humor of the
vertebrate eye its jellylike consistency.
(The Greek hyalos means “glass”). Hyaluronan is also a component
of the ECM of cartilage and tendons. In many species, a
hyaluronidase enzyme in sperm hydrolyzes an outer
glycosaminoglycan coat around the ovum, allowing sperm entry.
Other glycosaminoglycans differ from hyaluronan in three respects:
they are generally much shorter polymers, they are covalently
linked to specific proteins forming proteoglycans, and one or both
monomeric units differ from those of hyaluronan. Chondroitin
sulfate (Greek, chondros, “cartilage”) is a polymer of repeating Dglucuronic acid and sulfated N-acetylgalactosamine units (Fig. 722). It contributes to the tensile strength of cartilage, tendons,
ligaments, and the wall of the aorta.
Glycosaminoglycans (II)
Keratin sulfates (Greek keras, “horn”)
lack uronic acid and their sulfate content
is variable. The species shown in Fig. 722 is a repeating polymer of D-galactose
and sulfated N-acetylglucosamine
residues. Keratin sulfates are present in
the cornea, cartilage, bone, and a variety
of horny structures formed of dead cells:
horn, hair, hoofs, nails, and claws.
Heparan sulfate (Greek hepar, “liver”) is
produced by all animal cells and contains
variable arrangements of sulfated and
nonsulfated sugars. The species shown in
Fig. 7-22 is a repeating polymer of
sulfated L-iduronate and sulfated
D-glucosamine residues. The sulfated segments of the polymer
allow it to interact with a large number of proteins, including
growth factors and ECM components, as well as various enzymes
and factors present in serum. Heparin is a fractionated form of
heparan sulfate that is a therapeutic agent used to inhibit blood
coagulation. Heparin binds to the protease inhibitor antithrombin,
and causes it to bind to and inhibit thrombin, a protease essential
to blood clotting. Heparin has the highest charge density of any
known biological macromolecule.