–

Lipids are compounds that occur frequently in nature. They are

found in places as diverse as egg yolks and the human nervous system
and are an important component of plant, animal, and microbial
membranes. The definition of a lipid is based on solubility. Lipids are
marginally soluble (at best) in water but readily soluble in organic
solvents, such as chloroform or acetone.
Fats and oils are typical lipids in terms of their solubility, but that
fact does not really define their chemical nature. In terms of chemistry,
lipids are a mixed bag of compounds that share some properties based
on structural similarities, mainly a preponderance of nonpolar groups.
Classified according to their chemical nature, lipids fall into two
main groups. One group, which consists of open-chain compounds
with polar head groups and long nonpolar tails, includes fatty acids,
triacylglycerols, sphingolipids, phosphoacylglycerols, and glycolipids. The sec-
ond major group consists of fused-ring compounds, the steroids; an
important representative of this group is cholesterol.

A fatty acid has a carboxyl group at the polar end and a hydrocarbon
chain at the nonpolar tail. Fatty acids are amphipathic compounds be-
cause the carboxyl group is hydrophilic and the hydrocarbon tail is hy-
drophobic. The carboxyl group can ionize under the proper conditions.
A fatty acid that occurs in a living system normally contains an even
number of carbon atoms, and the hydrocarbon chain is usually un-
branched (Figure 8.1). If there are carbon–carbon double bonds in the
chain, the fatty acid is unsaturated; if there are only single bonds, the fatty
acid is saturated. Tables 8.1 and 8.2 list a few examples of the two classes.
In unsaturated fatty acids, the stereochemistry at the double bond is
usually cis rather than trans. The difference between cis and trans fatty
acids is very important to their overall shape. A cis double bond puts a

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 O OH O OH O OH O OH
C C C C
CH2
H2C
CH2
H2C
CH2
H2C
CH2
H2C
CH2 Palmitic acid Stearic acid Oleic acid
H2C
CH2
H2C
CH2
H2C
CH3

O OH O OH O OH
C C C

Linoleic acid -Linolenic acid Arachidonic acid

amphipathic refers to a molecule that has one

end with a polar, water-soluble group and another
end with a nonpolar hydrocarbon group that is
insoluble in water
Lauric 12 CH3(CH2)10CO2H 44
Myristic 14 CH3(CH2)12CO2H 58
Palmitic 16 CH3(CH2)14CO2H 63
Stearic 18 CH3(CH2)16CO2H 71
Arachidic 20 CH3(CH2)18CO2H 77

kink in the long-chain hydrocarbon tail, whereas the shape of a trans fatty acid is
like that of a saturated fatty acid in its fully extended conformation. Note that the
double bonds are isolated from one another by several singly bonded carbons;
fatty acids do not normally have conjugated double-bond systems. The notation
used for fatty acids indicates the number of carbon atoms and the number of
double bonds. In this system, 18:0 denotes an 18-carbon saturated fatty acid with
no double bonds, and 18:1 denotes an 18-carbon fatty acid with one double bond.
Note that in the unsaturated fatty acids in Table 8.2 (except arachidonic acid),

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 9
Palmitoleic 16 16:1— CH3(CH2)5CH CH(CH2)7CO2H 0.5
9
Oleic 18 18:1— CH3(CH2)7CH CH(CH2)7CO2H 16
9,12
Linoleic 18 18:2— CH3(CH2)4CH CH(CH2)CH CH(CH2)7CO2H 5
9,12,15
Linolenic 18 18:3— CH3(CH2CH CH)3(CH2)7CO2H 11
5,8,11,14
Arachidonic 20 20:4— CH3(CH2)4CH CH(CH2)4(CH2)2CO2H 50

there is a double bond at the ninth carbon atom from the carboxyl end. The posi-
tion of the double bond results from the way unsaturated fatty acids are synthesized
in organisms (Section 21-6). Unsaturated fatty acids have lower melting points than
saturated ones. Plant oils are liquid at room temperature because they have higher
proportions of unsaturated fatty acids than do animal fats, which tend to be solids.
Conversion of oils to fats is a commercially important process. It involves hydro-
genation, the process of adding hydrogen across the double bond of unsaturated
fatty acids to produce the saturated counterpart. Oleomargarine, in particular, uses
partially hydrogenated vegetable oils, which tend to include trans fatty acids (see
Biochemical Connections 8A).
Fatty acids are rarely found free in nature, but they form parts of many
commonly occurring lipids.

Glycerol is a simple compound that contains three hydroxyl groups (Figure 8.2). glycerol a three-carbon compound that contains
When all three of the alcohol groups form ester linkages with fatty acids, the three hydroxyl groups, one bound to each carbon
resulting compound is a triacylglycerol; an older name for this type of com- triacylglycerol a lipid formed by esterification of
pound is triglyceride. Note that the three ester groups are the polar part of the three fatty acids to glycerol; also called a triglyceride
molecule, whereas the tails of the fatty acids are nonpolar. It is usual for three
different fatty acids to be esterified to the alcohol groups of the same glycerol
molecule. Triacylglycerols do not occur as components of membranes (as do
other types of lipids), but they accumulate in adipose tissue (primarily fat cells)
and provide a means of storing fatty acids, particularly in animals. They serve
as concentrated stores of metabolic energy. Complete oxidation of fats yields

H2C CH CH2 H2C CH CH2 H2C CH CH2

HO OH OH O O O O O O
Charles Grisham, University of Virginia

Charles Grisham, University of Virginia

Glycerol O C C O C O O C C O C O

Myristic Palmitoleic

Stearic
Tristearin
(a simple triacylglycerol) A mixed triacylglycerol

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 about 9 kcal g 1, in contrast with 4 kcal g 1 for carbohydrates and proteins (see
Sections 21-3 and 24-2).
When an organism uses fatty acids, the ester linkages of triacylglycerols are
lipases enzymes that hydrolyze lipids hydrolyzed by enzymes called lipases. The same hydrolysis reaction can take
place outside organisms, with acids or bases as catalysts. When a base such as
sodium hydroxide or potassium hydroxide is used, the products of the reac-
tion, which is called saponification (Figure 8.3), are glycerol and the sodium or
potassium salts of the fatty acids. These salts are soaps. When soaps are used
O
with hard water, the calcium and magnesium ions in the water react with the
fatty acids to form a precipitate—the characteristic scum left on the insides of
H2CO C R1 sinks and bathtubs. The other product of saponification, glycerol, is used in
O creams and lotions as well as in the manufacture of nitroglycerin.

HCO C R2

O It is possible for one of the alcohol groups of glycerol to be esterified by a

H2CO C R3
phosphoric acid molecule rather than by a carboxylic acid. In such lipid mol-
ecules, two fatty acids are also esterified to the glycerol molecule. The resulting
Enzymatic Saponification compound is called a phosphatidic acid (Figure 8.4A). Fatty acids are usually
hydrolysis monoprotic acids with only one carboxyl group able to form an ester bond, but
phosphoric acid is triprotic and thus can form more than one ester linkage.
H2O, Lipases Aqueous NaOH
One molecule of phosphoric acid can form ester bonds both to glycerol and to
some other alcohol, creating a phosphatidyl ester (Figure 8.4B).
Glycerol Glycerol
Phosphatidyl esters are classed as phosphoacylglycerols. The natures of the
fatty acids vary widely, as they do in triacylglycerols. As a result, the names of
R1COO– R1COO– Na+
the types of lipids (such as triacylglycerols and phosphoacylglycerols) that con-
+ + tain fatty acids must be considered generic names.
–
R2COO R2COO– Na+ The classification of a phosphatidyl ester depends on the nature of the sec-
+ + ond alcohol esterified to the phosphoric acid. Some of the most important
R3COO –
R3COO– Na+ lipids in this class are phosphatidyl ethanolamine (cephalin), phosphatidyl serine,
Ionized Sodium salt phosphatidyl choline (lecithin), phosphatidyl inositol, phosphatidyl glycerol, and di-
fatty acid of fatty acid phosphatidyl glycerol (cardiolipin) (Figure 8.5). In each of these types of com-
pounds, the nature of the fatty acids in the molecule can vary widely. All these
compounds have long, nonpolar, hydrophobic tails and polar, highly hydro-
philic head groups and thus are markedly amphipathic. (We have already
seen this characteristic in fatty acids.) In a phosphoacylglycerol, the polar
head group is charged, because the phosphate group is ionized at neutral pH.

O O

H2COCR1 CH2OC(CH2)16CH3
O Stearyl group
O

HCOCR2 HCOC(CH2)7CH CHCH2CH CH(CH2)4CH3

Linoleyl group
O O

CH2O P OH CH2O POR

–
O O–
Phosphatidic acid Phosphatidyl ester

phosphatidic acid a compound in which two fatty

A A phosphatidic acid, in which glycerol B A phosphatidyl ester (phosphoacylglycerol).
acids and phosphoric acid are esterified to the
is esterified to phosphoric acid and to Glycerol is esterfied to two carboxylic acids,
three hydroxyl groups of glycerol two different carboxylic acids. R1 and stearic acid and linoleic acid, as well as to
phosphoaclyglycerol a phosphatidic acid with R2 represent the hydrocarbon chains phosphoric acid. Phosphoric acid, in turn,
of the two carboxylic acids. is esterified to a second alcohol, ROH.
another alcohol esterified to the phosphoric acid
moiety

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 O

C O
CH2
O

C O C H
O CH3

CH2 O P O CH2CH2 N + CH3

Phosphatidylcholine O– CH3

GLYCEROLIPIDS WITH OTHER HEAD GROUPS:

O O
+
O P O CH2CH2 NH3 O P O CH2

O– O–
H C OH
Phosphatidylethanolamine
O

O P O CH2
O COO–
O–
O P O CH2 CH
Diphosphatidylglycerol (Cardiolipin)
+
O– NH3
H OH
Phosphatidylserine
H H
OH H
H HO
O HO OH
O
H
O P O CH2 CH CH2 O P O

O– OH OH O–
Phosphatidylglycerol Phosphatidylinositol

A positively charged amino group is also frequently contributed by an amino

alcohol esterified to the phosphoric acid. Phosphoacylglycerols are important
components of biological membranes.

Waxes are complex mixtures of esters of long-chain carboxylic acids and long- waxes mixtures of esters of long-chain carboxylic
chain alcohols. They frequently serve as protective coatings for both plants acids and long-chain alcohols
and animals. In plants, they coat stems, leaves, and fruit; in animals, they are

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 O found on fur, feathers, and skin. Myricyl cerotate (Figure 8.6), the principal
component of carnauba wax, is produced by the Brazilian wax palm. Carnauba
CH3 (CH2)24 C O (CH2)29 CH3
wax is extensively used in floor wax and automobile wax. The principal compo-
Myricyl cerotate
nent of spermaceti, a wax produced by whales, is cetyl palmitate (Figure 8.6).
The use of spermaceti as a component of cosmetics made it one of the most
O highly prized products of 19th-century whaling efforts.
CH3 (CH2)14 C O (CH2)15 CH3 Sphingolipids do not contain glycerol, but they do contain the long-chain
amino alcohol sphingosine, from which this class of compounds takes its name
Cetyl palmitate
(Figure 8.6). Sphingolipids are found in both plants and animals; they are
particularly abundant in the nervous system. The simplest compounds of this
class are the ceramides, which consist of one fatty acid linked to the amino
CH CH(CH2)12CH3 CH CH(CH2)12CH3 group of sphingosine by an amide bond (Figure 8.6). In sphingomyelins, the
CHOH CHOH
primary alcohol group of sphingosine is esterified to phosphoric acid, which,
in turn, is esterified to another amino alcohol, choline (Figure 8.6). Note the
CHNH2 O structural similarities between sphingomyelin and other phospholipids. Two
From
CH2OH CHNHCR fatty long hydrocarbon chains are attached to a backbone that contains alcohol
acid groups. One of the alcohol groups of the backbone is esterified to phosphoric
CH2OH acid. A second alcohol—choline, in this case—is also esterified to the phos-
Sphingosine A ceramide phoric acid. We have already seen that choline occurs in phosphoacylglycer-
(N-acylsphingosine)
ols. Sphingomyelins are amphipathic; they occur in cell membranes in the
nervous system.
CH CH(CH2)12CH3

CHOH

O If a carbohydrate is bound to an alcohol group of a lipid by a glycosidic link-

CHNHCR
age (see Section 16-2 for a discussion of glycosidic linkages), the resulting com-
pound is a glycolipid. Quite frequently, ceramides (see Figure 8.6) are the parent
O compounds for glycolipids, and the glycosidic bond is formed between the pri-
+
CH2OPOCH2CH2N(CH3)3 mary alcohol group of the ceramide and a sugar residue. The resulting com-
pound is called a cerebroside. In most cases, the sugar is glucose or galactose; for
O– example, a glucocerebroside is a cerebroside that contains glucose (Figure 8.7).
A sphingomyelin As the name indicates, cerebrosides are found in nerve and brain cells, primarily
in cell membranes. The carbohydrate portion of these compounds can be very
complex. Gangliosides are examples of glycolipids with a complex carbohydrate
moiety that contains more than three sugars. One of them is always a sialic acid
CH CH(CH2)12CH3 (Figure 8.8). These compounds are also referred to as acidic glycosphingolipids
because of their net negative charge at neutral pH. Glycolipids are often found
H C OH as markers on cell membranes and play a large role in tissue and organ spec-
O
ificity. Gangliosides are also present in large quantities in nerve tissues. Their
HOCH2
H C N CR biosynthesis and breakdown are discussed in Section 21-7.
H
H O CH2
H
OH H
Many compounds of widely differing functions are classified as steroids be-
HO H cause they have the same general structure: a fused-ring system consisting of
H OH
three six-membered rings (the A, B, and C rings) and one five-membered ring
(the D ring). There are many important steroids, including sex hormones.
A glucocerebroside
(See Section 24-3 for more steroids of biological importance.) The steroid that
is of most interest in our discussion of membranes is cholesterol (Figure 8.9).
The only hydrophilic group in the cholesterol structure is the single hydroxyl
sphingolipids lipids whose structure is based on group. As a result, the molecule is highly hydrophobic. Cholesterol is wide-
sphingosine spread in biological membranes, especially in animals, but it does not occur
sphingomyelins compounds in which the primary in prokaryotic cell membranes. The presence of cholesterol in membranes
alcohol of sphingosine is esterified to phosphoric can modify the role of membrane-bound proteins. Cholesterol has a num-
acid, which is also esterified to another amino alcohol ber of important biological functions, including its role as a precursor of
glycolipid a lipid to which a sugar moiety is other steroids and of vitamin D 3. We will see a five-carbon structural motif
bonded (the isoprene unit) that is common to steroids and to fat-soluble vitamins,

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 GM1

GM2

GM3
N-Acetyl-
D-Galactose D-galactosamine D-Galactose D-Glucose

CH2OH CH2OH CH2OH CH2OH

HO O HO O O H O
H H O H H
OH H H H O OH H
H H H H H H H
H OH O H NH H OH H OH
O C OH H O
CH3 H O
O H C C CH2
O H
H
CH3 C N CHOH COO– C NH
CHOH C
C O
CH2OH H
H
H H R

OH H
N-Acetylneuraminidate
(sialic acid)

Gangliosides GM1,GM2, and GM3 Gangliosides

CH3
CHCH2CH2CH2CH(CH3)2
12 H3C
17
11
H
13
A 1 C D 16 B H3C H
9
2 14 15
10 8 H H
A B
3 5 7 HO
4 6 H Cholesterol

H3C

C O
CH3 OH CH3 OH CH3

C H3C H3C

O HO O
Testosterone Estradiol Progesterone

ceramides lipids that contain one fatty acid linked

to sphingosine by an amide bond

cerebroside a glycolipid that contains sphingosine

which is an indication of their biosynthetic relationship (Sections 8-6 and and a fatty acid in addition to the sugar moiety
21-8). However, cholesterol is best known for its harmful effects on health steroids lipids with a characteristic fused-ring
when it is present in excess in the blood. It plays a role in the development of structure
atherosclerosis, a condition in which lipid deposits block the blood vessels and cholesterol a steroid that occurs in cell
lead to heart disease (see Section 21-8). membranes; the precursor of other steroids

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 Every cell has a cell membrane (also called a plasma membrane); eukaryotic cells
also have membrane-enclosed organelles, such as nuclei and mitochondria. The
molecular basis of the membrane’s structure lies in its lipid and protein compo-
nents. Now it is time to see how the interaction between the lipid bilayer and mem-
brane proteins determines membrane function. Membranes not only separate cells
from the external environment, but also play important roles in the transport of
specific substances into and out of cells. In addition, a number of important en-
zymes are found in membranes and depend on this environment for their function.
Phosphoglycerides are prime examples of amphipathic molecules, and they are
the principal lipid components of membranes. The existence of lipid bilayers
depends on hydrophobic interactions, as described in Section 4-6. These bi-
layers are frequently used as models for biological membranes because they
have many features in common, such as a hydrophobic interior and an ability
to control the transport of small molecules and ions, but they are simpler and
easier to work with in the laboratory than biological membranes.
The most important difference between lipid bilayers and cell membranes
is that the latter contain proteins as well as lipids. The protein component of a
membrane can make up from 20% to 80% of its total weight. An understand-
ing of membrane structure requires knowledge of how the protein and lipid
components contribute to the properties of the membrane.

Biological membranes contain, in addition to phosphoglycerides, glycolipids

lipid bilayer an aggregate of a lipid molecule in as part of the lipid component. Steroids are present in eukaryotes—cholesterol
which the polar head groups are in contact with in animal membranes and similar compounds, called phytosterols, in plants.
water and the hydrophobic parts are not In the lipid bilayer part of the membrane (Figure 8.10), the polar head groups

Hydrophilic
surfaces

Hydrophobic
A tails

Hydrophilic
surfaces

Inner aqueous compartment

“ ”

Hydrophobic
Hydrophilic tails
surfaces

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 +
– Outer
– HO

+
–
+
–

HO
+
–
–
– Inner
+ + +
– + –
–
+
+ –
+ + –
– – –
+
+
– –
+ +
– –
+
+
– –
+
– + Sphingomyelin
OH
Cerebroside
– +
+ –
+ – Ganglioside
– –
Phosphoacylglycerol
– +
+
– –
+ Cholesterol

–
+
e
hob ic cor
ydrop
olar h 5–40Å
Nonp 3

are in contact with water, and the nonpolar tails lie in the interior of the mem-
brane. The whole bilayer arrangement is held together by noncovalent inter-
actions, such as van der Waals and hydrophobic interactions (Section 2-1).
The surface of the bilayer is polar and contains charged groups. The nonpolar
hydrocarbon interior of the bilayer consists of the saturated and unsaturated
chains of fatty acids and the fused-ring system of cholesterol.
Both the inner and outer layers of the bilayer contain mixtures of lipids, but
their compositions differ and can be used to distinguish the inner and outer
layers from each other (Figure 8.11). Bulkier molecules tend to occur in the
outer layer, and smaller molecules tend to occur in the inner layer.
Table 8.3 shows the lipid composition of various types of membranes in rat
liver cells. Note that the distribution of major lipid types such as phosphatidyl-
choline, phosphatidylethanolamine, and cholesterol varies widely.

The arrangement of the hydrocarbon interior of the bilayer can be ordered

and rigid or disordered and fluid. The bilayer’s fluidity depends on its compo-
sition. In saturated fatty acids, a linear arrangement of the hydrocarbon chains
leads to close packing of the molecules in the bilayer, and thus to rigidity.
Unsaturated fatty acids have a kink in the hydrocarbon chain that does not exist
in saturated fatty acids (Figure 8.12). The kinks cause disorder in the packing
of the chains, which makes for a more open structure than would be possible
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 Phosphatidylcholine 49 42 38 27 28
Phosphatidylethanolamine 13 17 34 9 16
Sphingolipids 3 7 0 13 12
Phosphatidylinositol 10 10 5 3 6
Phosphatidylserine 3 5 0 0 6
Cardiolipin 3 0 17 0 0
Minor lipids 4 3 0 0 0
Cholesterol 15 17 4 33 28

for straight saturated chains (Figure 8.13). In turn, the disordered structure
Saturated Unsaturated
caused by the presence of unsaturated fatty acids with cis double bonds (and
Polar therefore kinks) in their hydrocarbon chains causes greater fluidity in the bi-
head
layer. The lipid components of a bilayer are always in motion, to a greater ex-
tent in more fluid bilayers and to a lesser extent in more rigid ones.
One
double The presence of cholesterol may also enhance order and rigidity. The fused-
bond ring structure of cholesterol is itself quite rigid, and the presence of cholesterol
stabilizes the extended straight-chain arrangement of saturated fatty acids by
van der Waals interactions (Figure 8.14). The lipid portion of a plant mem-
Hydrocarbon Two brane has a higher percentage of unsaturated fatty acids, especially polyunsatu-
tail double bonds rated (containing two or more double bonds) fatty acids, than does the lipid
portion of an animal membrane. Furthermore, the presence of cholesterol
is characteristic of animal, rather than plant, membranes. As a result, animal
membranes are less fluid (more rigid) than plant membranes, and the mem-
branes of prokaryotes, which contain no appreciable amounts of steroids, are
the most fluid of all. Research suggests that plant sterols can act as natural cho-
lesterol blockers, interfering with the uptake of dietary cholesterol.

CH3 CH3
CH3
CH3
HO CH3

O Polar head group

C CH3
–O
Hydrocarbon tail

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 Heat

Gel Liquid crystal

With heat, ordered bilayers become less ordered; bilayers that are compara-
tively disordered become even more disordered. This cooperative transition
takes place at a characteristic temperature, like the melting of a crystal, which
is also a cooperative transition (Figure 8.15). The transition temperature is
higher for more rigid and ordered membranes than it is for relatively fluid and
disordered membranes. A powerful method called differential scanning calo-
rimetry (DSC) makes it possible to obtain information about phase transitions
in lipid bilayers. A DSC instrument has a sample cell for the bilayer and a refer-
ence cell containing a standard that will not undergo a phase transition. The
two cells are maintained at a given temperature that is increased in a controlled
fashion by passing an electric current through the cells. When a phase transi-
tion takes place, a different amount of power is needed to maintain the temper-
ature in the two cells. This amount of power can be measured and converted to
a graph that gives information about both the transition temperature and the
amount of energy needed to bring about the phase transition.
looks at some connections between the fatty acid composi-
tion of bilayers and membranes and how they behave at different temperatures.

—
e use the terms animal “fats” and plant “oils” because of Because cardiovascular disease is correlated with diets high
the solid and fluid nature of these two groups of lipids. The in saturated fats, a diet of more unsaturated fats may reduce the
major difference between fats and oils is the percentage of unsat- risk of heart attacks and strokes. Canola oil is an attractive dietary
urated fatty acids in the triglycerides and the phosphoglycerides choice because it has a high ratio of unsaturated fatty acids to satu-
of membranes. This difference is far more important than the rated fatty acids. Since the 1960s, we have known that foods higher
fact that the length of the fatty acid chain can affect the melting in polyunsaturated fats were healthier. Unfortunately, even though
points. Butter is an exception; it has a high proportion of short- olive oil is popular in cooking Italian food and canola oil is trendy
chain fatty acids and thus can “melt in your mouth.” Membranes for other cooking, pouring oil on bread or toast is not appealing.
must maintain a certain degree of fluidity to be functional. Con- Thus companies began to market butter substitutes that were based
sequently, unsaturated fats are distributed in varying proportions on unsaturated fatty acids but that would also have the physical char-
in different parts of the body. The membranes of internal organs acteristics of butter, such as being solid at room temperature. They
of warm-blooded mammals have a higher percentage of saturated accomplished this task by partially hydrogenating the double bonds
fats than do the membranes of skin tissues, which helps keep the in the unsaturated fatty acids making up the oils. The irony here is
membrane more solid at the higher temperature of the internal or- that, to avoid eating the saturated fatty acids in butter, butter sub-
gan. An extreme example of this is found in the legs and the body stitutes were created from polyunsaturated oils by removing some
of reindeer, where marked differences exist in the percentages of of the double bonds, thus making them more saturated. In addition,
saturated fatty acids. many of the soft spreads that are marketed as being healthy (safflower
When bacteria are grown at different temperatures, the fatty acid oil spread and canola oil spread) may indeed pose new health risks.
composition of the membranes changes to reflect more unsaturated In the hydrogenation process, some double bonds are converted to
fatty acids at lower temperatures and more saturated fatty acids at the trans form. Studies now show that trans fatty acids raise the ratio of
higher temperatures. The same type of difference can be seen in eu- LDL (low-density lipoprotein) cholesterol compared to HDL (high-
karyotic cells grown in tissue culture. density lipoprotein) cholesterol, a positive correlator of heart disease.
Even if we look at plant oils alone, we find different proportions Thus the effects of trans fatty acids are similar to those of saturated
of saturated fats in different oils. Table 8.4 gives the distribution for a fatty acids. In the last few years, however, new butter substitutes have
tablespoon (14 g) of different oils. been marketed that advertise “no trans fatty acids.”

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 Tropical oils Coconut oil 13 0.7 0.3
Semitropical oils Peanut oil 2.4 6.5 4.5
Olive oil 10.3 1.3
Temperate oils Canola oil 1 8.2 4.1
Safflower oil 1.3 1.7 10.4
Animal fat Lard 5.1 5.9 1.5
Butter 9.2 4.2 0.6

A y Recall that the distribution of lipids is not the same in the inner and outer
F PSF
portions of the bilayer. Because the bilayer is curved, the molecules of the inner
layer are more tightly packed (refer to Figure 8.11). Bulkier molecules, such as
cerebrosides (see Section 8-2), tend to be located in the outer layer. There is very
little tendency for “flip-flop” migration of lipid molecules from one layer of the
x
bilayer to another, but it does occur occasionally. Lateral motion of lipid mole-
cules within one of the two layers frequently takes place, however, especially in
B more fluid bilayers. Several methods exist for monitoring the motions of mole-
F2 y cules within a lipid bilayer. One of the most powerful ways uses fluorescence spec-
F1 troscopy. This method makes use of the fact that some molecules absorb light of
a given wavelength and then re-emit light of another, longer wavelength. Lipid
molecules are not themselves fluorescent, but they can be “tagged” with groups
x that are. Fluorescence can be detected even at very low levels. This fact makes
it possible to use the technique as the basis of fluorescence microscopy, which
will detect the tagged moieties in bilayers. There are many variations in detection
techniques, but in all cases they are based on the re-emitted fluorescent light. The
use of fluorescence can be expanded in studies on actual membranes rather than
bilayers. Membranes contain proteins in addition to the lipid bilayer. The side
chains of tryptophan and tyrosine have intrinsic fluorescence, and this property
can be used to obtain information about the protein portion of the membrane.
Fluorescence spectroscopy is so sensitive that it can be used to detect informa-
tion about single molecules. As shown in Figure 8.16A, a single macromolecule can
be labeled with a fluorescent moiety (the fluorophore, marked F in the figure).
The fluorescent signal is monitored in two dimensions on the oriented sample.
It becomes possible to localize the fluorophore in the molecule. “PSF” stands for
point-spread function, the error of estimate. In Figure 8.16B, two independent fluo-
rophores are present. The distance between them can be determined by subtracting
the distance between the centers of their PSFs.
discusses another application of the physical properties of membranes.

etting a drug to a place where it can be most effective is of obvious form layered structures, and these structures are the key point in de-
importance, with enormous commercial ramifications. A num- veloping a delivery system. In Chapter 2, we saw how amphipathic
ber of technologies have been applied to the task. They include injec- molecules such as fatty acids can form micelles, which are assemblages
tions, topical application to the skin, and implants. Most importantly with a single layer of fatty acids, with the nonpolar tails in the middle
for our purposes, they take advantage of the properties of membranes sequestered from water and the polar heads in contact with water
and model systems for membranes. We have seen how lipid molecules (Figure 2.7). Nonpolar substances can be packaged in micelles for

Copyright 2018 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. WCN 02-200-203
delivery where desired. In Chapter 4 and earlier in this chapter, we saw When the magnetic field is removed, the particles cool down, the gel
lipid bilayers (Figure 8.10) with a polar surface and interior and non- expands, and the channels are resealed.
polar portions of the component molecules sandwiched in between. It One of the first suggested uses for this technology is for
is also possible to construct multilayered lipid vesicles. patient-controlled administration of painkillers, but many more ap-
Because the driving force behind the formation of lipid bilayers plications can be expected as time goes on.
is the exclusion of water from the hydrophobic region of lipids, This example of using a synthetic membrane for drug delivery
and not some enzymatic process, artificial membranes can be cre- is but one research result in a very active field. Natural and syn-
ated in the lab. Liposomes are stable structures based on a lipid thetic membranes are being tested, with methods of controlling
bilayer that form a spherical vesicle. These vesicles can be prepared pore size as an important consideration. It is no surprise that the
with therapeutic agents on the inside and then used to deliver the National Institute of Health supports much of this work. Descrip-
agent to a target tissue. tions of many systems can be found at the Pubmed Website (www
To carry the process even further, vesicles can be prepared with .[Link]/pubmed/). We can expect to see many new
embedded artificial substances that can be used to control the pro- ways of drug delivery as time goes on.
cess of release of the therapeutic agent. Some of the embedded

Reprinted with permission from Nano Letters (September, 2009). Hoare,

T., Santamaria, J., Goya, G. F., Irusta, S., Lin, D., Lau, S., Padera, R.,Langer,
R., Kohane, D. S. A magnetically triggered composite membrane for on-
substances can be used to create an “on–off” switch for drug deliv-

demand drug delivery. Copyright © 2009 American Chemical Society.

ery. A recent report from researchers at Harvard Medical School
describes one such delivery process. Strong ux
Minimal or
Bilayers were prepared that were embedded with nanogels of no ux
a synthetic polymer. This polymer, poly(N-isopropylacrylamide)
(PNIPAM), forms a hydrogel that is swollen in its native state NP
NP NP NP
but collapses on heating. This polymer is similar to the poly- NP NP

Membrane
NP
acrylamide that is the basis of gels used in electrophoresis. A big
Nanogel NP
difference is that this application is a safe use of the material. NP
Heat
Acrylamides used for electrophoresis are neurotoxic. The size of
NP
the nanogels in their native state exactly matched the width of the NP NP NP NP NP
membrane. In addition, nanoparticles of magnetite (iron oxide)
were embedded in the membrane matrix. Drug Reservoir
When a magnetic field is applied, the magnetite particles
heat up, leading to a rise in temperature of a few degrees in the
PNIPAM. The hydrogel contracts, but the surrounding mem-
brane does not. The result is that channels are formed that allow
passage of a drug from one side of the membrane to the other.

liposomes spherical aggregates of lipids arranged

so that the polar head groups are in contact with
water and the nonpolar tails are sequestered from
water
Proteins in a biological membrane can be associated with the lipid bilayer in
either of two ways—as peripheral proteins on the surface of the membrane or peripheral proteins proteins loosely bound to the
as integral proteins within the lipid bilayer (Figure 8.18). Note that the inte- outside of a membrane
gral protein rhodopsin (shown in purple) consists mostly of helical portions integral proteins proteins embedded in a
that span the membrane. The peripheral G protein is a trimer. The three differ- membrane
ent subunits are shown in red, yellow, and blue. Peripheral proteins are usually
bound to the charged head groups of the lipid bilayer by polar interactions,
electrostatic interactions, or both. They can be removed by such mild treatment
as raising the ionic strength of the medium. The relatively numerous charged
particles present in a medium of higher ionic strength undergo more electro-
static interactions with the lipid and with the protein, “swamping out” the com-
paratively fewer electrostatic interactions between the protein and the lipid.
Removing integral proteins from membranes is much more difficult.
Harsh conditions, such as treatment with detergents or extensive sonication
(exposure to ultrasonic vibrations), are usually required. Such measures fre-
quently denature the protein, which often remains bound to lipids in spite
of all efforts to obtain it in pure form. The denatured protein is, of course,
inactive, whether or not it remains bound to lipids. Fortunately, nuclear
magnetic resonance techniques enable researchers to study proteins of this

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 Rhodopsin
Membrane

a
b

Heterotrimeric G protein

sort in living tissue or in reconstituted membranes. The structural integrity of

the whole membrane system appears to be necessary for the activities of most
membrane proteins.
Proteins can be attached to the membrane in a variety of ways. When a pro-
tein completely spans the membrane, it is often in the form of an -helix or
-sheet. These structures minimize contact of the polar parts of the peptide
backbone with the nonpolar lipids in the interior of the bilayer. Proteins can
also be anchored to the lipids via covalent bonds from cysteines or free amino
groups on the protein to one of several lipid anchors. Myristoyl and palmitoyl
groups are common anchors (Figure 8.19).
Membrane proteins have a variety of functions. Most, but not all, of the
important functions of the membrane as a whole are those of the protein

NH3+
Extracellular
side

C C
O O Cytoplasmic
HN S
side

O CH2 CH2
C

–
–OOC

COO–

N–Myristoylation S–Palmitoylation

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component. Transport proteins help move substances in and out of the cell, transport proteins components of a membrane
and receptor proteins are important in the transfer of extracellular signals, that mediate the entry of specific substances into
a cell
such as those carried by hormones or neurotransmitters, into the cell. In ad-
dition, some enzymes are tightly bound to membranes; examples include receptor proteins proteins on a cell membrane
many of the enzymes responsible for aerobic oxidation reactions, which are with specific binding sites for extracellular
substances
found in specific parts of mitochondrial membranes. Some of these enzymes
are on the inner surface of the membrane, and some are on the outer sur-
face. There is an uneven distribution of proteins of all types on the inner and
outer layers of all cell membranes, just as there is an asymmetric distribution
of lipids.

We have seen that biological membranes have both lipid and protein compo-
nents. How do these two parts combine to produce a biological membrane?
Currently, the fluid-mosaic model is the most widely accepted description of fluid-mosaic model the model for membrane
biological membranes. The term mosaic implies that the two components exist structure in which proteins and a lipid bilayer exist
side by side without forming some other substance of intermediate nature. The side by side without covalent bonds between the
proteins and lipids
basic structure of biological membranes is that of the lipid bilayer, with the
proteins embedded in the bilayer structure (Figure 8.20). As time goes on, it is
becoming apparent that preferential association can take place among sphin-
golipids, sterols, and membrane proteins. Lipids are sorted into assemblages
known as rafts, which become the fundamental building blocks on which mem-
brane specificity is based.
Membrane proteins tend to have a specific orientation in the membrane.
The term fluid mosaic implies that the same sort of lateral motion that we have
already seen in lipid bilayers also occurs in membranes. The proteins “float” in
the lipid bilayer and can move along the plane of the membrane.
Electron micrographs can be made of membranes that have been frozen
and then fractured along the interface between the two layers. The outer
layer is removed, exposing the interior of the membrane. The interior has
a granular appearance because of the presence of the integral membrane

Integral Outside cell

proteins Carbohydrate
groups Integral
proteins

Glycolipid

Plasma membrane

Gate Cholesterol Integral protein

(transport protein)

Integral protein Peripheral Glycoprotein Peripheral protein Peripheral

proteins protein
Cytosol

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 Freeze Fracture Purpose: Quick-frozen cells are fractured to split apart lipid bilayers for analysis
of the membrane interior.
Protocol:

The specimen is frozen quickly in liquid nitrogen The fracture may travel over membrane surfaces as it passes through the
1 2 specimen, or it may split membrane bilayers into inner and outer halves
and then fractured by a sharp blow by a knife edge.
as shown here.

Knife edge Ice

Outer membrane

Don W. Fawcett/Science Source

surface
Interpreting the Results: The image of a freeze-fractured plasma membrane is Exposed membrane
visualized using the electron microscope. The particles visible in the exposed interior
membrane interior are integral membrane proteins.
Ice surface

proteins (Figure 8.21). In addition to electron microscopy, atomic force

microscopy can provide useful and informative images of membranes. The
two methods differ in the physical principle on which the imaging process
is based. The usual electron microscopy depends on scattering of a beam of
electrons from the surface of the sample. In atomic force microscopy, the
sample surface is scanned using a cantilever with a sharp tip. Electrical mea-
surements determine the force generated between the tip and the sample
surface, which generates the image.

As already mentioned, three important functions take place in or on mem-

branes (in addition to the structural role of membranes as the boundaries
and containers of all cells and of the organelles within eukaryotic cells). The
first of these functions is transport. Membranes are semipermeable barri-
ers to the flow of substances into and out of cells and organelles. Transport
through the membrane can involve the lipid bilayer as well as the membrane
proteins. The other two important functions primarily involve the membrane
proteins. One of these functions is catalysis. As we have seen, enzymes can be
bound—in some cases very tightly—to membranes, and the enzymatic reac-
tion takes place on the membrane. The third significant function is the recep-
tor property, in which proteins bind specific biologically important substances
that trigger biochemical responses in the cell. We shall discuss enzymes bound
to membranes in subsequent chapters (especially in our treatment of aerobic
oxidation reactions in Chapters 19 and 20). The other two functions we now
consider in turn.

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 Membrane
Side 1 Side 2
The most important question about transport of substances across biologi-
Concentration C1 Concentration C2
cal membranes is whether the process requires the cell to expend energy. In
passive transport, a substance moves from a region of higher concentration to
one of lower concentration. In other words, the movement of the substance is
in the same direction as a concentration gradient, and the cell does not expend
energy. In active transport, a substance moves from a region of lower concen-
tration to one of higher concentration (against a concentration gradient), and
this process requires the cell to expend energy.
The process of passive transport can be subdivided into two categories—
simple diffusion and facilitated diffusion. In simple diffusion, a molecule
moves directly through the membrane without interacting with another mol-
ecule. Small, uncharged molecules, such as O2, N2, and CO2, can pass through G RT ln [C2]
membranes via simple diffusion. The rate of movement through the mem- [C1]
brane is controlled solely by the concentration difference across the membrane
(Figure 8.22). Larger molecules (especially polar ones) and ions cannot pass
through a membrane by simple diffusion. The process of moving a molecule
passively through a membrane using a carrier protein, to which molecules
bind, is called facilitated diffusion. A good example is the movement of glucose
into erythrocytes. The concentration of glucose in the blood is about 5 mM.
The glucose concentration in the erythrocyte is less than 5 mM. Glucose passes passive transport the process by which a
through a carrier protein called glucose permease (Figure 8.23). This process substance enters a cell without an expenditure of
is labeled as facilitated diffusion because no energy is expended and a protein energy by the cell
carrier is used. In addition, facilitated diffusion is identified by the fact that active transport the energy-requiring process
the rate of transport, when plotted against the concentration of the molecule of moving substances into a cell against a
being transported, gives a hyperbolic curve similar to that seen in Michaelis– concentration gradient
Menten enzyme kinetics (Figure 8.24). In a carrier protein, a pore is created by simple diffusion the process of passing through
folding the backbone and side chains. Many of these proteins have several - a pore or opening in a membrane without a
helical portions that span the membrane; in others, a -barrel forms the pore. requirement for a carrier or for the expenditure of
energy
In one example, the helical portion of the protein spans the membrane. The
exterior, which is in contact with the lipid bilayer, is hydrophobic, whereas the facilitated diffusion a process by which
interior, through which ions pass, is hydrophilic. Note that this orientation is substances enter a cell by binding to a carrier
protein; this process does not require energy
the inverse of that observed in water-soluble globular proteins.
Active transport requires moving substances against a concentration gra- sodium–potassium ion pump the export of
dient. It is identified by the presence of a carrier protein and the need for sodium ions from a cell with simultaneous inflow of
potassium ions, both against concentration gradients
an energy source to move solutes against a gradient. In primary active trans-
port, the movement of molecules against a gradient is directly linked to the
hydrolysis of a high-energy molecule, such as ATP. The situation is so mark-
edly similar to pumping water uphill that one of the most extensively studied Erythrocyte Glucose in blood,
conc. 5 mM
examples of active transport, moving potassium ions into a cell and simul-
taneously moving sodium ions out of the cell, is referred to as the sodium– Glucose
Facilitated
potassium ion pump (or Na /K pump). diffusion
permease
Under normal circumstances, the concentration of K is higher inside a cell
than in extracellular fluids ([K ]inside [K ]outside), but the concentration of Na
is lower inside the cell than out ([Na ]inside [Na ]outside). The energy required
to move these ions against their gradients comes from an exergonic (energy- Intracellular
releasing) reaction, the hydrolysis of ATP to ADP and Pi (phosphate ion). There glucose conc.
< 5 mM
can be no transport of ions without hydrolysis of ATP. The same protein appears
to serve both as the enzyme that hydrolyzes the ATP (the ATPase) and as the
transport protein; it consists of several subunits. The reactants and products of
this hydrolysis reaction—ATP, ADP, and Pi —remain within the cell, and the phos-
phate becomes covalently bonded to the transport protein for part of the process.
The Na /K pump operates in several steps (Figure 8.25). One subunit of
the protein hydrolyzes the ATP and transfers the phosphate group to an aspar-
tate side chain on another subunit (Step 1). (The bond formed here is a mixed
anhydride; see Section 1-2.) Simultaneously, binding of three Na ions from the

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 Facilitated interior of the cell takes place. The phosphorylation of one subunit causes a
diffusion conformational change in the protein, which opens a channel or pore through
which the three Na ions can be released to the extracellular fluid (Step 2).
Outside the cell, two K ions bind to the pump enzyme, which is still phosphory-
lated (Step 3). Another conformational change occurs when the bond between
v

Passive the enzyme and the phosphate group is hydrolyzed. This second conforma-
diffusion
tional change regenerates the original form of the enzyme and allows the two
K ions to enter the cell (Step 4). The pumping process transports three Na
S
ions out of the cell for every two K ions transported into the cell (Figure 8.26).
The operation of the pump can be reversed when there is no K and a high
concentration of Na in the extracellular medium; in this case, ATP is pro-
duced by the phosphorylation of ADP. The actual operation of the Na /K
pump is not completely understood and probably is even more complicated
than we now know. There is also a calcium ion (Ca2 ) pump, which is a subject
of equally active investigation. Unanswered questions about the detailed mech-
anism of active transport provide opportunities for future research.
Another type of transport is called secondary active transport. An example is
the galactoside permease in bacteria (Figure 8.27). The lactose concentration
inside the bacterial cell is higher than the concentration outside, so moving lac-
tose into the cell requires energy. The galactoside permease does not directly

Outside

–OOC
ATP
CH2

Original ADP
O
conformation
of the protein 3 Na+
P C CH2
2 K+

CH2 COO–
Na+ binding site

Conformational
change and P 2 Conformational
hydrolysis of
i Inside change
4
phosphate bound H2O
to protein

O
P C CH2
O
3 Na+
CH2 C P

O
K+ binding site P C CH2

2 K+

–
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 2 K+ 3 Na+ ADP
–
E1 K2 ATP E1 ATP E1 Na3 ATP E1 Na3 P

Na+
ATP
E2 K2 E 2 K2 P E2 P E2 Na2 P

P H2O 2 K+ 2 Na+

hydrolyze ATP, however. Instead, it harnesses the energy by letting hydrogen

ions flow through the permease into the cell with their concentration gradi-
ent. As long as more energy is available allowing the hydrogen ions to flow
( G) than is required to concentrate the lactose ( G), the process is pos-
sible. However, to arrive at a situation in which there is a higher concentration
of hydrogen ions on the outside than on the inside, some other primary active
transporter must establish the hydrogen ion gradient. Active transporters that
create hydrogen ion gradients are called proton pumps. proton pumps integral membrane proteins
that create a hydrogen ion gradient across the
membrane

The first step in producing the effects of some biologically active substances
is binding the substance to a protein receptor site on the exterior of the cell.
The interaction between receptor proteins and the active substances that bind
to them has features in common with enzyme–substrate recognition. There
is a requirement for essential functional groups that have the correct three-
dimensional conformation with respect to each other. The binding site, whether
on a receptor or an enzyme, must provide a good fit for the substrate. In receptor
binding, as in enzyme behavior, inhibition of the action of the protein by some
sort of “poison” or inhibitor is possible. The study of receptor proteins is less
advanced than the study of enzymes because many receptors are tightly bound
integral proteins, and their activity depends on the membrane environment.
Receptors are often large oligomeric proteins (ones with several subunits), with
molecular weights on the order of hundreds of thousands. Also, quite frequently,
the receptor has very few molecules in each cell, adding to the difficulties of
isolating and studying this type of protein.
gives an example of how important receptor functions can be.

H+ H+
H+ H+
Lactose H+
H+ H+

Galactoside
permease
OUTSIDE

Proton
pump

INSIDE

CO2
Lactose Fuel
H+
H+ H+

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 n electron micrographs of fat cells, large fat droplets are easily double mutant that cannot respond to leptin but also lacks perilipin.
visible. Very visible are the large lipid droplets. For decades these In this case the extra fat burning that takes place almost makes up for
structures have been thought of as great balls of fat, a convenient the increased appetite. Further research on such proteins in the mem-
way to store triacylglycerols for consumption. However, these drop- branes of lipid droplets could lead to useful antiobesity therapies.
lets are surrounded by a thin phospholipid membrane that con-
tains many membrane proteins with widely varying activities. On
the negative side, they may also be involved in several lipid diseases,

Courtesy of Drs. Pradip Saha & Lawrence Chan/Baylor College of Medicine

cardiovascular diseases, and diabetes. These lipid droplets are now
being thought of as a subcellular organelle in their own right.
One of the first clues that lipid droplets were more than a simple
pool of fat came in the early 1990s from research by Constantine
Londos. He and his colleagues identified a protein called perilipin
on the membrane of the lipid droplets in fat cells. They discovered
that when cells are stimulated to metabolize the fatty acids in the
lipid droplets, this protein is phosphorylated. This suggests a more
complicated mechanism for controlling lipid digestion in fat cells
than previously imagined. More than half a dozen proteins have
been identified on the membrane of lipid droplets.
It is now believed that perilipin guards the fat resources of the
lipid droplet. When not phosphorylated, the protein does not allow
fat-digesting enzymes access to the triacylglycerols. When phosphory-
lated, the protein shifts conformation and allows access. Studies with
mutant mice lacking perilipin have shown that such mice eat much
more than their wild-type counterparts, yet burn off two-thirds of the
extra calories consumed. Figure 8.28 shows three different strains of
mice. The mouse on the left is normal. The mouse on the right is an
obese mouse from a strain that lacks the ability to respond to an appe-
tite-suppressing hormone called leptin. The mouse in the middle is a

Receptor proteins operate in various ways, giving rise to different receptor

actions. We will see many examples in context when we discuss metabolism and
its control. One example is based on control of protein activity by phosphory-
lation or dephosphorylation of side chains, frequently the hydroxyl groups of
tyrosine. We saw this form of control of enzyme activity in Section 7-4, but the
effect is not confined to the enzymes of metabolic pathways. An important class
of receptor proteins, called tyrosine kinases, mediates the function of receptors
in this way. Tyrosine kinases play an important role in carbohydrate metabolism
by their effect on the way insulin controls blood sugar levels. Other important
proteins involved in cell signaling are called G proteins because their opera-
tion requires hydrolysis of guanosine triphosphate (GTP). They are widely dis-
tributed in eukaryotic membranes and have many functions. Figure 8.18 shows
an example of a G protein with its three subunits designated by Greek letters.
We will talk about G proteins extensively in Chapter 24. To take one example,
G proteins are permanently activated in cholera, rather than being activated
and deactivated. The result is unregulated active transport of Na+, which leads
to loss of water and electrolytes, and ultimately to the diarrhea characteristic of
cholera. Receptors can be very specific in their activity, and we can use one now
as a case study for receptor activity.
An important type of receptor is that for low-density lipoprotein (LDL), the
principal carrier of cholesterol in the bloodstream. LDL is a particle that consists

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 LDL

Binding Receptor
LDL
recycled
OUTSIDE

Endocytosis
INSIDE
Receptor
Synthesis
of
receptor
protein

Inhibits
LDL
Oversupply of
cholesterol
Cholesterol

of various lipids—in particular, cholesterol and phosphoglycerides—as well as a

protein. The protein portion of the LDL particle binds to the LDL receptor of
a cell. The complex formed between the LDL and the receptor is pinched off
into the cell in a process called endocytosis. The receptor protein is then recycled
back to the surface of the cell (Figure 8.29). The cholesterol portion of the LDL
is used in the cell, but an oversupply of cholesterol causes problems. Excess of
cholesterol inhibits the synthesis of LDL receptor. If there are too few recep-
tors for LDL, the level of cholesterol in the bloodstream increases. Eventually,
the excess cholesterol is deposited in the arteries, blocking them severely. This
blocking of arteries, called atherosclerosis, can eventually lead to heart attacks
and strokes. In many industrialized countries, typical blood cholesterol levels
are high, and the incidence of heart attacks and strokes is correspondingly high.
(We will say more about this subject after we have seen the pathway by which
cholesterol is synthesized in the body in Section 21-8.)
Membrane receptors are a fascinating subject as they combine protein
chemistry, lipid chemistry, interactions both inside and outside the cell, and
metabolic pathways. A good example of the elegance of such interactions is the
receptor for human growth hormone and how information from outside the
cell is transmitted to the cell. Human growth hormone (hGH) is a 191-amino
acid peptide hormone produced in the pituitary gland, which stimulates
growth, cell reproduction, and cell regeneration.
The hGH receptor has two identical protein subunits that extend from the
cell membrane outward, as shown in Figure 8.30.
This is a common design for cell receptors. A single molecule of hGH binds
sequentially to the outer domain of one subunit and then the other. Binding of
hGH causes movement of the dimer, and this movement is transmitted through
the transmembrane domain to the intracellular domain of the receptor. The
receptor is associated with a kinase enzyme called Janus kinase-2 ( JAK2), which
is inactive initially. The movement of the receptor caused by hormone binding

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 Growth
Growth hormone receptor Extracellular
hormone

Extracellular domain

Transmembrane domain Plasma membrane

Intracellular domain

Kinase domain
Catalytic domain

JAK2 (inactive) JAK2 (active) Intracellular

Growth hormone receptor (inactive) Growth hormone receptor (active)

changes the orientation of the catalytic site of JAK2 activating the enzyme. As we
will see in future chapters, activation of protein kinases is a common and critical
part of cell signaling. Frequently, activating a kinase starts a cascade of phos-
phorylation events that ultimately lead to the observed effect of the hormone.

Some vitamins, having a variety of functions, are of interest in this chapter

because they are soluble in lipids. These lipid-soluble vitamins are hydropho-
bic, which accounts for their solubility (Table 8.5).

-carotene an unsaturated hydrocarbon; the The extensively unsaturated hydrocarbon -carotene is the precursor of vitamin A,
precursor of vitamin A which is also known as retinol. As the name suggests, -carotene is abundant in car-
vitamin A the lipid-soluble compound responsible rots, but it also occurs in other vegetables, particularly the yellow ones. When an
for the primary photochemical event in vision organism requires vitamin A, -carotene is converted to the vitamin (Figure 8.31A).
retinol the alcohol form of vitamin A A derivative of vitamin A plays a crucial role in vision when it is bound to a
protein called opsin. The cone cells in the retina of the eye contain several types of
opsin and are responsible for vision in bright light and for color vision. The rod
cells in the retina contain only one type of opsin; they are responsible for vision in
dim light. The chemistry of vision has been more extensively studied in rod cells
than in cone cells, and we shall discuss events that take place in rod cells.
Vitamin A has an alcohol group that is enzymatically oxidized to an aldehyde
retinal the aldehyde form of vitamin A group, forming retinal (Figure 8.31B). Two isomeric forms of retinal, involving

Vitamin A Serves as the site of the primary photochemical reaction in vision

Vitamin D Regulates calcium (and phosphorus) metabolism
Vitamin E Serves as an antioxidant; necessary for reproduction in rats and may
be necessary for reproduction in humans
Vitamin K Has a regulatory function in blood clotting

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A
H3C
CH3 CH3 Cleavage
H3C CH3

H3C CH3
CH3 CH3
CH3 -Carotene

[O] Enzyme action in liver

CH3 CH3
H3C CH3
7 9 11 13 15
1 6
2
8 10 12 14
OH
2
3 5
4 CH3
Retinol (vitamin A)

B
CH3 CH3
H3C CH3 H H
11

12
OH

CH3
Retinol

Retinol dehydrogenase

CH3 CH3 H
H3C CH3
11

O
12

CH3
11-trans-Retinal

Retinal isomerase

CH3
H3C CH3
11
12

H3C

H O
11-cis-Retinal

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 11-cis-Retinal
CH3 Rhodopsin
H3C CH3
11 CH3
H 3C CH3
11
H2O

CH3 H3C
CH3 H3C
O H
Rest of protein
+
N H

+
H3N Rest of protein Imine (Schiff base)
Opsin

cis–trans isomerization around one of the double bonds, are important in the
behavior of this compound in vivo. The aldehyde group of retinal forms an
imine (also called a Schiff base) with the side-chain amino group of a lysine
residue in rod-cell opsin (Figure 8.32).
rhodopsin a molecule crucial to vision; it is The product of the reaction between retinal and opsin is rhodopsin. The
formed by the reaction of retinal and opsin outer segment of rod cells contains flat membrane-enclosed discs, the mem-
brane consisting of about 60% rhodopsin and 40% lipid. For more details about
how rhodopsin plays a role in vision, see .

The several forms of vitamin D play a major role in the regulation of calcium
vitamin D lipid-soluble compound that regulates
calcium and phosphorus metabolism and phosphorus metabolism. One of the most important of these compounds,
vitamin D3 (cholecalciferol), is formed from cholesterol by the action of ultra-
violet radiation from the Sun. Vitamin D3 is further processed in the body to
form hydroxylated derivatives, which are the metabolically active form of this

he primary chemical reaction in vision, the one responsible for brain to be processed as a visual event. The active form of rhodopsin is
generating an impulse in the optic nerve, involves cis–trans isomeri- regenerated by enzymatic isomerization of the all-trans-retinal back to
zation around one of the double bonds in the retinal portion of rho- the 11-cis form and subsequent re-formation of the rhodopsin.
dopsin. When rhodopsin is active (that is, when it can respond to visible Vitamin A deficiency can have drastic consequences, as would
light), the double bond between carbon atoms 11 and 12 of the retinal be predicted from its importance in vision. Night blindness—and
(11-cis-retinal) has the cis orientation. Under the influence of light, an even total blindness—can result, especially in children. On the
isomerization reaction occurs at this double bond, producing all-trans- other hand, an excess of vitamin A can have harmful effects, such
retinal. Because the all-trans form of retinal cannot bind to opsin, all- as bone fragility. Lipid-soluble compounds are not excreted as
trans-retinal and free opsin are released. As a result of this reaction, an readily as water-soluble substances, and excessive amounts of lipid-
electrical impulse is generated in the optic nerve and transmitted to the soluble vitamins can accumulate in adipose tissue.

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 11-cis-orientation
H around double bond
CH3
9 11
H
10 12

H 13 H
H3C 14

CH NH (CH2)4 Rest of protein

Rhodopsin

(Active photoreceptor = 11-cis-retinal linked to lysine of opsin)

Sensory Regeneration of
activation active receptor

Light

11-trans-orientation CH3 H
around double bond
9 11
12 H
CH3 H CH3
10
9 11 13 13
CHO H H
12 14
Isomerase H3C
10 14

H H H Regeneration of CHO
11-cis-retinal
All-trans-retinal 11-cis-retinal
+ +
+ +
H3N (CH2)4 Rest of protein H3N (CH2)4 Rest of protein
Opsin Opsin

vitamin (Figure 8.34). The presence of vitamin D3 leads to increased synthesis

of a Ca2 -binding protein, which increases the absorption of dietary calcium in
the intestines. This process results in calcium uptake by the bones.
A deficiency of vitamin D can lead to rickets, a condition in which the bones of
growing children become soft, resulting in skeletal deformities. Children, espe-
cially infants, have higher requirements for vitamin D than do adults. Milk with
vitamin D supplements is available to most children. Adults who are exposed to
normal amounts of sunlight do not usually require vitamin D supplements.

vitamin E a lipid-soluble antioxidant

The most active form of vitamin E is -tocopherol (Figure 8.35). In rats, vitamin E
-tocopherol the most active form of vitamin E
is required for reproduction and for prevention of the disease muscular dystro-
phy. It is not known whether this requirement exists in humans. A well-estab- antioxidant a strong reducing agent, which is
lished chemical property of vitamin E is that it is an antioxidant—that is, a good easily oxidized and thus prevents the oxidation of
reducing agent—so it reacts with oxidizing agents before they can attack other other substances

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 Enzymatic
H3C H3C H3C

H3C C D H3C C D
Ultraviolet
A B radiation Cholecalciferol
HO HO (vitamin D3)
Cholesterol 7-Dehydrocholesterol CH2
A
HO

Enzyme
(liver) O2

H3C OH H3C OH

Enzyme
(kidney)

O2
CH2 CH2

HO OH HO
1,25-Dihydroxycholecalciferol 25-Hydroxycholecalciferol

OH

H3C CH3

H3C
CH3 CH3 CH3
O
CH2 CH CH2 CH CH2 CH
H3C CH2 CH2 CH2 CH2 CH2 CH2 CH3

Vitamin E ( -tocopherol)

biomolecules. The antioxidant action of vitamin E has been shown to protect im-
portant compounds, including vitamin A, from degradation in the laboratory; it
probably also serves this function in organisms.
Recent research has shown that the interaction of vitamin E with membranes
enhances its effectiveness as an antioxidant. Another function of antioxidants
such as vitamin E is to react with, and thus to remove, the very reactive and
free radicals highly reactive molecules that have highly dangerous substances known as free radicals. A free radical has at least
at least one unpaired electron one unpaired electron, which accounts for its high degree of reactivity. Free
radicals may play a part in the development of cancer and in the aging process.
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The name of vitamin K comes from the Danish Koagulation because this vitamin vitamin K lipid-soluble compound that plays an
is an important factor in the blood-clotting process. The bicyclic ring system con- important role in blood clotting
tains two carbonyl groups, the only polar groups on the molecule (Figure 8.36).
A long unsaturated hydrocarbon side chain consists of repeating isoprene units,
the number of which determines the exact form of vitamin K. Several forms of
this vitamin can be found in a single organism, but the reason for this variation
is not well understood. Vitamin K is not the first vitamin we have encountered
that contains isoprene units, but it is the first one in which the number of iso-
prene units and their degree of saturation make a difference. (Can you pick out
the isoprene-derived portions of the structures of vitamins A and E?) It is also
known that the steroids are biosynthetically derived from isoprene units, but the
structural relationship is not immediately obvious (Section 21-8).
The presence of vitamin K is required in the complex process of blood clot-
ting, which involves many steps and many proteins and has stimulated numer-
ous unanswered questions. It is known definitely that vitamin K is required to
modify prothrombin and other proteins involved in the clotting process. Spe-
cifically, with prothrombin, the addition of another carboxyl group alters the
side chains of several glutamate residues of prothrombin. This modification
of glutamate produces -carboxyglutamate residues (Figure 8.37). The two
carboxyl groups in proximity form a bidentate (“two teeth”) ligand, which can
bind calcium ion (Ca2 ). If prothrombin is not modified in this way, it does not
bind Ca2 . Even though there is a lot more to be learned about blood clotting
and the role of vitamin K in the process, this point, at least, is well established,
because Ca2 is required for blood clotting. (Two well-known anticoagulants,
dicumarol and warfarin [a rat poison], are vitamin K antagonists.)

A
O

CH3

O
] CH2CH
CH3

Isoprene unit
CH2 ] n H ] CH3
Isoprene unit
]
Vitamin K

B
O

CH3

CH3 CH3

CH2CH C CH2 (CH2 CH2 CH CH2)3 H

O
Vitamin K1 (Phylloquinone)

CH3

CH3

(CH2CH C CH2)8 H
O

Vitamin K2 (Menaquinone)
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 Glutamic
O C O C COO– COO–
acid
Vitamin K Ca2+
HC CH2CH2COO– HC CH2CH CH Ca2+
residue – –
N H CO2 N H COO COO

Occurs at a total
Prothrombin Modified of 10 glutamic
prothrombin acid residues

O O
H H
C N C C

CH2
O O
CH
C C
– –
O O

Ca(II)
-Carboxyglutamate complexed with Ca(II)

A group of compounds derived from fatty acids has a wide range of physiologi-
prostaglandins derivatives of arachidonic acid cal activities; they are called prostaglandins because they were first detected in
that contain a five-membered ring and are of seminal fluid, which is produced by the prostate gland. It has since been shown
pharmaceutical importance that they are widely distributed in a variety of tissues. The metabolic precursor of
arachidonic acid a fatty acid that contains 20 all prostaglandins is arachidonic acid, a fatty acid that contains 20 carbon atoms
carbon atoms and 4 double bonds; the precursor of and four double bonds. The double bonds are not conjugated. The production
prostaglandins and leukotrienes of the prostaglandins from arachidonic acid takes place in several steps, which are
catalyzed by enzymes. The prostaglandins themselves each have a five-membered
ring; they differ from one another in the numbers and positions of double bonds
and oxygen-containing functional groups (Figure 8.38).

COO–

CH3

Arachidonic acid (Arachidonate form)

O HO
COO– COO–

CH3 CH3

HO HO
OH OH
PGE1 PGE3a

O HO
COO– COO–

CH3 CH3

HO HO
OH OH
PGE2 PGE2a

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 The structures of prostaglandins and their laboratory syntheses have been
topics of great interest to organic chemists, largely because of the many physi-
ological effects of these compounds and their possible usefulness in the phar-
maceutical industry (Figure 8.39). Some of the functions of prostaglandins are
control of blood pressure, stimulation of smooth-muscle contraction, and in-

© Jason Stitt/[Link]
duction of inflammation. Aspirin inhibits the synthesis of prostaglandins, par-
ticularly in blood platelets, a property that accounts for its anti-inflammatory
and fever-reducing properties. Cortisone and other steroids also have anti-
inflammatory effects because of their inhibition of prostaglandin synthesis.
Prostaglandins are known to inhibit the aggregation of platelets. They may
thus be of therapeutic value by preventing the formation of blood clots, which
can cut off the blood supply to the brain or the heart and cause certain types of
strokes and heart attacks. Even if this behavior were the only useful property of
prostaglandins, it would justify considerable research effort. Heart attacks and
strokes are two of the leading causes of death in industrialized countries. More
recently, the study of prostaglandins has been a topic of great interest because
leukotrienes substances derived from leukocytes
of their possible antitumor and antiviral activity. (white blood cells) that have three double bonds
Leukotrienes are compounds that, like prostaglandins, are derived from and are of pharmaceutical importance
arachidonic acid. They are found in leukocytes (white blood cells) and have
three conjugated double bonds; these two facts account for the name. (Fatty
acids and their derivatives do not normally contain conjugated double bonds.) H2C CH COO–
Cysteine
Leukotriene C (Figure 8.40) is a typical member of this group; note the 20 S
+
NH3
carbon atoms in the carboxylic acid backbone, a feature that relates this com-
pound structurally to arachidonic acid. (The 20-carbon prostaglandins and COO–
leukotrienes are also called eicosinoids.) An important property of leukotri- Triene
enes is their constriction of smooth muscle, especially in the lungs. Asthma
attacks may result from this constricting action because the synthesis of leu-
kotriene C appears to be facilitated by allergic reactions, such as a reaction to
pollen. Drugs that inhibit the synthesis of leukotriene C are now being used
in the treatment of asthma, as are other drugs designed to block leukotriene
receptors. In the United States, the incidence of asthma has increased drasti-
cally since 1980, providing considerable incentive to find new treatments. The COO–
Centers for Disease Control and Prevention have made information available
on the Internet at [Link] Leukotrienes may also have
inflammatory properties and may be involved in rheumatoid arthritis.
O
Thromboxanes are a third class of derivatives of arachidonic acid. They con-
tain cyclic ethers as part of their structures. The most widely studied member O
of the group, thromboxane A2 (TxA2) (Figure 8.41), is known to induce plate- OH
let aggregation and smooth-muscle contraction. Thromboxane A2
discusses some connections among topics (TxA2)
in this chapter.

latelets are elements in the blood that initiate blood clotting conditions that exist under a large plaque deposit may lead to weak-
and tissue repair by releasing clotting factors and platelet- ness and dead cells in the arterial wall, aggravating the problem.
derived growth factor (PDGF). Turbulence in the bloodstream may Among peoples who depend on fish as a major food source, in-
cause platelets to rupture. Fat deposits and bifurcations of arteries lead cluding some Eskimo tribes, very little heart disease is diagnosed,
to such turbulence, so platelets and PDGF are implicated in blood clot- even though people in these groups eat high-fat diets and have high
ting and growth of atherosclerotic plaque. Furthermore, the anaerobic levels of blood cholesterol. Analysis of their diet led to the discovery

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that certain highly unsaturated fatty acids are found in the oils of fish
and diving mammals. One class of these fatty acids is called omega-3
( 3), an example of which is eicosapentenoic acid (EPA):
CH3CH2(CH CHCH2)5(CH2)2COOH
Eicosapentenoic acid (EPA)
Note the presence of a double bond at the third carbon atom
from the end of the hydrocarbon tail. The omega system of
nomenclature is based on numbering the double bonds from the
last carbon in the fatty acid instead of the carbonyl group (the
delta [ ] system). Omega is the last letter in the Greek alphabet.
The omega-3 fatty acids inhibit the formation of certain pros-
taglandins and thromboxane A, which is similar in structure to
prostaglandins. Thromboxane released by ruptured arteries causes

© Liliya Kandrashevich/[Link]
other platelets to clump in the immediate area and to increase the
size of the blood clot. Any disruption in thromboxane synthesis
results in a lower tendency to form blood clots and, thus, in a lower
potential for artery damage.
Aspirin also inhibits prostaglandin synthesis, although it is less
potent than EPA. Aspirin inhibits the synthesis of the prostaglan-
dins responsible for inflammation and the perception of pain. Aspi-
rin has been implicated in reducing the incidence of heart disease,
probably by a mechanism similar to that of EPA. However, people
who are being treated with blood thinners or who are prone to easy
bleeding should not take aspirin.

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