26
Lipids
stearic acid
L
ipids are organic compounds, found in living organisms, that are
soluble in nonpolar organic solvents. Because compounds
are classified as lipids on the basis of a physical property—
their solubility in an organic solvent—rather than as a result of their
structures, lipids have a variety of structures and functions, as the
following examples illustrate:
linoleic acid
CH2OH
O
H
COOH
CH3 C
O
H3C
H
OH
PGE1
a vasodilator
H3C
H
CH3
CH3
CH3
CH2OH
H
H
HO
O
OH
O
CH3
cortisone
a hormone
vitamin A
a vitamin
limonene
in orange and
lemon oils
O
O
O
CH
O
O
CH2
O
CH2
tristearin
a fat
The solubility of lipids in nonpolar organic solvents results from their significant
hydrocarbon component. The hydrocarbon portion of the compound is responsible
for its “oiliness” or “fattiness.” The word lipid comes from the Greek lipos, which
means “fat.”
001
002
CHAPTER 26
Lipids
26.1 Fatty Acids
3-D Molecules:
Stearic acid; Oleic acid;
Linoleic acid; Linolenic acid
Table 26.1
Fatty acids are carboxylic acids with long hydrocarbon chains. The fatty acids most
frequently found in nature are shown in Table 26.1. Because they are synthesized from
acetate, a compound with two carbon atoms, most naturally occurring fatty acids contain an even number of carbon atoms and are unbranched. The mechanism for the
biosynthesis of fatty acids is discussed in Section 19.21. Fatty acids can be saturated
with hydrogen (and therefore have no carbon–carbon double bonds) or unsaturated
(have carbon–carbon double bonds). Fatty acids with more than one double bond are
called polyunsaturated fatty acids. Double bonds in naturally occurring unsaturated
fatty acids are never conjugated—they are always separated by one methylene group.
The physical properties of a fatty acid depend on the length of the hydrocarbon
chain and the degree of unsaturation. As expected, the melting points of saturated fatty
acids increase with increasing molecular weight because of increased van der Waals
interactions between the molecules (Section 2.9).
The double bonds in unsaturated fatty acids generally have the cis configuration. This
configuration produces a bend in the molecules, which prevents them from packing
together as tightly as fully saturated fatty acids. As a result, unsaturated fatty acids have
Common Naturally Occurring Fatty Acids
Melting
point
°C
Number
of carbons Common name
Systematic name
Saturated
lauric acid
12
dodecanoic acid
COOH
44
Structure
14
myristic acid
tetradecanoic acid
COOH
58
16
palmitic acid
hexadecanoic acid
COOH
63
18
stearic acid
octadecanoic acid
COOH
69
20
arachidic acid
eicosanoic acid
COOH
77
Unsaturated
16
palmitoleic acid
(9Z )-hexadecenoic acid
COOH
0
18
oleic acid
(9Z )-octadecenoic acid
COOH
13
18
linoleic acid
(9Z,12Z)-octadecadienoic acid
COOH
−5
18
linolenic acid
(9Z,12Z,15Z)-octadecatrienoic acid
COOH
− 11
20
arachidonic acid (5Z,8Z,11Z,14Z )-eicosatetraenoic acid
COOH
− 50
20
EPA
COOH
− 50
(5Z,8Z,11Z,14Z,17Z )-eicosapentaenoic acid
Section 26.1
Fatty Acids
fewer intermolecular interactions and, therefore, lower melting points than saturated
fatty acids with comparable molecular weights (Table 26.1). The melting points of the
unsaturated fatty acids decrease as the number of double bonds increases. For example,
an 18-carbon fatty acid melts at 69 °C if it is saturated, at 13 °C if it has one double bond,
at -5 °C if it has two double bonds, and at -11 °C if it has three double bonds.
Art to be fixed
stearic acid
an 18-carbon fatty acid
with one double bond
oleic acid
an 18-carbon fatty acid
with one double bond
an 18-carbon fatty acid
with three double bonds
linoleic acid
linolenic acid
an 18-carbon fatty acid
with three double bonds
PROBLEM 1
Explain the difference in the melting points of the following fatty acids:
a. palmitic acid and stearic acid
b. palmitic acid and palmitoleic acid
c. oleic acid and linoleic acid
PROBLEM 2
What products are formed when arachidonic acid reacts with excess ozone followed by
treatment with H 2O2 ? (Hint: See Section 20.8.)
OMEGA FATTY ACIDS
Omega is a term used to indicate the position of
the first double bond—from the methyl end—in an
unsaturated fatty acid. For example, linoleic acid is called
omega-6 fatty acid because its first double bond is after the sixth
carbon, and linolenic acid is called omega-3 fatty acid because
its first double bond is after the third carbon. Mammals lack the
enzyme that introduces a double bond beyond C-9 (the carboxyl
carbon is C-1). Linoleic acid and linolenic acids, therefore, are
essential fatty acids for mammals. In other words, the acids must
be included in the diet because, although they cannot be synthesized, they are required for normal body function.
COOH
omega-6
fatty acid
linoleic acid
missing art 26PYB02
omega-3
fatty acid
COOH
linolenic acid
003
004
CHAPTER 26
Lipids
26.2 Waxes
Waxes are esters formed from long-chain carboxylic acids and long-chain alcohols.
For example, beeswax, the structural material of beehives, has a 16-carbon carboxylic
acid component and a 30-carbon alcohol component. The word wax comes from the
Old English weax, meaning “material of the honeycomb.” Carnauba wax is a particularly hard wax because of its relatively high molecular weight, arising from a
32-carbon carboxylic acid component and a 34-carbon alcohol component. Carnauba
wax is widely used as a car wax and in floor polishes.
▲ Layers of honeycomb in a beehive
O
O
O
CH3(CH2)24CO(CH2)29CH3
CH3(CH2)30CO(CH2)33CH3
CH3(CH2)14CO(CH2)15CH3
a major component of
beeswax
structural material
of beehives
a major component of
carnauba wax
coating on the leaves
of a Brazilian palm
a major component of
spermaceti wax
from the heads of
sperm whales
Waxes are common in living organisms. The feathers of birds are coated with wax to
make them water repellent. Some vertebrates secrete wax in order to keep their fur lubricated and water repellent. Insects secrete a waterproof, waxy layer on the outside of their
exoskeletons. Wax is also found on the surfaces of certain leaves and fruits, where it
serves as a protectant against parasites and minimizes the evaporation of water.
▲ Raindrops on a feather
26.3 Fats and Oils
Triacylglycerols, also called triglycerides, are compounds in which the three OH
groups of glycerol are esterified with fatty acids. If the three fatty acid components of a
triacylglycerol are the same, the compound is called a simple triacylglycerol. Mixed
triacylglycerols, on the other hand, contain two or three different fatty acid components and are more common than simple triacylglycerols. Not all triacylglycerol molecules from a single source are necessarily identical; substances such as lard and olive
oil, for example, are mixtures of several different triacylglycerols (Table 26.2).
Table 26.2
Approximate Percentage of Fatty Acids in Some Common Fats and Oils
Saturated fatty acids
Animal fats
Butter
Lard
Human fat
Whale blubber
Plant oils
Corn
Cottonseed
Linseed
Olive
Peanut
Safflower
Sesame
Soybean
Unsaturated fatty acids
mp
(°C)
lauric
C12
myristic
C14
palmitic
C16
stearic
C18
oleic
C18
linoleic
C18
linolenic
C18
32
30
15
24
2
—
1
—
11
1
3
8
29
28
25
12
9
12
8
3
27
48
46
35
4
6
10
10
—
—
—
—
20
-1
- 24
-6
3
- 15
-6
- 16
—
—
—
—
—
—
—
—
1
1
—
—
—
—
—
—
10
23
6
7
8
3
10
10
3
1
3
2
3
3
4
2
50
23
19
84
56
19
45
29
34
48
24
5
26
70
40
51
—
—
47
—
—
3
—
7
Section 26.3
O
CH2
CH
CH2
OH
OH
OH
glycerol
Fats and Oils
005
O
R1
C OH
O
CH2
R2
C OH
O
CH
R3
C
CH2
OH
fatty acids
O
O
O
C
O
R1
C R2
O
C
R3
a triacylglycerol
a fat or an oil
Triacylglycerols that are solids or semisolids at room temperature are called fats.
Fats are usually obtained from animals and are composed largely of triacylglycerols
with either saturated fatty acids or fatty acids with only one double bond. The saturated fatty acid tails pack closely together, giving the triacylglycerols relatively high
melting points, causing them to be solids at room temperature.
an oil
a fat
Liquid triacylglycerols are called oils. Oils typically come from plant products such
as corn, soybeans, olives, and peanuts. They are composed primarily of triacylglycerols
with unsaturated fatty acids that cannot pack tightly together. Consequently, they have
relatively low melting points, causing them to be liquids at room temperature. The
approximate fatty acid compositions of some common fats and oils are shown in
Table 26.2.
Some or all of the double bonds of polyunsaturated oils can be reduced by catalytic
hydrogenation (Section 4.11). Margarine and shortening are prepared by hydrogenating vegetable oils such as soybean oil and safflower oil until they have the desired consistency. This process is called “hardening of oils.” The hydrogenation reaction must
be carefully controlled, however, because reducing all the carbon–carbon double
bonds would produce a hard fat with the consistency of beef tallow.
RCH
CHCH2CH
CHCH2CH
CH
H2
Pt
RCH2CH2CH2CH
CHCH2CH2CH2
Vegetable oils have become popular in food preparation because some studies have
linked the consumption of saturated fats with heart disease. Recent studies have shown
that unsaturated fats may also be implicated in heart disease. However, one
unsaturated fatty acid—a 20-carbon fatty acid with five double bonds, known as EPA
and found in high concentrations in fish oils—is thought to lower the chance of developing certain forms of heart disease. Once consumed, dietary fat is hydrolyzed in the
intestine, regenerating glycerol and fatty acids. We have seen that the hydrolysis of fats
under basic conditions forms glycerol and salts of fatty acids that are commonly
known as soap (Section 17.13).
▲ This puffin’s diet is high in fish oil.
006
CHAPTER 26
Lipids
PROBLEM 3
Do all triacylglycerols have the same number of asymmetric carbons?
PROBLEM 4
Which has a higher melting point, glyceryl tripalmitoleate or glyceryl tripalmitate?
3-D Molecule:
Olestra
Organisms store energy in the form of triacylglycerols. A fat provides about six
times as much metabolic energy as an equal weight of hydrated glycogen because fats
are less oxidized than carbohydrates and, since fats are nonpolar, they do not bind
water. In contrast, two-thirds of the weight of stored glycogen is water (Section 22.18).
Animals have a subcutaneous layer of fat cells that serves as both an energy source
and an insulator. The fat content of the average man is about 21%, whereas the fat content of the average woman is about 25%. Humans can store sufficient fat to provide for
the body’s metabolic needs for two to three months, but can store only enough carbohydrate to provide for its metabolic needs for less than 24 hours. Carbohydrates, therefore, are used primarily as a quick, short-term energy source.
Polyunsaturated fats and oils are easily oxidized by O2 by means of a radical chain
reaction. In the initiation step, a radical removes a hydrogen from a methylene group
that is flanked by two double bonds. This hydrogen is the most easily removed one
OLESTRA: NONFAT WITH FLAVOR
oil. Olestra works as a fat substitute because its ester linkages
are too hindered to be hydrolyzed by digestive enzymes. As a
result, Olestra tastes like fat, but it has no caloric value since it
cannot be digested.
Chemists have been searching for ways to reduce
the caloric content of foods without decreasing
their flavor. Many people who believe that “no fat” is synonymous with “no flavor” can understand this problem. The federal
Food and Drug Administration (Section 30.13) approved the
limited use of Olestra as a substitute for dietary fat in snack
foods. Procter and Gamble spent 30 years and more than $2
billion to develop this compound. Its approval was based on the
results of more than 150 studies.
Olestra is a semisynthetic compound. That is, Olestra does
not exist in nature, but its components do. Developing a compound that can be made from units that are a normal part of our
diet decreases the potential toxic effects of the new compound.
Olestra is made by esterifying all the OH groups of sucrose
with fatty acids obtained from cottonseed oil and soybean oil.
Therefore, its component parts are table sugar and vegetable
O
OC
O
CH2
O
CO
CO
O
1
OC
O
O
COCH2 O
O
O
CO 2
CH2OC
O
OC
O
olestra
Section 26.3
Fats and Oils
because the resulting radical is resonance stabilized by both double bonds. This radical
reacts with O2 , forming a peroxy radical with conjugated double bonds. The peroxy
radical removes a hydrogen from a methylene group of another molecule of fatty acid,
forming an alkyl hydroperoxide. The two propagating steps are repeated over and over.
RCH
CH
CH
CH
CH
+ X
initiation
H
RCH
CH
CH
CH
CH
+ HX
resonance contributor with
isolated double bonds
RCH
CH
CH
CH
CH
resonance contributor with
conjugated double bonds
O
O
RCH
O
CH
propagation
CH
CH
CH
O
a peroxy radical
RCH
CH
CH
RCH
CH
CH
CH
CH2
CH
CH
+ RCH
CH
O
propagation
CH
CH
CH
OH
an alkyl hydroperoxide
The reaction of fatty acids with O2 causes them to become rancid. The unpleasant
taste and smell associated with rancidity are the results of further oxidation of the alkyl
hydroperoxide to shorter chain carboxylic acids such as butyric acid that have strong
odors. The same process contributes to the odor associated with sour milk.
PROBLEM 5
Draw the resonance contributors for the radical formed when a hydrogen atom is removed
from C-10 of arachidonic acid.
WHALES AND ECHOLOCATION
Whales have enormous heads, accounting for 33%
of their total weight. They have large deposits of
fat in their heads and lower jaws. This fat is very different from
both the whale’s normal body fat and its dietary fat. Because
major anatomical modifications were necessary to accommodate this fat, it must have some important function for the
animal. It is now believed that the fat is used for echolocation—
emitting sounds in pulses and gaining information by analyzing
the returning echoes. The fat in the whale’s head focuses the
emitted sound waves in a directional beam, and the echoes are
received by the fat organ in the lower jaw. This organ transmits
the sound to the brain for processing and interpretation, providing the whale with information about the depth of the water,
changes in the seafloor, and the position of the coastline. The
fat deposits in the whale’s head and jaw therefore give the animal a unique acoustic sensory system and allow it to compete
successfully for survival with the shark, which also has a welldeveloped sense of sound direction.
Humpback whale in Alaska
007
008
CHAPTER 26
Lipids
26.4 Membranes
For biological systems to operate, some parts of organisms must be separated from
other parts. On a cellular level, the outside of the cell must be separated from the inside. “Greasy” lipid membranes serve as the barrier. In addition to isolating the cell’s
contents, these membranes allow the selective transport of ions and organic molecules
into and out of the cell.
Phospholipids
Phosphoacylglycerols (also called phosphoglycerides) are the major components
of cell membranes. They are similar to triacylglycerols except that a terminal OH
group of glycerol is esterified with phosphoric acid rather than with a fatty acid,
forming a phosphatidic acid. Because phosphoacylglycerols are lipids that contain
a phosphate group, they are classified as phospholipids. The C-2 carbon of glycerol
in phosphoacylglycerols has the R configuration.
O
R configuration
CH2
CH
O
O
CH2
O
C
O
R1
C R2
O
P
OH
−
O
a phosphatidic acid
Phosphatidic acids are the simplest phosphoacylglycerols and are present only in
small amounts in membranes. The most common phosphoacylglycerols in membranes
have a second phosphate ester linkage. The alcohols most commonly used to form this
second ester group are ethanolamine, choline, and serine. Phosphatidylethanolamines
are also called cephalins, and phosphatidylcholines are called lecithins. Used as
emulsifying agents, lecithins are added to foods such as mayonnaise to prevent the
aqueous and fat components from separating.
phosphatidylserine
O
CH2
CH
CH2
O
O
O
O
R1
C
O
CH2
C R2
O
CH
+
P
OCH2CH2NH3
O−
a phosphatidylethanolamine
a cephalin
3-D Molecule:
Phosphatidic acid
CH2
O
O
O
C
O
O
R1
C R2
O
P
O−
CH2
CH
O
O
CH3
+
OCH2CH2NCH3
CH3
a phosphatidylcholine
a lecithin
CH2
O
C
O
R1
C R2
O
P
OCH2CHCOO−
O−
NH3
+
a phosphatidylserine
Phosphoacylglycerols form membranes by arranging themselves in a lipid bilayer.
The polar heads of the phosphoacylglycerols are on the outside of the bilayer, and the
fatty acid chains form the interior of the bilayer. Cholesterol—a membrane lipid discussed in Section 26.9—is also found in the interior of the bilayer (Figure 26.1). A
typical bilayer is about 50 Å thick. [Compare the bilayer with the micelles formed by
soap in aqueous solution (Section 17.13).]
Section 26.4
Membranes
009
O
polar
head
cholesterol
molecule
nonpolar
fatty acid
chains
=
CH2O
C
O
R1
CHO
C
O
R2
CH2O
P
+
O(CH2)2NH3
O−
enlargement of a
phosphoacylglycerol
The fluidity of a membrane is controlled by the fatty acid components of the phosphoacylglycerols. Saturated fatty acids decrease membrane fluidity because their
hydrocarbon chains can pack closely together. Unsaturated fatty acids increase fluidity
because they pack less closely together. Cholesterol also decreases fluidity (Section 26.9). Only animal membranes contain cholesterol, so they are more rigid than
plant membranes.
The unsaturated fatty acid chains of phosphoacylglycerols are susceptible to reaction with O2 , similar to the reaction described on p. 7 for fats and oils. Oxidation of
phosphoacylglycerols can lead to the degradation of membranes. Vitamin E is an important antioxidant that protects fatty acid chains from degradation via oxidation. Vitamin E, also called a-tocopherol, is classified as a lipid because it is soluble in
nonpolar organic solvents. Because vitamin E reacts more rapidly with oxygen than
triacylglycerols do, the vitamin prevents biological membranes from reacting with
oxygen (Section 9.8). There are some who believe that vitamin E slows the aging
process. Because vitamin E also reacts with oxygen more rapidly than fats do, it is
added to many foods to prevent spoilage.
▲ Figure 26.1
A lipid bilayer.
Pg number to be fixed
AU: Sentence above is not definite,
whereas sentence in box
is quite definite. Want to be consistent?
CH3
HO
H3C
O
CH3
-tocopherol
vitamin E
IS CHOCOLATE A HEALTH FOOD?
We have long been told that our diets should include lots of fruits and vegetables because they are
good sources of antioxidants. Antioxidants protect against cardiovascular disease, cancer, and cataracts, and they slow the effects of aging. Recent studies show that chocolate has high levels
of antioxidants—complex mixtures of phenolic compounds
(Section 9.8). On a weight basis, the concentration of antioxidants in chocolate is higher than the concentration in red wine or
green tea and 20 times higher than the concentration in tomatoes.
Dark chocolate contains more than twice the level of antioxidants as milk chocolate. Unfortunately, white chocolate contains
no antioxidants. Another piece of good news is that stearic acid,
the main fatty acid in chocolate, does not appear to raise blood
cholesterol levels the way other saturated fatty acids do.
3-D Molecule:
Vitamin E
010
CHAPTER 26
Lipids
PROBLEM 6
Membranes contain proteins. Integral membrane proteins extend partly or completely
through the membrane, whereas peripheral membrane proteins are found on the inner or
outer surfaces of the membrane. What is the likely difference in the overall amino acid
composition of integral and peripheral membrane proteins?
PROBLEM 7
A colony of bacteria accustomed to an environment at 25 °C was moved to an identical environment, at 35 °C. The higher temperature increased the fluidity of the bacterial membranes. What could the bacteria do to regain their original membrane fluidity?
Sphingolipids
CH
CH(CH2)12CH3
CH
OH
CH
NH2
CH2
OH
s configuration
sphingosine
3-D Molecule:
Sphingosine
Sphingolipids are also found in membranes. They are the major lipid components in
the myelin sheaths of nerve fibers. Sphingolipids contain sphingosine instead of glycerol. In sphingolipids, the amino group of sphingosine is bonded to the acyl group of
a fatty acid. Both asymmetric carbons in sphingosine have the S configuration.
Two of the most common kinds of sphingolipids are sphingomyelins and
cerebrosides. In sphingomyelins, the primary OH group of sphingosine is bonded
to phosphocholine or phosphoethanolamine, similar to the bonding in lecithins and
cephalins. In cerebrosides, the primary OH group of sphingosine is bonded to a
sugar residue through a b-glycosidic linkage (Section 22.13). Sphingomyelins are
phospholipids because they contain a phosphate group. Cerebrosides, on the other
hand, are not phospholipids.
CH
CH(CH2)12CH3
CH
CH(CH2)12CH3
CH
OH
O
CH
OH
O
CH
NH
C
O
CH NH
CH2OH
CH2
O
HO
H
O
HO H
OH
H
H
C
CH2
O
P
R
CH3
+
OCH2CH2NCH3
O−
CH3
a sphingomyelin
H
R
a glucocerebroside
MULTIPLE SCLEROSIS
AND THE MYELIN SHEATH
The myelin sheath is a lipid-rich material that is
wrapped around the axons of nerve cells. Composed largely of
sphingomyelins and cerebrosides, the sheath functions so as to
increase the velocity of nerve impulses. Multiple sclerosis is a
disease characterized by loss of the myelin sheath, a consequent
slowing of nerve impulses, and eventual paralysis.
PROBLEM 8
a. Draw the structures of three different sphingomyelins.
b. Draw the structure of a galactocerebroside.
PROBLEM 9
The membrane phospholipids in animals such as deer and elk have a higher degree of unsaturation in cells closer to the hoof than in cells closer to the body. Explain how this trait
can be important for survival.
Section 26.5
Prostaglandins
011
26.5 Prostaglandins
Prostaglandins are found in all body tissues and are responsible for regulating a variety of physiological responses, such as inflammation, blood pressure, blood clotting,
fever, pain, the induction of labor, and the sleep–wake cycle. All prostaglandins have
a five-membered ring with a seven-carbon carboxylic acid substituent and an eightcarbon hydrocarbon substituent. The two substituents are trans to each other.
H
COOH
H
prostaglandin skeleton
Prostaglandins are named in accordance with the format PGX, where X designates
the functional groups of the five-membered ring. PGAs, PGBs, and PGCs all contain a
carbonyl group and a double bond in the five-membered ring. The location of the double bond determines whether a prostaglandin is a PGA, PGB, or PGC. PGDs and
PGEs are b-hydroxy ketones, and PGFs are 1,3-diols. A subscript indicates the total
number of double bonds in the side chains, and “a” and “b” indicate the configuration
of the two OH groups in a PGF: “a” indicates a cis diol and “b” indicates a trans diol.
O
O
H
R1
O
R1
R2
PGAs
R2
PGBs
H
H
R1
2
H R
O
HO
H
PGCs
O
COOH
R1
R2
O
H
PGDs
Ulf Svante von Euler (1905–1983)
first identified prostaglandins—from
semen—in the early 1930s. He
named them for their source, the
prostate gland. By the time it was
realized that all cells except red
blood cells synthesize prostaglandins,
their name had become entrenched.
Von Euler was born in Stockholm and
received an M.D. from the Karolinska
Institute, where he remained as a
member of the faculty. He discovered
noradrenaline and identified its
function as a chemical intermediate
in nerve transmission. For this work,
he shared the 1970 Nobel Prize in
physiology or medicine with Julius
Axelrod and Sir Bernard Katz.
H
COOH
HO
H
HO
OH
PGE1
H
OH
PGE2
HO
H
COOH
HO
H
OH
PGF2
Prostaglandins are synthesized from arachidonic acid, a 20-carbon fatty acid with four
cis double bonds. In the cell, arachidonic acid is found esterified to the 2-position of
glycerol in many phospholipids. Arachidonic acid is synthesized from linoleic acid.
Because linoleic acid cannot be synthesized by mammals, it must be included in the diet.
An enzyme called prostaglandin endoperoxide synthase catalyzes the conversion of
arachidonic acid to PGH 2 , the precursor of all prostaglandins. There are two forms of
this enzyme; one carries out the normal physiological production of prostaglandin,
and the other synthesizes additional prostaglandin in response to inflammation. The
enzyme has two activities: a cyclooxygenase activity and a hydroperoxidase activity. It
uses its cyclooxygenase activity to form the five-membered ring. In the first step of
this transformation, a hydrogen atom is removed from a carbon flanked by two double
bonds. This hydrogen is removed relatively easily because the resulting radical is
For their work on prostaglandins,
Sune Bergström, Bengt Ingemar
Samuelsson, and John Robert Vane
shared the 1982 Nobel Prize in
physiology or medicine. Bergström
and Samuelsson were born in
Sweden—Bergström in 1916 and
Samuelsson in 1934. They are both at
the Karolinska Institute. Vane was
born in England in 1927 and is at the
Wellcome Foundation in Beckenham,
England.
012
CHAPTER 26
Lipids
stabilized by electron delocalization. The radical reacts with oxygen to form a peroxy
radical. Notice that these two steps are the same as the first two steps in the reaction
that causes fats to become rancid (Section 26.3). The peroxy radical rearranges and reacts with a second molecule of oxygen. The enzyme then uses its hydroperoxidase activity to convert the OOH group into an OH group, forming PGH 2 , which rearranges
to form PGE 2 , a prostaglandin.
biosynthesis of prostaglandins, thromboxanes, and prostacyclins
COOH
H
COOH
cyclooxygenase
H
H
arachidonic acid
O
O
COOH
a peroxy radical
O
O
O
O
H
O
H
COOH
O
OH
H
H
OOH
COOH
HO
O
H
several
steps
OH
a thromboxane
O
several
steps
O
hydroperoxidase
HH
COOH
O
H
OH
PGH2
H
COOH
HO H
OH
O H
a prostacyclin
COOH
HO H
OH
PGE2
a prostaglandin
In addition to serving as a precursor for the synthesis of prostaglandins, PGH 2 is a
precursor for the synthesis of thromboxanes and prostacyclins. Thromboxanes constrict blood vessels and stimulate the aggregation of platelets, the first step in blood
clotting. Prostacyclins have the opposite effect, dilating blood vessels and inhibiting
Section 26.5
the aggregation of platelets. The levels of these two compounds must be carefully controlled to maintain the proper balance in the blood.
Aspirin (acetylsalicylic acid) inhibits the cyclooxygenase activity of prostaglandin
endoperoxide synthase. It does this by transferring an acetyl group to a serine hydroxyl group of the enzyme (Section 17.10). Aspirin, therefore, inhibits the synthesis of
prostaglandins and, in that way, decreases the inflammation produced by these compounds. Aspirin also inhibits the synthesis of thromboxanes and prostacyclins. Overall, this causes a slight decrease in the rate of blood clotting, which is why some
doctors recommend one aspirin tablet every other day to reduce the chance of a heart
attack or stroke caused by clotting in blood vessels.
acetyl
group
serine hydroxyl
group
O
O
CH3C
+ HOCH2
O
CH3C
+ HO
OCH2
HOOC
HOOC
acetylsalicylic acid
aspirin
cyclooxygenase
active enzyme
cyclooxygenase
inactive enzyme
Other anti-inflammatory drugs, such as ibuprofen (the active ingredient in Advil®,
Motrin®, and Nuprin®) and naproxen (the active ingredient in Aleve ®), also inhibit
the synthesis of prostaglandins. They compete with either arachidonic acid or the
peroxy radical for the enzyme’s binding site.
CH3
COOH
CH3
OCCH3
O
CH3CHCH2
CHCOOH
ibuprofen
CHCOOH
CH3
CH3O
naproxen

aspirin
Both aspirin and these other nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit
the synthesis of all prostaglandins—those produced under normal physiological conditions and those produced in response to inflammation. The production of acid in the
stomach is regulated by a prostaglandin. When prostaglandin synthesis stops, therefore,
the acidity of the stomach can rise above normal levels. New drugs—Celebrex ® and
Vioxx ®—that recently have become available inhibit only the enzyme that produces
prostaglandin in response to stress. Thus, inflammatory conditions now can be treated
without some of the harmful side effects.
O
O
S
CH3
F3C
CH3
N N
O
CH3
Celebrex
O
O
S
O
Vioxx
Prostaglandins
013
014
CHAPTER 26
Lipids
Arachidonic acid can also be converted into a leukotriene. Because they induce
contraction of the muscle that lines the airways to the lungs, leukotrienes are implicated in allergic reactions, inflammatory reactions, and heart attacks. Leukotrienes also
bring on the symptoms of asthma and are implicated in anaphylactic shock, a potentially fatal allergic reaction. There are several antileukotriene agents available for the
treatment of asthma.
OH
OH
COOH
COOH
arachidonic acid
a leukotriene
PROBLEM 10
Treating PGA 2 with a strong base such as sodium tert-butoxide followed by addition of
acid converts it to PGC2 . Propose a mechanism for this reaction.
26.6 Terpenes
Terpenes are a diverse class of lipids. More than 20,000 terpenes are known. They
can be hydrocarbons, or they can contain oxygen and be alcohols, ketones, or
aldehydes. Oxygen-containing terpenes are sometimes called terpenoids. Certain
terpenes and terpenoids have been used as spices, perfumes, and medicines for many
thousands of years.
OH
HO
menthol
peppermint oil
Leopold Stephen RuzM icM ka
(1887–1976) was the first to
recognize that many organic
compounds contain multiples of five
carbons. A Croatian, Ru zMicMka
attended college in Switzerland
and became a Swiss citizen in 1917.
He was a professor of chemistry at
the University of Utrecht in the
Netherlands and later at the Federal
Institute of Technology in Zürich.
For his work on terpenes, he shared
the 1939 Nobel Prize in chemistry
with Adolph Butenandt (p. 25).
Pg number to be fixed
geraniol
geranium oil
zingiberene
oil of ginger
-selinene
oil of celery
After analyzing a large number of terpenes, organic chemists realized that they
contained carbon atoms in multiples of 5. These naturally occurring compounds contain 10, 15, 20, 25, 30, and 40 carbon atoms, which suggests that there is a compound
with five carbon atoms that serves as their building block. Further investigation
showed that their structures are consistent with the assumption that they were made by
joining together isoprene units, usually in a head-to-tail fashion. (The branched end of
isoprene is called the head, and the unbranched end is called the tail.) Isoprene is the
common name for 2-methyl-1,3-butadiene, a compound containing five carbon atoms.
That isoprene units are linked in a head-to-tail fashion to form terpenes is known as
the isoprene rule.
tail
head
tail
head
carbon skeleton of two isoprene units with a bond
between the tail of one and the head of another
Section 26.6
In the case of cyclic compounds, the linkage of the head of one isoprene unit to the tail
of another is followed by an additional linkage to form the ring. The second linkage is
not necessarily head-to-tail, but is whatever is necessary to form a stable five- or sixmembered ring.
head
head
tail
-farnesene
a sesquiterpene found in the
waxy coating on apple skins
tail
In Section 26.8, we will see that the compound actually used in the biosynthesis of
terpenes is not isoprene, but isopentenyl pyrophosphate, a compound that has the same
carbon skeleton as isoprene. We will also look at the mechanism by which isopentenyl
pyrophosphate units are joined together in a head-to-tail fashion.
Terpenes are classified according to the number of carbons they contain (Table 26.3).
Monoterpenes are composed of two isoprene units, so they have 10 carbons.
Sesquiterpenes, with 15 carbons, are composed of three isoprene units. Many fragrances and flavorings found in plants are monoterpenes and sesquiterpenes. These
compounds are known as essential oils.
O
O
head
carvone
spearmint oil
a monoterpene
tail
Table 26.3
Classification of Terpenes
Carbon atoms
Classification
Carbon atoms
Classification
10
15
20
monoterpenes
sesquiterpenes
diterpenes
25
30
40
sesterterpenes
triterpenes
tetraterpenes
Triterpenes (six isoprene units) and tetraterpenes (eight isoprene units) have important biological roles. For example, squalene, a triterpene, is a precursor of steroid
molecules (Section 26.9).
squalene
Carotenoids are tetraterpenes. Lycopene, the compound responsible for the red coloring of tomatoes and watermelon, and b-carotene, the compound that causes carrots
and apricots to be orange, are examples of carotenoids. b-Carotene is also the coloring
Terpenes
015
016
CHAPTER 26
Lipids
agent used in margarine. b-Carotene and other colored compounds are found in the
leaves of trees, but their characteristic colors are usually obscured by the green color of
chlorophyll. In the fall, when chlorophyll degrades, the colors become apparent. The
many conjugated double bonds in lycopene and b-carotene cause the compounds to be
colored (Section 8.13).
lycopene
-carotene
PROBLEM 11
Tutorial:
Isoprene units in terpenes
SOLVED
Mark off the isoprene units in menthol, zingiberene, b-selinene, and squalene.
SOLUTION
For zingiberene, we have
PROBLEM 12
One of the linkages in squalene is tail-to-tail, not head-to-tail. What does this suggest
about how squalene is synthesized in nature? (Hint: Locate the position of the tail-to-tail
linkage.)
PROBLEM 13
Mark off the isoprene units in lycopene and b-carotene. Can you detect a similarity in the
way in which squalene, lycopene, and b-carotene are biosynthesized?
26.7 Vitamin A
Vitamins A, D, E, and K are lipids (Sections 25.9 and 29.6). Vitamin A is the only
water-insoluble vitamin we have not already discussed. b-Carotene, which is cleaved
to form two molecules of vitamin A, is the major dietary source of the vitamin. Vitamin A, also called retinol, plays an important role in vision.
The retina of the eye contains cone cells and rod cells. The cone cells are responsible for color vision and for vision in bright light. The rod cells are responsible for vision in dim light. In rod cells, vitamin A is oxidized to an aldehyde and the trans
double bond at C-11 is isomerized to a cis double bond. The mechanism for the enzyme-catalyzed interconversion of cis and trans double bonds is discussed in
Section 18.15. The protein opsin uses a lysine side chain (Lys 216) to form an imine
with (11Z)-retinal, resulting in a complex known as rhodopsin. When rhodopsin
Section 26.8
Biosynthesis of Terpenes
absorbs visible light, it isomerizes to the trans isomer. This change in molecular geometry causes an electrical signal to be sent to the brain, where it is perceived as a visual
image. The trans isomer of rhodopsin is not stable and is hydrolyzed to (11E)-retinal
and opsin in a reaction referred to as bleaching of the visual pigment. (11E)-Retinal is
then converted back to (11Z)-retinal to complete the vision cycle.
the chemistry of vision
15
11
9
12
10
13
11
CH2OH
12
14
oxidation
(isomerization)
retinol
vitamin A
O
H
(11Z)-retinal
H2N
opsin
H
11
N
visible light
opsin
11
(isomerization)
12
12
activated rhodopsin
H
H+ H2O
rhodopsin
H
11
O
+
H2N
opsin
12
(11E)-retinal
The details of how the foregoing sequence of reactions creates a visual image are
not clearly understood. The fact that a simple change in configuration can be responsible for initiating a process as complicated as vision, though, is remarkable.
26.8 Biosynthesis of Terpenes
Biosynthesis of Isopentenyl Pyrophosphate
The five-carbon compound used for the biosynthesis of terpenes is 3-methyl3-butenylpyrophosphate, loosely called isopentenyl pyrophosphate by biochemists.
Each step in its biosynthesis is catalyzed by a different enzyme. The first step is the
same Claisen condensation that occurs in the first step of the biosynthesis of fatty
acids, except that the acetyl and malonyl groups remain attached to coenzyme A rather
than being transferred to the acyl carrier protein (Section 19.21). The Claisen condensation is followed by an aldol addition with a second molecule of malonyl-CoA. The
resulting thioester is reduced with two equivalents of NADPH to form mevalonic acid
(Section 25.2). A pyrophosphate group is added by means of two successive phosphorylations with ATP. Decarboxylation and loss of the OH group result in isopentenyl
pyrophosphate.
N
opsin
017
018
CHAPTER 26
Lipids
biosynthesis of isopentenyl pyrophosphate
O
O
+
SCoA
O
−O
SCoA
acetyl-CoA
O
Claisen
condensation
O
SCoA
malonyl-CoA
+
CO2
O
O
+
CoASH
acetoacetyl-CoA
1. −
O
SCoA
2. H2O
O
OH
O
COO−
P
O−
ADP
O−
OH
ATP
2 NADP+
OH
2 NADPH
SCoA
OH
+
COO−
COO−
mevalonyl phosphate
O
CoASH
+
CO2
hydroxymethylglutaryl-CoA
mevalonic acid
ATP
ADP
O
OH
O
COO−
O
O
P
O−
O
ATP
P
O−
ADP
P
O
O−
O−
O
O
O
P
O−
O−
+
+
CO2
HO
P
O−
O−
isopentenyl pyrophosphate
mevalonyl pyrophosphate
The mechanism for converting mevalonic acid into mevalonyl phosphate is essentially an SN2 reaction with an adenosyl pyrophosphate leaving group (Section 27.3). A
second SN2 reaction converts mevalonyl phosphate to mevalonyl pyrophosphate. ATP
is an excellent phosphorylating reagent for nucleophiles because its phosphoanhydride
bonds are easily broken. The reason that phosphoanhydride bonds are so easily broken
is discussed in Section 27.4.
O
O
OH
OH
COO−
mevalonic acid
+
−O
P
O−
O
P
O−
O
O
P
O−
adenosine
O
ATP
O
O
OH
P
O
COO−
O
−
O–
O
COO−
P
O−
O
P
O−
P
O−
O
adenosine
P
O−
O
O
P
O−
O
O
adenosine
P
O−
O
O
O
OH
−O
ADP
O
−O
+
O
O
P
O−
O
O−
mevalonyl pyrophosphate
+
−O
P
O−
O
O
adenosine
P
O−
O
ADP
+ H+
Section 26.8
PROBLEM 14
Biosynthesis of Terpenes
SOLVED
Give the mechanism for the last step in the biosynthesis of isopentenyl pyrophosphate,
showing why ATP is required.
SOLUTION In the last step of the biosynthesis of isopentenyl pyrophosphate, elimination of CO2 is accompanied by elimination of an -OH group, which is a strong base and
therefore a poor leaving group. ATP is used to convert the OH group into a phosphate
group, which is easily eliminated because it is a weak base.
O
OH
P
O
O−
C
O−
O
O
P
O−
O
O
+
O−
−O
P
O−
O
O
P
O−
O
P
O−
adenosine
O
ATP
O
AU: Add - H + here?
?
O
P
O
O−
O−
O
−
O
C
O
P
O−
O
O
P
O−
O
O
+
O−
−O
P
O−
P
O
O−
ADP
+ H+
O
O
O
P
O−
adenosine
O
O
O
O
P
O−
+ CO2
O−
+
HO
P
O−
O−
PROBLEM 15
Give the mechanisms for the Claisen condensation and aldol addition that occur in the first
two steps of the biosynthesis of isopentenyl pyrophosphate.
Biosynthesis of Dimethylallyl Pyrophosphate
Both isopentenyl pyrophosphate and dimethylallyl pyrophosphate are needed for
the biosynthesis of terpenes. Therefore, some isopentenyl pyrophosphate is converted
to dimethylallyl pyrophosphate by an enzyme-catalyzed isomerization reaction. The
isomerization involves addition of a proton to the sp 2 carbon of isopentenyl pyrophosphate that is bonded to the greater number of hydrogens (Section 4.4) and elimination of a proton from the carbocation intermediate in accordance with Zaitsev’s
rule (Section 11.2).
O
O
O
P
O−
O
P
O−
O
O
O−
isopentenyl pyrophosphate
H+
+
O
P
O−
O
P
O−
O
O
O−
O
P
O−
O
P
O−
O−
dimethylallyl pyrophosphate
+ H+
019
020
CHAPTER 26
Lipids
Terpene Biosynthesis
The reaction of dimethylallyl pyrophosphate with isopentenyl pyrophosphate forms
geranyl pyrophosphate, a 10-carbon compound. In the first step of the reaction,
isopentenyl pyrophosphate acts as a nucleophile and displaces a pyrophosphate group
from dimethylallyl pyrophosphate. Pyrophosphate is an excellent leaving group: Its
four OH groups have pKa values of 0.9, 2.0, 6.6, and 9.4. Therefore, three of the four
groups will be primarily in their basic forms at physiological pH 1pH = 7.32. A proton is removed in the next step, resulting in the formation of geranyl pyrophosphate.
O
O
O
P
O
O−
P
O−
O
O
+
O−
O
dimethylallyl pyrophosphate
O−
O
P
O−
O−
isopentenyl pyrophosphate
O
O
P
O
P
O−
O
P
O
O
+
O−
O−
+ H+
O
P
O−
O
P
O−
O
O
O−
+
−O
P
O−
O
P
O−
O−
pyrophosphate
geranyl pyrophosphate
The following scheme shows how some of the many monoterpenes could be synthesized from geranyl pyrophosphate:
O
O
O
P
O−
O
P
O−
O−
H2O
geranyl pyrophosphate
OH
reduction
geraniol
in rose and
geranium oils
citronellol
in rose and
geranium oils
OH
H+
H2O
H2O
+
OH
-terpineol
in juniper oil
OH
terpin hydrate
a common constituent
of cough medicine
oxidation
reduction
O
limonene
in orange and
lemon oils
OH
OH
menthol
in peppermint oil
oxidation
C O
H
citronellal
in lemon oil
Section 26.8
PROBLEM 16
Propose a mechanism for the conversion of the E isomer of geranyl pyrophosphate to the Z
isomer.
O
O
O
P
−
O
O
O
P
−
O−
O
P
O
O
O
−
O
P
O
−
O−
E isomer
Z isomer
PROBLEM 17
Propose mechanisms for the formation of a-terpineol and limonene from geranyl
pyrophosphate.
Geranyl pyrophosphate can react with another molecule of isopentenyl pyrophosphate to form farnesyl pyrophosphate, a 15-carbon compound.
O
O
O
P
O−
O
O
O
P
O−
O−
+
O
geranyl pyrophosphate
P
O−
O
P
O−
O−
isopentenyl pyrophosphate
O
O
+
O
P
O−
O
P
O−
O−
O−
+
−O
O−
+
H+
P
O−
O
P
O−
O−
O
O
O
P
O
O
O
P
O−
farnesyl pyrophosphate
Two molecules of farnesyl pyrophosphate form squalene, a 30-carbon compound.
The reaction is catalyzed by the enzyme squalene synthase, which joins the two molecules in a tail-to-tail linkage. Squalene is the precursor of cholesterol, and cholesterol
is the precursor of all other steroids.
Biosynthesis of Terpenes
021
022
CHAPTER 26
Lipids
O
O
O
P
O−
O
O
P
O−
O−
+
−O
P
O−
O
O
P
O−
farnesyl pyrophosphate
O
farnesyl pyrophosphate
squalene synthase
tail to tail
squalene
Farnesyl pyrophosphate can react with another molecule of isopentenyl pyrophosphate to form geranylgeranyl pyrophosphate, a 20-carbon compound. Two geranylgeranyl pyrophosphates can join to form phytoene, a 40-carbon compound. Phytoene is
the precursor of the carotenoid (tetraterpene) pigments in plants.
PROBLEM 18
In aqueous acidic solution, farnesyl pyrophosphate forms the following sesquiterpene:
Propose a mechanism for this reaction.
PROBLEM 19
SOLVED
If squalene were synthesized in a medium containing acetate whose carbonyl carbon were
labeled with radioactive 14C, which carbons in squalene would be labeled?
SOLUTION Acetate reacts with ATP to form acetyl adenylate, which then reacts with
CoASH to form acetyl-CoA (Section 17.20). Because malonyl-CoA is prepared from
acetyl-CoA, the thioester carbonyl carbon of malonyl-CoA will also be labeled. Examining each step of the mechanism for the biosynthesis of isopentenyl pyrophosphate from
acetyl-CoA and malonyl-CoA allows you to determine the locations of the radioactively
labeled carbons in isopentenyl pyrophosphate. Similarly, the locations of the radioactively labeled carbons in geranyl pyrophosphate can be determined from the mechanism
for its biosynthesis from isopentenyl pyrophosphate. And the locations of the radioactively labeled carbons in farnesyl pyrophosphate can be determined from the mechanism
for its biosynthesis from geranyl pyrophosphate. Knowing that squalene is obtained
from a tail-to-tail linkage of two farnesyl pyrophosphates tells you which carbons in
squalene will be labeled.
O
C
CH3
14
O
O
C
−
O
−O
O
P
O
O
O
−
P
O
O
O
−
CH3
adenosine
P
O
O
P
O−
14
adenosine
O
14
O
SCoA
acetyl-CoA
SCoA
acetyl-CoA
+ pyrophosphate
O
−
14
O
CoASH
−O
O
14
SCoA
malonyl-CoA
+
AMP
Section 26.9
O
O
14
14
023
Steroids
SCoA
acetoacetyl-CoA
O
O
14
1. −O
2. H2O
3. NADPH
4. ATP
5. ATP
14
14
O
O
O
P
P
O−
O
O−
14
O−
14
dimethylallyl pyrophosphate
O
O
O
P
P
O−
O
O−
14
14
P
O
14
C
isopentenyl pyrophosphate
O
O
OH
O−
SCoA
O−
O−
O
P
O−
O−
O
mevalonyl pyrophosphate
14
14
14
O
P
O−
O
O
O
14
O
P
O−
14
O−
14
14
14
14
O
14
farnesyl pyrophosphate
geranyl pyrophosphate
14
14
14
14
14
14
P
O−
O
O
P
O−
O−
14
14
14
14
14
14
squalene
26.9 Steroids
Hormones are chemical messengers—organic compounds synthesized in glands and
delivered by the bloodstream to target tissues in order to stimulate or inhibit some
process. Many hormones are steroids. Because steroids are nonpolar compounds, they
are lipids. Their nonpolar character allows them to cross cell membranes, so they can
leave the cells in which they are synthesized and enter their target cells.
All steroids contain a tetracyclic ring system. The four rings are designated A, B,
C, and D. A, B, and C are six-membered rings and D is a five-membered ring. The
carbons in the steroid ring system are numbered as shown.
We have seen that rings can be trans fused or cis fused and that trans fused rings
are more stable (Section 2.15). In steroids, the B, C, and D rings are all trans fused. In
most naturally occurring steroids, the A and B rings are also trans fused.
angular methyl
groups
H3C R H
H3C
CH3 and H
are trans
H
H
H
H3C R H
H
H3C
H
CH3 and H
are cis
H
H
H
12
11
1
2
10
A
3
9
B
C
8
D
14
16
15
7
5
4
13 17
6
the steroid ring system
024
CHAPTER 26
Lipids
CH3 R
CH3
H
CH3 and H
are trans
CH3 and H
are cis
H
H
A and B rings are trans fused
Heinrich Wieland, the son of a
chemist, was a professor at the
University of Munich, where he
showed that bile acids were steroids
and determined their individual
structures. During World War II, he
remained in Germany but was openly
anti-Nazi.
Adolf Windaus originally intended
to be a physician, but the experience
of working with Emil Fischer for a
year changed his mind. He
discovered that vitamin D was a
steroid, and he was the first to
recognize that vitamin B1 contained
sulfur.
H
H
H
Two German chemists, Heinrich
Otto Wieland (1877–1957) and
Adolf Windaus (1876–1959), each
received a Nobel Prize in chemistry
(Wieland in 1927 and Windaus
in 1928) for work that led to the
determination of the structure of
cholesterol.
CH3 R
CH3
A and B rings are cis fused
Many steroids have methyl groups at the 10- and 13-positions. These are called
angular methyl groups. When steroids are drawn, both angular methyl groups are
shown to be above the plane of the steroid ring system. Substituents on the same side
of the steroid ring system as the angular methyl groups are designated B-substituents
(indicated by a solid wedge). Those on the opposite side of the plane of the ring
system are A-substituents (indicated by a hatched wedge).
PROBLEM 20
A b-hydrogen at C-5 means that the A and B rings are _____ fused; an a-hydrogen at C-5
means that they are _____ fused.
The most abundant member of the steroid family in animals is cholesterol, the precursor of all other steroids. Cholesterol is biosynthesized from squalene, a triterpene
(Section 26.6). Cholesterol is an important component of cell membranes
(Figure 26.1). Its ring structure makes it more rigid than other membrane lipids. Because cholesterol has eight asymmetric carbons, 256 stereoisomers are possible, but
only one exists in nature (Chapter 5, Problem 20).
H3C
H3C
H
H
H
HO
cholesterol
The steroid hormones can be divided into five classes: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestins. Glucocorticoids and mineralocorticoids are synthesized in the adrenal cortex and are collectively known as adrenal
cortical steroids. All adrenal cortical steroids have an oxygen at C-11.
Glucocorticoids, as their name suggests, are involved in glucose metabolism, as
well as in the metabolism of proteins and fatty acids. Cortisone is an example of a
glucocorticoid. Because of its anti-inflammatory effect, it is used clinically to treat
arthritis and other inflammatory conditions.
CH2OH
CH3 C
O
H3C
O
O
OH
H3C
H
H
HC
HO
H
CH2OH
C
O
H
H
H
O
O
cortisone
aldosterone
Mineralocorticoids cause increased reabsorption of Na+, Cl-, and HCO3 - by the
kidneys, leading to an increase in blood pressure. Aldosterone is an example of a
mineralocorticoid.
Section 26.9
Steroids
025
PROBLEM 21
Is the OH substituent of the A ring of cholesterol an a-substituent or a b-substituent?
PROBLEM 22
Aldosterone is in equilibrium with its cyclic hemiacetal. Draw the hemiacetal form of
aldosterone.
Pg number to be fixed
The male sex hormones, known as androgens, are secreted by the testes. They are
responsible for the development of male secondary sex characteristics during puberty.
They also promote muscle growth. Testosterone and 5a-dihydrotestosterone are
androgens.
CH3OH
H3C
CH3OH
H
H
H3C
H
H
H
O
O
testosterone
H
H
5 -dihydrotestosterone
Adolf Friedrich Johann Butenandt
(1903–1995) was born in Germany.
He shared the 1939 Nobel Prize in
chemistry (with RuzM icM ka; see p. 14)
for isolating and determining the
structures of estrone, androsterone,
and progesterone. Forced by the Nazi
government to refuse the prize, he
accepted it after World War II. He
was the director of the Kaiser
Wilhelm Institute in Berlin and later
was a professor at the Universities of
Tübingen and Munich.
Estradiol and estrone are female sex hormones known as estrogens. They are secreted by the ovaries and are responsible for the development of female secondary sex
characteristics. They also regulate the menstrual cycle. Progesterone is the hormone
that prepares the lining of the uterus for implantation of an ovum and is essential for
the maintenance of pregnancy. It also prevents ovulation during pregnancy.
CH3
CH3 OH
H
H
estradiol
H3C
H
H
H
HO
HO
CH3 C
CH3 O
H
O
H
H
H
O
estrone
progesterone
Although the various steroid hormones have remarkably different physiological effects, their structures are quite similar. For example, the only difference between
testosterone and progesterone is the substituent at C-17, and the only difference between 5a-dihydrotestosterone and estradiol is one carbon and six hydrogens, but these
compounds make the difference between being male and being female. These examples illustrate the extreme specificity of biochemical reactions.
PROBLEM 23
The acid component of a cholesterol ester is a fatty acid such as linoleic acid. Draw the
structure of a cholesterol ester.
In addition to being the precursor of all the steroid hormones in animals, cholesterol
is the precursor of the bile acids. In fact, the word cholesterol is derived from the
Greek words chole meaning “bile” and stereos meaning “solid.” The bile acids—
cholic acid and chenodeoxycholic acid—are synthesized in the liver, stored in the gallbladder, and secreted into the small intestine, where they act as emulsifying agents so
that fats and oils can be digested by water-soluble digestive enzymes. Cholesterol is
also the precursor of vitamin D (Section 29.6).
Michael S. Brown and Joseph
Leonard Goldstein shared the 1985
Nobel Prize in physiology or
medicine for their work on the
regulation of cholesterol metabolism
and the treatment of disease caused
by elevated cholesterol levels in the
blood. Brown was born in New York
in 1941; Goldstein, in South Carolina
in 1940. They are both professors of
medicine at the University of Texas
Southwestern Medical Center.
026
CHAPTER 26
Lipids
HO
Steroids
H
HO
H3C
H
H3C
Tutorial:
COOH
COOH
CH3
H
OH
H
H
H3C
H
HO
cholic acid
H
H
OH
chenodeoxycholic acid
PROBLEM 24
Are the three OH groups of cholic acid axial or equatorial?
CHOLESTEROL AND
HEART DISEASE
particles are classified according to their density. LDL (lowdensity lipoprotein) particles transport cholesterol from the liver
to other tissues. Receptors on the surfaces of cells bind LDL particles, allowing them to be brought into the cell so that it can use
the cholesterol. HDL (high-density lipoprotein) is a cholesterol
scavenger, removing cholesterol from the surfaces of membranes and delivering it back to the liver, where it is converted
into bile acids. LDL is the so-called bad cholesterol, whereas
HDL is the “good” cholesterol. The more cholesterol we eat, the
less the body synthesizes. But this does not mean that the presence of dietary cholesterol has no effect on the total amount of
cholesterol in the bloodstream, because dietary cholesterol also
inhibits the synthesis of the LDL receptors. So the more cholesterol we eat, the less the body synthesizes, but also, the less the
body can get rid of by bringing it into target cells.
Cholesterol is probably the best-known lipid because of the correlation between cholesterol levels in the blood
and heart disease. Cholesterol is synthesized in the liver and is
also found in almost all body tissues. Cholesterol is also found
in many foods, but we do not require it in our diet because the
body can synthesize all we need. A diet high in cholesterol can
lead to high levels of cholesterol in the bloodstream, and the excess can accumulate on the walls of arteries, restricting the flow
of blood. This disease of the circulatory system is known as
atherosclerosis and is a primary cause of heart disease. Cholesterol travels through the bloodstream packaged in particles that
also contain cholesterol esters, phospholipids, and proteins. The
CLINICAL TREATMENT OF
HIGH CHOLESTEROL
terol is reduced, deaths from coronary heart disease are reduced
by 15% and total death risk is reduced by 11%.
Compactin and lovastatin are natural statins used clinically
under the trade names Zocor ® and Mevacor ®. Atorvastatin
(Lipitor)®, a synthetic statin, is now the most popular statin.
Lipitor ® has greater potency and a longer half-life than natural
statins have, because its metabolites are as active as the parent
drug in reducing cholesterol levels. Therefore, smaller doses of
the drug may be administered. The required dose is reduced
further because Lipitor ® is marketed as a single enantiomer. In
addition, it is more lipophilic than compactin and lovastatin, so
it has a greater tendency to remain in the endoplasmic reticulum of the liver cells, where it is needed.
Statins are the newest class of cholesterol-reducing drugs. Statins reduce serum cholesterol levels by inhibiting
the enzyme that catalyzes the reduction of hydroxymethylglutaryl-CoA to mevalonic acid (Section 26.8). Decreasing the
mevalonic acid concentration decreases the isopentenyl pyrophosphate concentration, so the biosynthesis of all terpenes,
including cholesterol, is diminished. As a consequence of diminished cholesterol synthesis in the liver, the liver expresses
more LDL receptors—the receptors that help clear LDL from
the bloodstream. Studies show that for every 10% that choles-
O
HO
O
H3C
O
O
O
CH3
H3C
lovastatin
Mevacor
H3C
CH3
O
HO
O
HOC
O
OH
F
OH
N
(CH3)2CH
O
H3C CH3
H3C
simvastatin
Zocor
CH3
NH
C
O
atorvastatin
Lipitor
Section 26.10
Biosynthesis of Cholesterol
027
26.10 Biosynthesis of Cholesterol
How is cholesterol, the precursor of all the steroid hormones, biosynthesized? The
starting material for the biosynthesis is the triterpene squalene, which must first be
converted to lanosterol. Lanosterol is converted to cholesterol in a series of 19 steps.
The first step in the conversion of squalene to lanosterol is epoxidation of the
2,3-double bond of squalene. Acid-catalyzed opening of the epoxide initiates a series
of cyclizations resulting in the protosterol cation. Elimination of a C-9 proton from the
cation initiates a series of 1,2-hydride and 1,2-methyl shifts, resulting in lanosterol.
biosynthesis of lanosterol and cholesterol
squalene
epoxidase
O2
H+
O
squalene
H3C
squalene oxide
H
H
H
+ H+
CH3
H
CH3
H3C
H3C
+
CH3
HO
HO
lanosterol
protosterol cation
19 steps
H3C
H3C
H
H
H
H
Konrad Bloch and Feodor Lynen
shared the 1964 Nobel Prize in
physiology or medicine. Bloch
showed how fatty acids and
cholesterol are biosynthesized from
acetate. Lynen showed that the twocarbon acetate unit is actually acetylCoA, and he determined the structure
of coenzyme A.
HO
cholesterol
Converting lanosterol to cholesterol requires removing three methyl groups from
lanosterol (in addition to reducing two double bonds and creating a new double bond).
Removing methyl groups from carbon atoms is not easy: Many different enzymes are required to carry out the 19 steps. So why does nature bother? Why not just use lanosterol
instead of cholesterol? Konrad Bloch answered that question when he found that membranes containing lanosterol instead of cholesterol are much more permeable. Small molecules are able to pass easily through lanosterol-containing membranes. As each methyl
group is removed from lanosterol, the membrane becomes less and less permeable.
PROBLEM 25
Draw the individual 1,2-hydride and 1,2-methyl shifts responsible for conversion of the protosterol cation to lanosterol. How many hydride shifts are involved? How many methyl shifts?
Konrad Emil Bloch (1912–2000)
was born in Upper Silesia (then a
part of Germany), left Nazi Germany
for Switzerland in 1934, and came to
the United States in 1936, becoming
a U.S. citizen in 1944. He received a
Ph.D. from Columbia in 1938, taught
at the University of Chicago, and
became a professor of biochemistry
at Harvard in 1954.
Feodor Lynen (1911–1979) was
born in Germany, received a Ph.D.
under Heinrich Wieland, and married
Wieland’s daughter. He was head of
the Institute of Cell Chemistry at the
University of Munich.
028
CHAPTER 26
Lipids
26.11 Synthetic Steroids
The potent physiological effects of steroids led scientists, in their search for new
drugs, to synthesize steroids that are not available in nature and to investigate their
physiological effects. Stanozolol and Dianabol are drugs developed in this way. They
have the same muscle-building effect as testosterone. Steroids that aid in the development of muscle are called anabolic steroids. These drugs are available by prescription
and are used to treat people suffering from traumas accompanied by muscle deterioration. The same drugs have been administered to athletes and racehorses to increase
their muscle mass. Stanozolol was the drug detected in several athletes in the 1988
Olympics. Anabolic steroids, when taken in relatively high dosages, have been found
to cause liver tumors, personality disorders, and testicular atrophy.
H3C
H3C
N
H3C
H
H
HN
OH
CH3
H3C
H
OH
CH3
H
H
H
O
H
stanozolol
Dianabol
Many synthetic steroids have been found to be much more potent than natural
steroids. Norethindrone, for example, is better than progesterone in arresting ovulation. Another synthetic steroid, RU 486, when taken along with prostaglandins, terminates pregnancy within the first nine weeks of gestation. Notice that these oral
contraceptives have structures similar to that of progesterone.
CH3
CH3N
H3C
OH
C
H3C
CH
H
H
H
OH
C
CCH3
H
H
H
O
O
norethindrone
RU 486
Summary
Lipids are organic compounds, found in living organisms,
that are soluble in nonpolar organic solvents. Fatty acids
are carboxylic acids with long hydrocarbon chains. Double
bonds in fatty acids have the cis configuration. Fatty acids
with more than one double bond are called polyunsaturated fatty acids. Double bonds in naturally occurring unsaturated fatty acids are separated by one methylene group.
Waxes are esters formed from long-chain carboxylic acids
and long-chain alcohols. Prostaglandins are synthesized
from arachidonic acid and are responsible for regulating a
variety of physiological responses.
Triacylglycerols (triglycerides) are compounds in which
the three OH groups of glycerol are esterified with fatty acids.
Triacylglycerols that are solids or semisolids at room temper-
ature are called fats. Liquid triacylglycerols are called oils.
Some or all of the double bonds of polyunsaturated oils can be
reduced by catalytic hydrogenation. Phosphoacylglycerols
differ from triacylglycerols in that the terminal OH group of
glycerol is esterified with phosphoric acid instead of a fatty
acid. Phosphoacylglycerols form membranes by arranging
themselves in a lipid bilayer. Phospholipids are lipids that
contain a phosphate group. Sphingolipids, also found in
membranes, contain sphingosine instead of glycerol.
Terpenes contain carbon atoms in multiples of 5. They
are made by joining together five-carbon isoprene units,
usually in a head-to-tail fashion—the isoprene rule.
Monoterpenes—terpenes with two isoprene units—have
10 carbons; sesquiterpenes have 15. Squalene, a triterpene
Problems
(a terpene with six isoprene units), is a precursor of steroid
molecules. Lycopene and b-carotene are tetraterpenes
called carotenoids. b-Carotene is cleaved to form two
molecules of vitamin A.
The five-carbon compound used for the synthesis of terpenes is isopentenyl pyrophosphate. The reaction of
dimethylallyl pyrophosphate (formed from isopentenyl
pyrophosphate) with isopentenyl pyrophosphate forms
geranyl pyrophosphate, a 10-carbon compound. Geranyl
pyrophosphate can react with another molecule of isopentenyl pyrophosphate to form farnesyl pyrophosphate, a
15-carbon compound. Two molecules of farnesyl pyrophosphate form squalene, a 30-carbon compound. Squalene is
the precursor of cholesterol. Farnesyl pyrophosphate can
react with another molecule of isopentenyl pyrophosphate
to form geranylgeranyl pyrophosphate, a 20-carbon
compound. Two geranylgeranyl pyrophosphates join to
029
form phytoene, a 40-carbon compound. Phytoene is the
precursor of the carotenoids.
Hormones are chemical messengers. Many hormones
are steroids. All steroids contain a tetracyclic ring system.
The B, C, and D rings are trans fused. In most naturally
occurring steroids, the A and B rings are also trans fused.
Methyl groups at C-10 and C-13 are called angular methyl
groups. B -Substituents are on the same side of the steroid
ring system as the angular methyl groups; A-substituents
are on the opposite side. Synthetic steroids are steroids that
are not found in nature.
The most abundant member of the steroid family in
animals is cholesterol, the precursor of all other steroids.
Cholesterol is an important component of cell membranes;
its ring structure causes it to be more rigid than other membrane lipids. In the biosynthesis of cholesterol, squalene is
converted to lanosterol, which is converted to cholesterol.
Key Terms
adrenal cortical steroids (p. 024)
anabolic steroids (p. 028)
androgens (p. 025)
angular methyl group (p. 024)
bile acids (p. 025)
carotenoid (p. 015)
cephalins (p. 008)
cerebroside (p. 010)
cholesterol (p. 024)
cis fused (p. 023)
dymethyl allyl pyrophosphate (p. 019)
essential oils (p. 015)
estrogens (p. 025)
fat (p. 005)
fatty acid (p. 002
hormone (p. 023)
isopentenyl pyrophosphate (p. 019)
isoprene rule (p. 014)
lecithins (p. 008)
lipid (p. 001)
lipid bilayer (p. 008)
leukotriene (p. 014)
membrane (p. 008)
mixed triacylglycerol (p. 004)
monoterpene (p. 015)
oil (p. 005)
phosphatidic acid (p. 008)
phosphoacylglycerol (p. 008)
phosphoglycerides (p. 008)
phospholipid (p. 008)
polyunsaturated fatty acid (p. 002)
prostacyclins (p. 012)
prostaglandin (p. 011)
sesquiterpene (p. 015)
simple triacylglycerol (p. 004)
sphingomyelins (p. 010)
sphingolipid (p. 010)
squalene (p. 015)
steroid (p. 023)
a-substituent (p. 024)
b-substituent (p. 024)
terpene (p. 014)
terpenoid (p. 014)
AU: Insert boldface
tetraterpene (p. 015)
terms in Key Terms?
thromboxanes (p. 012)
(boxed) Or make
trans fused (p. 023)
lightface in text?
triacylglycerol (p. 004)
triterpene (p. 015)
wax (p. 004)
Problems
26. An optically active fat, when completely hydrolyzed, yields twice as much stearic acid as palmitic acid. Draw the structure of the fat.
27. a. How many different triacylglycerols are there in which one of the fatty acid components is lauric acid and two are myristic acid?
b. How many different triacylglycerols are there in which one of the fatty acid components is lauric acid, one is myristic acid, and
one is palmitic acid?
28. Cardiolipins are found in heart muscles. Give the products formed when a cardiolipin undergoes complete acid-catalyzed hydrolysis.
O
O
CH2O
CR1
O
R3C
O
OCH2
CHO
CR2
O
R4C
O
OCH
CH2O
P
O
OCH2CHCH2O
−
OH
a cardiolipin
P
OCH2
−
O
030
CHAPTER 26
Lipids
29. Nutmeg contains a simple, fully saturated triacylglycerol with a molecular weight of 722. Draw its structure.
30. Give the product that would be obtained from the reaction of cholesterol with each of the following reagents: (Hint: Because of
steric hindrance from the angular methyl groups, the a-face is more susceptible to attack by reagents than the b-face.)
a. H 2O, H +
b. BH 3 in THF, followed by H 2O2 + HO c. H 2 , Pd> C
d. Br2 + H 2O
e. peroxyacetic acid
f. the product of part e + CH 3O H3C
H3C
H
H
H
HO
cholesterol
31. Dr. Cole S. Terol synthesized the following samples of mevalonic acid and fed them to a group of lemon trees:
OH
OH
OH
14
CH3CCH2CH2OH
CH3CCH2CH2OH
CH2CO−
14
CH2CO−
CH3CCH2CH2OH
14
CH2CO−
O
O
O
sample A
sample B
sample C
Which carbons in citronellal, which is isolated from lemon oil, will be labeled in trees that were fed the following?
a. sample A
b. sample B
c. sample C
32. An optically active monoterpene (compound A) with molecular formula C10H 18O undergoes catalytic hydrogenation to form an
optically inactive compound with molecular formula C10H 20O (compound B). When compound B is heated with acid, followed by
reaction with O3 , and workup under reducing conditions 1Zn, H 2O2, one of the products obtained is 4-methylcyclohexanone. Give
possible structures for compound A.
33. If junipers were allowed to grow in a medium containing acetate in which the methyl carbon was labeled with 14C, which carbons
in a-terpineol would be labeled?
34. a. Propose a mechanism for the following reaction:
H3C CH3
H3C
H3C CH3
CH3
CH3
H3C
H+
CH3
CH3 CH3
HO
+ H3O+
CH3
CH
CH3 3
H3C
CH3
b. To what class of terpene does the starting material belong? Mark off the isoprene units in the starting material.
35. 5-Androstene-3,17-dione is isomerized to 4-androstene-3,17-dione by hydroxide ion. Propose a mechanism for this reaction.
H3C
O
H3C
H3C
O
H3C
HO−
H2O
O
O
5-androstene-3,17-dione
4-androstene-3,17-dione
Problems
031
36. Both OH groups of one of the following steroid diols react with excess ethyl chloroformate, but only one OH group of the other
steroid diol reacts under the same conditions:
H3C
H3C
O
HO
CH3CH2OCCl
OH
H
CH3CH2OCO
OCOCH2CH3
H
O
5 -cholestane-3 ,7 -diol
O
H3C
H3C
O
HO
H
OH
CH3CH2OCCl
CH3CH2OCO
H
OH
O
5 -cholestane-3 ,7 -diol
Explain the difference in reactivity.
37. The acid-catalyzed dehydration of an alcohol to a rearranged alkene is known as a Wagner–Meerwein rearrangement. Propose a
mechanism for the following Wagner–Meerwein rearrangement:
OH
H+
+ H3O+
isoborneol
camphene
38. Diethylstilbestrol (DES) was given to pregnant women to prevent miscarriage, until it was found that the drug caused cancer in
both the mothers and their female children. DES has estradiol activity even though it is not a steroid. Draw DES in a way that
shows that it is structurally similar to estradiol.
CH2CH3
HO
OH
CH3CH2
diethylstilbestrol
DES