c10Lipids.

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10
Lipids
10.1 Storage Lipids 357 triacylglycerols and waxes, are described to illustrate
the diversity of structure and physical properties in this
10.2 Structural Lipids in Membranes 362 family of compounds.
10.3 Lipids as Signals, Cofactors, and Pigments 370
10.4 Working with Lipids 377 Fatty Acids Are Hydrocarbon Derivatives
Fatty acids are carboxylic acids with hydrocarbon

B
chains ranging from 4 to 36 carbons long (C4 to C36). In
iological lipids are a chemically diverse group of
some fatty acids, this chain is unbranched and fully
compounds, the common and defining feature of
saturated (contains no double bonds); in others the
which is their insolubility in water. The biological
chain contains one or more double bonds (Table 10–1).
functions of the lipids are as diverse as their chemistry.
A few contain three-carbon rings, hydroxyl groups, or
Fats and oils are the principal stored forms of energy in
methyl-group branches.
many organisms. Phospholipids and sterols are major
structural elements of biological membranes. Other lip-
ids, although present in relatively small quantities, play
KEY CONVENTION: A simplified nomenclature for unbranched
fatty acids specifies the chain length and number of
crucial roles as enzyme cofactors, electron carriers,
double bonds, separated by a colon (Fig. 10–1a); for
light-absorbing pigments, hydrophobic anchors for pro-
example, the 16-carbon saturated palmitic acid is abbre-
teins, “chaperones” to help membrane proteins fold,
viated 16:0, and the 18-carbon oleic acid, with one dou-
emulsifying agents in the digestive tract, hormones, and
ble bond, is 18:1. The positions of any double bonds are
intracellular messengers. This chapter introduces rep-
resentative lipids of each type, organized according to
their functional roles, with emphasis on their chemical
O ! 4
structure and physical properties. Although we follow a 1
C 2
functional organization for our discussion, the literally 3 9 10
18
!
O
thousands of different lipids can also be organized into
(a) 18:1("9) cis-9-Octadecenoic acid
eight general categories of chemical structure (see
Table 10–3). We discuss the energy-yielding oxidation O
!
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
1
of lipids in Chapter 17 and their synthesis in Chapter 21. C
7 6 5 4 3 2 1
!
O "

10.1 Storage Lipids (b) 20:5(" 5,8,11,14,17

) Eicosapentaenoic acid (EPA),
an omega-3 fatty acid
The fats and oils used almost universally as stored forms
FIGURE 10–1 Two conventions for naming fatty acids. (a) Standard
of energy in living organisms are derivatives of fatty nomenclature assigns the number 1 to the carboxyl carbon (C-1), and !
acids. The fatty acids are hydrocarbon derivatives, at to the carbon next to it. Each line segment of the zigzag represents a
about the same low oxidation state (that is, as highly single bond between adjacent carbons. The position of any double
reduced) as the hydrocarbons in fossil fuels. The cellu- bond(s) is indicated by D followed by a superscript number indicating
lar oxidation of fatty acids (to CO2 and H2O), like the the lower-numbered carbon in the double bond. (b) For polyunsaturated
controlled, rapid burning of fossil fuels in internal com- fatty acids (PUFAs), an alternative convention numbers the carbons in
bustion engines, is highly exergonic. the opposite direction, assigning the number 1 to the methyl carbon at
We introduce here the structures and nomenclature the other end of the chain; this carbon is also designated " (omega; the
of the fatty acids most commonly found in living organ- last letter in the Greek alphabet). The positions of the double bonds are
isms. Two types of fatty acid–containing compounds, indicated relative to the v carbon.

357
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358 Lipids

TABLE 10–1 Some Naturally Occurring Fatty Acids: Structure, Properties, and Nomenclature
Solubility at 30 8C
Carbon Common name Melting (mg/g solvent)
skeleton Structure* Systematic name† (derivation) point (8C) Water Benzene
12:0 CH3(CH2)10COOH n-Dodecanoic acid Lauric acid 44.2 0.063 2,600
(Latin laurus,
“laurel plant”)
14:0 CH3(CH2)12COOH n-Tetradecanoic acid Myristic acid 53.9 0.024 874
(Latin Myristica,
nutmeg genus)
16:0 CH3(CH2)14COOH n-Hexadecanoic acid Palmitic acid 63.1 0.0083 348
(Latin palma,
“palm tree”)
18:0 CH3(CH2)16COOH n-Octadecanoic acid Stearic acid 69.6 0.0034 124
(Greek stear,
“hard fat”)
20:0 CH3(CH2)18COOH n-Eicosanoic acid Arachidic acid 76.5
(Latin Arachis,
legume genus)
24:0 CH3(CH2)22COOH n-Tetracosanoic acid Lignoceric acid 86.0
(Latin lignum,
“wood” 1 cera,
“wax”)
16:1(D9) CH3(CH2)5CHP cis-9-Hexadecenoic Palmitoleic acid 1 to –0.5
CH(CH2)7COOH acid
18:1(D9) CH3(CH2)7CHP cis-9-Octadecenoic Oleic acid (Latin 13.4
CH(CH2)7COOH acid oleum, “oil”)
18:2(D9,12) CH3(CH2)4CHP cis-,cis-9,12- Linoleic acid 1–5
CHCH2CHP Octadecadienoic (Greek linon,
CH(CH2)7COOH acid “flax”)
18:3(D9,12,15) CH3CH2CHP cis-,cis-,cis-9,12,15- a-Linolenic acid 211
CHCH2CHP Octadecatrienoic
CHCH2CHP acid
CH(CH2)7COOH
20:4(D5,8,11,14) CH3(CH2)4CHP cis-,cis-,cis-, Arachidonic acid 249.5
CHCH2CHP cis-5,8,11,14-
CHCH2CHP Icosatetraenoic
CHCH2CHP acid
CH(CH2)3COOH
*All acids are shown in their nonionized form. At pH 7, all free fatty acids have an ionized carboxylate. Note that numbering of carbon atoms begins at the carboxyl carbon.
†
The prefix n- indicates the “normal” unbranched structure. For instance, “dodecanoic” simply indicates 12 carbon atoms, which could be arranged in a variety of branched
forms; “n-dodecanoic” specifies the linear, unbranched form. For unsaturated fatty acids, the configuration of each double bond is indicated; in biological fatty acids the
configuration is almost always cis.

specified relative to the carboxyl carbon, numbered 1, synthesis of these compounds, which involves succes-
by superscript numbers following D (delta); a 20-carbon sive condensations of two-carbon (acetate) units.
fatty acid with one double bond between C-9 and C-10 There is also a common pattern in the location of
(C-1 being the carboxyl carbon) and another between double bonds; in most monounsaturated fatty acids
C-12 and C-13 is designated 20:2(D9,12). ■ the double bond is between C-9 and C-10 (D9), and
the other double bonds of polyunsaturated fatty acids
The most commonly occurring fatty acids have even are generally D12 and D15. (Arachidonic acid is an
numbers of carbon atoms in an unbranched chain of 12 exception to this generalization.) The double bonds of
to 24 carbons (Table 10–1). As we shall see in Chapter 21, polyunsaturated fatty acids are almost never conju-
the even number of carbons results from the mode of gated (alternating single and double bonds, as in
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10.1 Storage Lipids 359

OCHPCHOCHPCHO), but are separated by a meth- unsaturated fatty acids of these lengths are oily liquids.
ylene group: OCHPCHOCH2OCHPCHO (Fig. 10–1b). This difference in melting points is due to different
In nearly all naturally occurring unsaturated fatty acids, degrees of packing of the fatty acid molecules (Fig.
the double bonds are in the cis configuration. Trans 10–2). In the fully saturated compounds, free rotation
fatty acids are produced by fermentation in the rumen around each carbon–carbon bond gives the hydrocarbon
of dairy animals and are obtained from dairy products chain great flexibility; the most stable conformation is the
and meat. fully extended form, in which the steric hindrance of
neighboring atoms is minimized. These molecules can
KEY CONVENTION: The family of polyunsaturated fatty pack together tightly in nearly crystalline arrays, with
acids (PUFAs) with a double bond between the third atoms all along their lengths in van der Waals contact
and fourth carbon from the methyl end of the chain with the atoms of neighboring molecules. In unsaturated
are of special importance in human nutrition. Because fatty acids, a cis double bond forces a kink in the hydro-
the physiological role of PUFAs is related more to the carbon chain. Fatty acids with one or several such kinks
position of the first double bond near the methyl end cannot pack together as tightly as fully saturated fatty
of the chain than to the carboxyl end, an alternative acids, and their interactions with each other are there-
nomenclature is sometimes used for these fatty acids. fore weaker. Because less thermal energy is needed to
The carbon of the methyl group—that is, the carbon disorder these poorly ordered arrays of unsaturated fatty
most distant from the carboxyl group—is called the acids, they have markedly lower melting points than sat-
! (omega) carbon and is given the number 1 (Fig. 10–1b). urated fatty acids of the same chain length (Table 10–1).
In this convention, PUFAs with a double bond between In vertebrates, free fatty acids (unesterified fatty
C-3 and C-4 are called omega-3 (!-3) fatty acids, acids, with a free carboxylate group) circulate in the
and those with a double bond between C-6 and C-7 are blood bound noncovalently to a protein carrier, serum
omega-6 (!-6) fatty acids. ■ albumin. However, fatty acids are present in blood
plasma mostly as carboxylic acid derivatives such as
Humans require but do not have the enzymatic
capacity to synthesize the omega-3 PUFA
"-linolenic acid (ALA; 18:3(D9,12,15), in the standard
convention), and must therefore obtain it in the diet. (a) Carboxyl !O O (b) !
O O
group C C
From ALA, humans can synthesize two other omega-3
PUFAs important in cellular function: eicosapentaenoic
acid (EPA; 20:5(D5,8,11,14,17), shown in Fig. 10–1b) and
docosahexaenoic acid (DHA; 22:6(D4,7,10,13,16,19)). An
imbalance of omega-6 and omega-3 PUFAs in the diet is
associated with an increased risk of cardiovascular dis-
ease. The optimal dietary ratio of omega-6 to omega-3 Hydrocarbon
chain
PUFAs is between 1:1 and 4:1, but the ratio in the diets
of most North Americans is closer to 10:1 to 30:1. The
“Mediterranean diet,” which has been associated with
lowered cardiovascular risk, is richer in omega-3 PUFAs,
(c) Saturated (d) Mixture of saturated and
obtained in leafy vegetables (salads) and fish oils. The fatty acids unsaturated fatty acids
latter oils are especially rich in EPA and DHA, and fish
oil supplements are often prescribed for individuals
with a history of cardiovascular disease. ■
The physical properties of the fatty acids, and of
compounds that contain them, are largely determined
by the length and degree of unsaturation of the hydro-
carbon chain. The nonpolar hydrocarbon chain accounts
for the poor solubility of fatty acids in water. Lauric acid
(12:0, Mr 200), for example, has a solubility in water of
0.063 mg/g—much less than that of glucose (Mr 180), FIGURE 10–2 The packing of fatty acids into stable aggregates. The
which is 1,100 mg/g. The longer the fatty acyl chain and extent of packing depends on the degree of saturation. (a) Two repre-
the fewer the double bonds, the lower is the solubility in sentations of the fully saturated acid stearic acid, 18:0 (stearate at pH
water. The carboxylic acid group is polar (and ionized at 7), in its usual extended conformation. (b) The cis double bond (red) in
neutral pH) and accounts for the slight solubility of oleic acid, 18:1(D9) (oleate), restricts rotation and introduces a rigid
short-chain fatty acids in water. bend in the hydrocarbon tail. All other bonds in the chain are free to
Melting points are also strongly influenced by the rotate. (c) Fully saturated fatty acids in the extended form pack into
length and degree of unsaturation of the hydrocarbon nearly crystalline arrays, stabilized by many hydrophobic interactions.
chain. At room temperature (25 8C), the saturated fatty (d) The presence of one or more fatty acids with cis double bonds (red)
acids from 12:0 to 24:0 have a waxy consistency, whereas interferes with this tight packing and results in less stable aggregates.
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360 Lipids

esters or amides. Lacking the charged carboxylate lower specific gravities than water, which explains why
group, these fatty acid derivatives are generally even mixtures of oil and water (oil-and-vinegar salad dress-
less soluble in water than are the free fatty acids. ing, for example) have two phases: oil, with the lower
specific gravity, floats on the aqueous phase.
Triacylglycerols Are Fatty Acid Esters of Glycerol
The simplest lipids constructed from fatty acids are the Triacylglycerols Provide Stored Energy and Insulation
triacylglycerols, also referred to as triglycerides, fats, In most eukaryotic cells, triacylglycerols form a separate
or neutral fats. Triacylglycerols are composed of three phase of microscopic, oily droplets in the aqueous cyto-
fatty acids each in ester linkage with a single glycerol sol, serving as depots of metabolic fuel. In vertebrates,
(Fig. 10–3). Those containing the same kind of fatty specialized cells called adipocytes, or fat cells, store
acid in all three positions are called simple triacylglycer- large amounts of triacylglycerols as fat droplets that
ols and are named after the fatty acid they contain. nearly fill the cell (Fig. 10–4a). Triacylglycerols are also
Simple triacylglycerols of 16:0, 18:0, and 18:1, for exam- stored as oils in the seeds of many types of plants,
ple, are tripalmitin, tristearin, and triolein, respectively. providing energy and biosynthetic precursors during
Most naturally occurring triacylglycerols are mixed; seed germination (Fig. 10–4b). Adipocytes and germi-
they contain two or three different fatty acids. To name nating seeds contain lipases, enzymes that catalyze the
these compounds unambiguously, the name and posi- hydrolysis of stored triacylglycerols, releasing fatty acids
tion of each fatty acid must be specified. for export to sites where they are required as fuel.
Because the polar hydroxyls of glycerol and the There are two significant advantages to using tri-
polar carboxylates of the fatty acids are bound in ester acylglycerols as stored fuels, rather than polysaccha-
linkages, triacylglycerols are nonpolar, hydrophobic rides such as glycogen and starch. First, the carbon
molecules, essentially insoluble in water. Lipids have atoms of fatty acids are more reduced than those of

1 3
CH2 CH2
HO 2 CH OH
OH
Glycerol

(a) 125 ! m

O 1
CH2 3 CH2 O
C O 2
CH O C
O
O
C

(b) 3 !m

1-Stearoyl, 2-linoleoyl, 3-palmitoyl glycerol, FIGURE 10–4 Fat stores in cells. (a) Cross section of human white adi-
a mixed triacylglycerol
pose tissue. Each cell contains a fat droplet (white) so large that it
FIGURE 10–3 Glycerol and a triacylglycerol. The mixed triacylglycerol squeezes the nucleus (stained red) against the plasma membrane. (b)
shown here has three different fatty acids attached to the glycerol back- Cross section of a cotyledon cell from a seed of the plant Arabidopsis.
bone. When glycerol has different fatty acids at C-1 and C-3, C-2 is a The large dark structures are protein bodies, which are surrounded by
chiral center (p. 17). stored oils in the light-colored oil bodies.
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10.1 Storage Lipids 361

sugars, and oxidation of triacylglycerols yields more triacylglycerols with unsaturated fatty acids and thus
than twice as much energy, gram for gram, as the oxida- are liquids at room temperature. Triacylglycerols con-
tion of carbohydrates. Second, because triacylglycerols taining only saturated fatty acids, such as tristearin, the
are hydrophobic and therefore unhydrated, the organ- major component of beef fat, are white, greasy solids at
ism that carries fat as fuel does not have to carry the room temperature.
extra weight of water of hydration that is associated When lipid-rich foods are exposed too long to the
with stored polysaccharides (2 g per gram of polysac- oxygen in air, they may spoil and become rancid. The
charide). Humans have fat tissue (composed primarily unpleasant taste and smell associated with rancidity
of adipocytes) under the skin, in the abdominal cavity, result from the oxidative cleavage of double bonds in
and in the mammary glands. Moderately obese people unsaturated fatty acids, which produces aldehydes and
with 15 to 20 kg of triacylglycerols deposited in their carboxylic acids of shorter chain length and therefore
adipocytes could meet their energy needs for months by higher volatility; these compounds pass readily through
drawing on their fat stores. In contrast, the human body the air to your nose. To improve the shelf life of vegeta-
can store less than a day’s energy supply in the form of ble oils used in cooking, and to increase their stability at
glycogen. Carbohydrates such as glucose do offer cer- the high temperatures used in deep-frying, commercial
tain advantages as quick sources of metabolic energy, vegetable oils are prepared by partial hydrogenation.
one of which is their ready solubility in water. This process converts many of the cis double bonds in
In some animals, triacylglycerols stored under the the fatty acids to single bonds and increases the melting
skin serve not only as energy stores but as insulation temperature of the oils so that they are more nearly
against low temperatures. Seals, walruses, penguins, solid at room temperature (margarine is produced from
and other warm-blooded polar animals are amply pad- vegetable oil in this way). Partial hydrogenation has
ded with triacylglycerols. In hibernating animals (bears, another, undesirable, effect: some cis double bonds are
for example), the huge fat reserves accumulated before converted to trans double bonds. There is now strong
hibernation serve the dual purposes of insulation and evidence that dietary intake of trans fatty acids (often
energy storage (see Box 17–1). referred to simply as “trans fats”) leads to a higher inci-
dence of cardiovascular disease, and that avoiding these
fats in the diet substantially reduces the risk of coronary
Partial Hydrogenation of Cooking Oils Produces heart disease. Dietary trans fatty acids raise the level of
Trans Fatty Acids triacylglycerols and of LDL (“bad”) cholesterol in the
Most natural fats, such as those in vegetable oils, blood, and lower the level of HDL (“good”) cholesterol,
dairy products, and animal fat, are complex mix- and these changes alone are enough to increase the risk
tures of simple and mixed triacylglycerols. These con- of coronary heart disease. But trans fatty acids may
tain a variety of fatty acids differing in chain length and have further adverse effects. They seem, for example,
degree of saturation (Fig. 10–5). Vegetable oils such as to increase the body's inflammatory response, which is
corn (maize) and olive oil are composed largely of another risk factor for heart disease. (See Chapter 21
for a description of LDL and HDL—low-density and
high-density lipoprotein—cholesterol and their health
Natural fats at 25 °C effects.)
Olive oil, Butter, Beef fat, Many fast foods are deep-fried in partially hydroge-
liquid soft solid hard solid nated vegetable oils and therefore contain high levels of
100
trans fatty acids (Table 10–2). In view of the detrimental
Fatty acids (% of total)

C16 and C18

80 saturated effects of these fats, some countries (Denmark, for
example) and some cities (New York City and Philadel-
60
phia) severely restrict the use of partially hydrogenated
C16 and C18
40 unsaturated
oils in restaurants. French fries prepared in a chain fast-
food restaurant in Denmark now contain almost no
20 C4 to C14 detectable trans fatty acids, whereas the same product
saturated
prepared in the United States contains 5 to 10 g of trans
FIGURE 10–5 Fatty acid composition of three food fats. Olive oil, butter,
fatty acids per serving (Table 10–2). The deleterious
and beef fat consist of mixtures of triacylglycerols, differing in their fatty
effects of trans fats occur at intakes of 2 to 7 g/day (20
acid composition. The melting points of these fats—and hence their to 60 kcal in a daily caloric intake of 2,000 kcal; note that
physical state at room temperature (25 8C)—are a direct function of a nutritional Calorie is the equivalent of the kilocalorie
their fatty acid composition. Olive oil has a high proportion of long-chain used by chemists and biochemists, so a 2,000 Calorie
(C16 and C18) unsaturated fatty acids, which accounts for its liquid state diet is the equivalent of a 2,000 kcal diet). A single serv-
at 25 8C. The higher proportion of long-chain (C16 and C18) saturated ing of french fries in a U.S. restaurant may contain this
fatty acids in butter increases its melting point, so butter is a soft solid at amount of trans fatty acid! Many other prepared foods,
room temperature. Beef fat, with an even higher proportion of long-chain baked goods, and snacks on the shelves of supermarkets
saturated fatty acids, is a hard solid. have comparably high levels of trans fats. ■
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362 Lipids

O
TABLE 10–2 Trans Fatty Acids in Some Typical Fast
CH3 (CH2 ) 14 C O CH2 (CH2 ) 28 CH3
Foods and Snacks
Palmitic acid 1-Triacontanol
Trans fatty acid content
(a)
In a typical As % of
serving (g) total fatty acids
French fries 4.7–6.1 28–36
Breaded fish burger 5.6 28
Breaded chicken
nuggets 5.0 25
Pizza 1.1 9
Corn tortilla chips 1.6 22
Doughnut 2.7 25
Muffin 0.7 14
Chocolate bar 0.2 2
Source: Adapted from Table 1 in Mozaffarian, D., Katan, M.B., Ascherio, P.H., Stampfer, M.J.,
& Willet, W.C. (2006). Trans fatty acids and cardiovascular disease. N. Engl. J. Med. 354,
1604–1605.
Note: All data for foods prepared with partially hydrogenated vegetable oil in the United
States in 2002. (b)

FIGURE 10–6 Biological wax. (a) Triacontanoylpalmitate, the major

component of beeswax, is an ester of palmitic acid with the alcohol
Waxes Serve as Energy Stores and Water Repellents triacontanol. (b) A honeycomb, constructed of beeswax, is firm at 25 8C
Biological waxes are esters of long-chain (C14 to C36) and completely impervious to water. The term “wax” originates in the
saturated and unsaturated fatty acids with long-chain Old English weax, meaning “the material of the honeycomb.”
(C16 to C30) alcohols (Fig. 10–6). Their melting points
(60 to 100 8C) are generally higher than those of tri-
acylglycerols. In plankton, the free-floating microorgan- atoms (usually 12 to 24); they are either saturated
isms at the bottom of the food chain for marine animals, or unsaturated, with double bonds almost always
waxes are the chief storage form of metabolic fuel. in the cis configuration.
Waxes also serve a diversity of other functions ! Triacylglycerols contain three fatty acid molecules
related to their water-repellent properties and their esterified to the three hydroxyl groups of glycerol.
firm consistency. Certain skin glands of vertebrates Simple triacylglycerols contain only one type of
secrete waxes to protect hair and skin and keep it pli- fatty acid; mixed triacylglycerols, two or three
able, lubricated, and waterproof. Birds, particularly types. Triacylglycerols are primarily storage fats;
waterfowl, secrete waxes from their preen glands to they are present in many foods.
keep their feathers water-repellent. The shiny leaves of
! Partial hydrogenation of vegetable oils in the food
holly, rhododendrons, poison ivy, and many tropical
plants are coated with a thick layer of waxes, which industry converts some cis double bonds to the
prevents excessive evaporation of water and protects trans configuration. Trans fatty acids in the diet
against parasites. are an important risk factor for coronary heart
Biological waxes find a variety of applications in the disease.
pharmaceutical, cosmetic, and other industries. Lanolin
(from lamb’s wool), beeswax (Fig. 10–6), carnauba wax 10.2 Structural Lipids in Membranes
(from a Brazilian palm tree), and wax extracted from
spermaceti oil (from whales) are widely used in the The central architectural feature of biological mem-
manufacture of lotions, ointments, and polishes. branes is a double layer of lipids, which acts as a barrier
to the passage of polar molecules and ions. Membrane
SUMMARY 10.1 Storage Lipids lipids are amphipathic: one end of the molecule is
hydrophobic, the other hydrophilic. Their hydrophobic
! Lipids are water-insoluble cellular components, of interactions with each other and their hydrophilic inter-
diverse structure, that can be extracted from actions with water direct their packing into sheets
tissues by nonpolar solvents. called membrane bilayers. In this section we describe
! Almost all fatty acids, the hydrocarbon components five general types of membrane lipids: glycerophospho-
of many lipids, have an even number of carbon lipids, in which the hydrophobic regions are composed
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10.2 Structural Lipids in Membranes 363

Storage Membrane lipids (polar)

lipids
(neutral)

Phospholipids Glycolipids Archaeal ether lipids

Triacylglycerols Glycerophospholipids Sphingolipids Sphingolipids Galactolipids (sulfolipids) PO4

Glycerol

Glycerol
Fatty acid Fatty acid Fatty acid Diphytanyl

Sphingosine

Sphingosine
Glycerol

Glycerol

Glycerol

Glycerol
Fatty acid Fatty acid Fatty acid Fatty acid Fatty acid Diphytanyl

Mono- or Mono- or
Fatty acid PO4 Alcohol PO4 Choline oligosaccharide (SO4) PO4 ( ether linkage)
disaccharide

FIGURE 10–7 Some common types of storage and membrane lipids. All fatty acid, in amide linkage to the sphingosine backbone. The membrane
the lipid types shown here have either glycerol or sphingosine as the lipids of archaea are variable; that shown here has two very long,
backbone (light red screen), to which are attached one or more long- branched alkyl chains, each end in ether linkage with a glycerol moiety.
chain alkyl groups (yellow) and a polar head group (blue). In triacylglyc- In phospholipids the polar head group is joined through a phosphodies-
erols, glycerophospholipids, galactolipids, and sulfolipids, the alkyl ter, whereas glycolipids have a direct glycosidic linkage between the
groups are fatty acids in ester linkage. Sphingolipids contain a single head-group sugar and the backbone glycerol.

of two fatty acids joined to glycerol; galactolipids and tidic acid (Fig. 10–9), according to the polar alcohol in
sulfolipids, which also contain two fatty acids esterified the head group. Phosphatidylcholine and phosphatidyl-
to glycerol, but lack the characteristic phosphate of ethanolamine have choline and ethanolamine as their
phospholipids; archaeal tetraether lipids, in which two polar head groups, for example. In all these com-
very long alkyl chains are ether-linked to glycerol at pounds, the head group is joined to glycerol through a
both ends; sphingolipids, in which a single fatty acid is phosphodiester bond, in which the phosphate group
joined to a fatty amine, sphingosine; and sterols, com- bears a negative charge at neutral pH. The polar alcohol
pounds characterized by a rigid system of four fused may be negatively charged (as in phosphatidylinositol
hydrocarbon rings. 4,5-bisphosphate), neutral (phosphatidylserine), or
The hydrophilic moieties in these amphipathic com- positively charged (phosphatidylcholine, phosphatidyl-
pounds may be as simple as a single OOH group at one ethanolamine). As we shall see in Chapter 11, these
end of the sterol ring system, or they may be much more charges contribute greatly to the surface properties of
complex. In glycerophospholipids and some sphingolip- membranes.
ids, a polar head group is joined to the hydrophobic The fatty acids in glycerophospholipids can be any of a
moiety by a phosphodiester linkage; these are the phos- wide variety, so a given phospholipid (phosphatidylcholine,
pholipids. Other sphingolipids lack phosphate but have
a simple sugar or complex oligosaccharide at their polar
ends; these are the glycolipids (Fig. 10–7). Within 1CH OH
2
O
these groups of membrane lipids, enormous diversity HO 2C H O 1 3
results from various combinations of fatty acid “tails” 2 P
3CH O P O! HO O O!
and polar “heads.” The arrangement of these lipids in 2
HO H O!
membranes, and their structural and functional roles O!
therein, are considered in the next chapter. L-Glycerol 3-phosphate (sn-glycerol 3-phosphate)

FIGURE 10–8 L-Glycerol 3-phosphate, the backbone of phospholipids.

Glycerophospholipids Are Derivatives Glycerol itself is not chiral, as it has a plane of symmetry through C-2.
of Phosphatidic Acid However, glycerol is prochiral—it can be converted to a chiral com-
pound by adding a substituent such as phosphate to either of the
Glycerophospholipids, also called phosphoglycerides,
—CH2OH groups. One unambiguous nomenclature for glycerol phos-
are membrane lipids in which two fatty acids are attached phate is the D, L system (described on p. 78), in which the isomers are
in ester linkage to the first and second carbons of glycerol, named according to their stereochemical relationships to glyceraldehyde
and a highly polar or charged group is attached through a isomers. By this system, the stereoisomer of glycerol phosphate found in
phosphodiester linkage to the third carbon. Glycerol is most lipids is correctly named either L-glycerol 3-phosphate or D-glycerol
prochiral; it has no asymmetric carbons, but attachment 1-phosphate. Another way to specify stereoisomers is the sn (stereo-
of phosphate at one end converts it into a chiral com- specific numbering) system, in which C-1 is, by definition, the group of
pound, which can be correctly named either L-glycerol the prochiral compound that occupies the pro-S position. The common
3-phosphate, D-glycerol 1-phosphate, or sn-glycerol form of glycerol phosphate in phospholipids is, by this system, sn-glycerol
3-phosphate (Fig. 10–8). Glycerophospholipids are 3-phosphate (in which C-2 has the R configuration). In archaea, the
named as derivatives of the parent compound, phospha- glycerol in lipids has the other configuration; it is D-glycerol 3-phosphate.
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364 Lipids

O
O Glycerol
Saturated fatty acid
P
(e.g., palmitic acid)
O O O X
Unsaturated fatty acid O H O!
Head-group
(e.g., linoleic acid) substituent
O
Fatty acids

Name of Net charge

glycerophospholipid Name of X O Formula of X (at pH 7)

Phosphatidic acid H 2
!2

"
Phosphatidylethanolamine Ethanolamine NH 3 0

Phosphatidylcholine Choline N" N 0

O
Phosphatidylserine Serine H
"
O! !1
NH 3

HO H
Phosphatidylglycerol Glycerol !1
OH

OH OPO32!
Phosphatidylinositol myo-Inositol 4,5- HO OPO2!
3 !4*
4,5-bisphosphate bisphosphate
OH

HO H
O O
Cardiolipin Phosphatidyl- P !2
glycerol R2 O O O
O H O!
R1
O

FIGURE 10–9 Glycerophospholipids. The common glycerophospholipids “phosphatidyl-.” In cardiolipin, two phosphatidic acids share a single
are diacylglycerols linked to head-group alcohols through a phosphodiester glycerol (R1 and R2 are fatty acyl groups). *Note that the phosphate
bond. Phosphatidic acid, a phosphomonoester, is the parent compound. esters in phosphatidylinositol 4,5-bisphosphate each have a charge of
Each derivative is named for the head-group alcohol (X), with the prefix about 21.5; one of their 2OH groups is only partially ionized at pH 7.

for example) may consist of several molecular species, Some Glycerophospholipids Have Ether-Linked
each with its unique complement of fatty acids. The
Fatty Acids
distribution of molecular species is specific for different
organisms, different tissues of the same organism, and Some animal tissues and some unicellular organisms are
different glycerophospholipids in the same cell or tis- rich in ether lipids, in which one of the two acyl chains
sue. In general, glycerophospholipids contain a C16 or is attached to glycerol in ether, rather than ester, linkage.
C18 saturated fatty acid at C-1 and a C18 or C20 unsatu- The ether-linked chain may be saturated, as in the alkyl
rated fatty acid at C-2. With few exceptions, the bio- ether lipids, or may contain a double bond between C-1
logical significance of the variation in fatty acids and and C-2, as in plasmalogens (Fig. 10–10). Vertebrate
head groups is not yet understood. heart tissue is uniquely enriched in ether lipids; about
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10.2 Structural Lipids in Membranes 365

ether-linked O FIGURE 10–10 Ether lipids. Plasmalogens have an ether-linked

alkene
P ethanolamine alkenyl chain where most glycerophospholipids have an ester-
O O O "
NH3
linked fatty acid (compare Fig. 10–9). Platelet-activating factor
O O! has a long ether-linked alkyl chain at C-1 of glycerol, but C-2 is
C ester-linked to acetic acid, which makes the compound much
O more water-soluble than most glycerophospholipids and plas-
Plasmalogen
malogens. The head-group alcohol is ethanolamine in plasmalo-
ether-linked O
alkane
gens and choline in platelet-activating factor.
P choline
O O O N
"
Platelet-activating factor O H O!

O
acetyl-ester

half of the heart phospholipids are plasmalogens. The vascular plant, and are therefore probably the most abun-
membranes of halophilic bacteria, ciliated protists, and dant membrane lipids in the biosphere. Phosphate is often
certain invertebrates also contain high proportions of the limiting plant nutrient in soil, and perhaps the evolu-
ether lipids. The functional significance of ether lipids in tionary pressure to conserve phosphate for more critical
these membranes is unknown; perhaps their resistance roles favored plants that made phosphate-free lipids.
to the phospholipases that cleave ester-linked fatty acids Plant membranes also contain sulfolipids, in which a sul-
from membrane lipids is important in some roles. fonated glucose residue is joined to a diacylglycerol in
At least one ether lipid, platelet-activating glycosidic linkage. The sulfonate group bears a negative
factor, is a potent molecular signal. It is released charge like that of the phosphate group in phospholipids.
from leukocytes called basophils and stimulates platelet
aggregation and the release of serotonin (a vasocon-
strictor) from platelets. It also exerts a variety of effects
Archaea Contain Unique Membrane Lipids
on liver, smooth muscle, heart, uterine, and lung tissues Some archaea that live in ecological niches with extreme
and plays an important role in inflammation and the conditions—high temperatures (boiling water), low pH,
allergic response. ■ high ionic strength, for example—have membrane lipids
containing long-chain (32 carbons) branched hydrocar-
bons linked at each end to glycerol (Fig. 10–12). These
Chloroplasts Contain Galactolipids and Sulfolipids linkages are through ether bonds, which are much more
The second group of membrane lipids are those that pre- stable to hydrolysis at low pH and high temperature than
dominate in plant cells: the galactolipids, in which one are the ester bonds found in the lipids of bacteria and
or two galactose residues are connected by a glycosidic eukaryotes. In their fully extended form, these archaeal
linkage to C-3 of a 1,2-diacylglycerol (Fig. 10–11; see also lipids are twice the length of phospholipids and sphingo-
Fig. 10–7). Galactolipids are localized in the thylakoid lipids, and can span the full width of the plasma mem-
membranes (internal membranes) of chloroplasts; they brane. At each end of the extended molecule is a polar
make up 70% to 80% of the total membrane lipids of a head consisting of glycerol linked to either phosphate or

O OH OH
HO
O O O
O H OH

O
Monogalactosyldiacylglycerol (MGDG)

HO OH
O HO OH
HO
HO O
O O O OH
O H O

O
Digalactosyldiacylglycerol (DGDG)

FIGURE 10–11 Two galactolipids of chloroplast thylakoid membranes. In (DGDGs) the acyl groups are both polyunsaturated and the head groups
monogalactosyldiacylglycerols (MGDGs) and digalactosyldiacylglycerols are uncharged.
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366 Lipids

Glycerol phosphate
O
Diphytanyl groups !
O P O CH2
H O HCOH
H2C O
O C2 CH2 CH2OH
1

Glycerol HC O
O CH2
3 Glycerol
H2C
O

aGlc(b1—›2)Gal-1

FIGURE 10–12 An unusual membrane lipid found only in some archaea. typically found in the membrane lipids of bacteria and eukaryotes. The
In this diphytanyl tetraether lipid, the diphytanyl moieties (yellow) are glycerol moieties in the archaeal lipids are in the R configuration, in
long hydrocarbons composed of eight five-carbon isoprene groups con- contrast to those of bacteria and eukaryotes, which have the S configu-
densed end-to-end (on the condensation of isoprene units, see Fig. ration. Archaeal lipids differ in the substituents on the glycerols. In the
21–36; also, compare the diphytanyl groups with the 20-carbon phytol molecule shown here, one glycerol is linked to the disaccharide
side chain of chlorophylls in Fig. 19–49a). In this extended form, the "-glucopyranosyl-(1→2)-#-galactofuranose; the other glycerol is linked
diphytanyl groups are about twice the length of a 16-carbon fatty acid to a glycerol phosphate head group.

sugar residues. The general name for these compounds, cells and are especially prominent in myelin, a membra-
glycerol dialkyl glycerol tetraethers (GDGTs), reflects nous sheath that surrounds and insulates the axons of
their unique structure. The glycerol moiety of the some neurons—thus the name “sphingomyelins.”
archaeal lipids is not the same stereoisomer as that in Glycosphingolipids, which occur largely in the
the lipids of bacteria and eukaryotes; the central carbon outer face of plasma membranes, have head groups with
is in the R configuration in archaea, in the S configura- one or more sugars connected directly to the —OH at
tion in bacteria and eukaryotes (Fig. 10–8). C-1 of the ceramide moiety; they do not contain phos-
phate. Cerebrosides have a single sugar linked to
Sphingolipids Are Derivatives of Sphingosine ceramide; those with galactose are characteristically
found in the plasma membranes of cells in neural tissue,
Sphingolipids, the fourth large class of membrane lip- and those with glucose in the plasma membranes of
ids, also have a polar head group and two nonpolar tails, cells in nonneural tissues. Globosides are glycosphin-
but unlike glycerophospholipids and galactolipids they golipids with two or more sugars, usually D-glucose,
contain no glycerol. Sphingolipids are composed of one D-galactose, or N-acetyl-D-galactosamine. Cerebrosides
molecule of the long-chain amino alcohol sphingosine and globosides are sometimes called neutral glycolip-
(also called 4-sphingenine) or one of its derivatives, one ids, as they have no charge at pH 7.
molecule of a long-chain fatty acid, and a polar head Gangliosides, the most complex sphingolipids, have
group that is joined by a glycosidic linkage in some oligosaccharides as their polar head groups and one or
cases and a phosphodiester in others (Fig. 10–13). more residues of N-acetylneuraminic acid (Neu5Ac), a
Carbons C-1, C-2, and C-3 of the sphingosine mol- sialic acid (often simply called “sialic acid”), at the termi-
ecule are structurally analogous to the three carbons of ni. Sialic acid gives gangliosides the negative charge at pH
glycerol in glycerophospholipids. When a fatty acid is 7 that distinguishes them from globosides. Gangliosides
attached in amide linkage to the ONH2 on C-2, the with one sialic acid residue are in the GM (M for mono-)
resulting compound is a ceramide, which is structur- series, those with two are in the GD (D for di-) series, and
ally similar to a diacylglycerol. Ceramide is the struc- so on (GT, three sialic acid residues; GQ, four).
tural parent of all sphingolipids.
There are three subclasses of sphingolipids, all
derivatives of ceramide but differing in their head groups: OH
HOH2C H
sphingomyelins, neutral (uncharged) glycolipids, and C
gangliosides. Sphingomyelins contain phosphocholine H COO!
H C
or phosphoethanolamine as their polar head group and OH
HO O
are therefore classified along with glycerophospholipids
as phospholipids (Fig. 10–7). Indeed, sphingomyelins HN
OH H
resemble phosphatidylcholines in their general proper- H3C C H
ties and three-dimensional structure, and in having no O
net charge on their head groups (Fig. 10–14). Sphingo- N-Acetylneuraminic acid (a sialic acid)
myelins are present in the plasma membranes of animal (Neu5Ac)
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10.2 Structural Lipids in Membranes 367

Sphingosine
OH
3 1
2
O X
Fatty acid
Head-group
NH substituent

Name of sphingolipid Name of X O Formula of X

Ceramide H

O
"
Sphingomyelin Phosphocholine P O CH2 CH2 N(CH3)3
!
O

CH2OH
O
Neutral glycolipids H H
Glucosylcerebroside Glucose
OH H
H
OH
H OH

Lactosylceramide Di-, tri-, or

(a globoside) tetrasaccharide

Complex
Ganglioside GM2
oligosaccharide
Johann Thudichum,
1829–1901

FIGURE 10–13 Sphingolipids. The first three carbons at the polar end of carbon atoms. Ceramide is the parent compound for this group. Other
sphingosine are analogous to the three carbons of glycerol in glycerophos- sphingolipids differ in the polar head group (X) attached at C-1. Ganglio-
pholipids. The amino group at C-2 bears a fatty acid in amide linkage. The sides have very complex oligosaccharide head groups. Standard symbols
fatty acid is usually saturated or monounsaturated, with 16, 18, 22, or 24 for sugars are used in this figure, as shown in Table 7–1.

Sphingolipids at Cell Surfaces Are Sites for which he therefore named them. In humans, at least
60 different sphingolipids have been identified in cel-
of Biological Recognition
lular membranes. Many of these are especially promi-
When sphingolipids were discovered more than a cen- nent in the plasma membranes of neurons, and some
tury ago by the physician-chemist Johann Thudichum, are clearly recognition sites on the cell surface, but a
their biological role seemed as enigmatic as the Sphinx, specific function for only a few sphingolipids has been

O
O
P
O O O
O! N"
O H
Phosphatidylcholine phosphocholine
O

H OH O
P FIGURE 10–14 The molecular structures of two types of
O O membrane lipid classes are similar. Phosphatidylcholine
O! N "
HN H (a glycerophospholipid) and sphingomyelin (a sphingolipid)
phosphocholine have similar dimensions and physical properties, but pre-
Sphingomyelin
O sumably play different roles in membranes.
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368 Lipids

Sphingosine Phospholipase A1
Ceramide Fatty acid O Antigen O
1
CH2 O C
O
2
CH O C
A Antigen

Phospholipase A2
3
C H2

O Phospholipase C
B Antigen H O P

O P O OH H H
OH HO
O! H O P
FIGURE 10–15 Glycosphingolipids as determinants of blood
groups. The human blood groups (O, A, B) are determined in H H
part by the oligosaccharide head groups of these glycosphingolipids. The Phospholipase D
same three oligosaccharides are also found attached to certain blood Phosphatidylinositol 4,5-bisphosphate
proteins of individuals of blood types O, A, and B, respectively. Standard
FIGURE 10–16 The specificities of phospholipases. Phospholipases A1
symbols for sugars are used here (see Table 7–1).
and A2 hydrolyze the ester bonds of intact glycerophospholipids at C-1 and
C-2 of glycerol, respectively. When one of the fatty acids has been removed
discovered thus far. The carbohydrate moieties of cer- by a type A phospholipase, the second fatty acid is removed by a lysophos-
tain sphingolipids define the human blood groups and pholipase (not shown). Phospholipases C and D each split one of the phos-
therefore determine the type of blood that individuals phodiester bonds in the head group. Some phospholipases act on only one
can safely receive in blood transfusions (Fig. 10–15). type of glycerophospholipid, such as phosphatidylinositol 4,5-bisphosphate
Gangliosides are concentrated in the outer surface (shown here) or phosphatidylcholine; others are less specific.
of cells, where they present points of recognition for
extracellular molecules or surfaces of neighboring cells.
this fifth group of membrane lipids is the steroid nucle-
The kinds and amounts of gangliosides in the plasma
us, consisting of four fused rings, three with six carbons
membrane change dramatically during embryonic devel-
and one with five (Fig. 10–17). The steroid nucleus is
opment. Tumor formation induces the synthesis of a
almost planar and is relatively rigid; the fused rings do
new complement of gangliosides, and very low concen-
not allow rotation about COC bonds. Cholesterol, the
trations of a specific ganglioside have been found to
major sterol in animal tissues, is amphipathic, with a
induce differentiation of cultured neuronal tumor cells.
polar head group (the hydroxyl group at C-3) and a non-
Investigation of the biological roles of diverse ganglio-
polar hydrocarbon body (the steroid nucleus and the
sides remains fertile ground for future research.
hydrocarbon side chain at C-17), about as long as a
16-carbon fatty acid in its extended form. Similar sterols
Phospholipids and Sphingolipids Are Degraded are found in other eukaryotes: stigmasterol in plants and
in Lysosomes ergosterol in fungi, for example. Bacteria cannot syn-
Most cells continually degrade and replace their membrane thesize sterols; a few bacterial species, however, can
lipids. For each hydrolyzable bond in a glycerophospholipid,
there is a specific hydrolytic enzyme in the lysosome Alkyl side chain
(Fig. 10–16). Phospholipases of the A type remove one of H 22 24 26
21
the two fatty acids, producing a lysophospholipid. (These 20 23 25
12 18 H
esterases do not attack the ether link of plasmalogens.) 17 27
11 16
Lysophospholipases remove the remaining fatty acid. C 13
H 14 D
1 19 9
Gangliosides are degraded by a set of lysosomal 2
15
10 8
enzymes that catalyze the stepwise removal of sugar A H H
Polar 3 5 B 7 Steroid nucleus
units, finally yielding a ceramide. A genetic defect in any
head HO 4 6
of these hydrolytic enzymes leads to the accumulation group
of gangliosides in the cell, with severe medical conse-
quences (Box 10–1). FIGURE 10–17 Cholesterol. In this chemical structure of cholesterol, the
rings are labeled A through D to simplify reference to derivatives of the
steroid nucleus; the carbon atoms are numbered in blue. The C-3
Sterols Have Four Fused Carbon Rings hydroxyl group (shaded blue) is the polar head group. For storage and
Sterols are structural lipids present in the membranes transport of the sterol, this hydroxyl group condenses with a fatty acid
of most eukaryotic cells. The characteristic structure of to form a sterol ester.
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10.2 Structural Lipids in Membranes 369

Abnormal Accumulations of Membrane Lipids:

BOX 10–1 MEDICINE
Some Inherited Human Diseases
The polar lipids of membranes undergo constant meta- mon is Tay-Sachs disease, in which ganglioside GM2
bolic turnover, the rate of their synthesis normally accumulates in the brain and spleen (Fig. 2) owing to
counterbalanced by the rate of breakdown. The lack of the enzyme hexosaminidase A. The symptoms
breakdown of lipids is promoted by hydrolytic of Tay-Sachs disease are progressive developmental
enzymes in lysosomes, each enzyme capable of hydro- retardation, paralysis, blindness, and death by the age
lyzing a specific bond. When sphingolipid degradation of 3 or 4 years.
is impaired by a defect in one of these enzymes Genetic counseling can predict and avert many
(Fig. 1), partial breakdown products accumulate in inheritable diseases. Tests on prospective parents
the tissues, causing serious disease. can detect abnormal enzymes, then DNA testing
For example, Niemann-Pick disease is caused by can determine the exact nature of the defect and
a rare genetic defect in the enzyme sphingomyelinase, the risk it poses for offspring. Once a pregnancy
which cleaves phosphocholine from sphingomyelin. occurs, fetal cells obtained by sampling a part of
Sphingomyelin accumulates in the brain, spleen, and the placenta (chorionic villus sampling) or the fluid
liver. The disease becomes evident in infants and surrounding the fetus (amniocentesis) can be tested
causes mental retardation and early death. More com- in the same way.

FIGURE 1 Pathways for the breakdown of GM1, globoside, and sphin-

gomyelin to ceramide. A defect in the enzyme hydrolyzing a particular
Ceramide GM1
step is indicated by ; the disease that results from accumulation of
the partial breakdown product is noted.
!-galactosidase Generalized gangliosidosis

Glc GalNAc

Gal Neu5Ac

Ceramide GM2

Globoside
hexosaminidase A Tay-Sachs disease
Ceramide

hexosaminidase
A and B Sandhoff disease

Ceramide GM3
Ceramide
ganglioside
neuraminidase
"-galactosidase A Fabry disease

Ceramide

!-galactosidase

1 !m
Sphingomyelin
Ceramide
Ceramide Phosphocholine FIGURE 2 Electron micrograph
glucocerebrosidase Gaucher disease of a portion of a brain cell from
sphingomyelinase Niemann-Pick disease an infant with Tay-Sachs dis-
ease, obtained post mortem,
Phosphocholine showing abnormal ganglioside
Ceramide deposits in the lysosomes.

incorporate exogenous sterols into their membranes. In addition to their roles as membrane constituents,
The sterols of all eukaryotes are synthesized from simple the sterols serve as precursors for a variety of products
five-carbon isoprene subunits, as are the fat-soluble vita- with specific biological activities. Steroid hormones, for
mins, quinones, and dolichols described in Section 10.3. example, are potent biological signals that regulate gene
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370 Lipids

expression. Bile acids are polar derivatives of choles- ! Sterols have four fused rings and a hydroxyl group.
terol that act as detergents in the intestine, emulsifying Cholesterol, the major sterol in animals, is both a
dietary fats to make them more readily accessible to structural component of membranes and precursor
digestive lipases. to a wide variety of steroids.
Taurine
OH
C NH CH2 CH2 SO!
3 10.3 Lipids as Signals, Cofactors,
and Pigments
17
O

The two functional classes of lipids considered thus far

(storage lipids and structural lipids) are major cellular
HO OH
components; membrane lipids make up 5% to 10% of the
Taurocholic acid
(a bile acid) dry mass of most cells, and storage lipids more than 80%
of the mass of an adipocyte. With some important excep-
We return to cholesterol and other sterols in later tions, these lipids play a passive role in the cell; lipid
chapters, to consider the structural role of cholesterol fuels are stored until oxidized by enzymes, and mem-
in biological membranes (Chapter 11), signaling by brane lipids form impermeable barriers around cells and
steroid hormones (Chapter 12), and the remarkable cellular compartments. Another group of lipids, present
biosynthetic pathway to cholesterol and transport of in much smaller amounts, have active roles in the meta-
cholesterol by lipoprotein carriers (Chapter 21). bolic traffic as metabolites and messengers. Some serve
as potent signals—as hormones, carried in the blood
from one tissue to another, or as intracellular messengers
SUMMARY 10.2 Structural Lipids in Membranes generated in response to an extracellular signal (hor-
! The polar lipids, with polar heads and nonpolar mone or growth factor). Others function as enzyme
tails, are major components of membranes. The cofactors in electron-transfer reactions in chloroplasts
most abundant are the glycerophospholipids, and mitochondria, or in the transfer of sugar moieties in
which contain fatty acids esterified to two of the a variety of glycosylation reactions. A third group con-
hydroxyl groups of glycerol, and a second alcohol, sists of lipids with a system of conjugated double bonds:
the head group, esterified to the third hydroxyl of pigment molecules that absorb visible light. Some of
glycerol via a phosphodiester bond. Other polar these act as light-capturing pigments in vision and photo-
lipids are the sterols. synthesis; others produce natural colorations, such as the
! Glycerophospholipids differ in the structure of orange of pumpkins and carrots and the yellow of canary
their head group; common glycerophospholipids feathers. Finally, a very large group of volatile lipids pro-
are phosphatidylethanolamine and duced in plants serve as signals that pass through the air,
phosphatidylcholine. The polar heads of the allowing plants to communicate with each other, and to
glycerophospholipids are charged at pH near 7. invite animal friends and deter foes. We describe in this
!
section a few representatives of these biologically active
Chloroplast membranes are rich in galactolipids,
lipids. In later chapters, their synthesis and biological
composed of a diacylglycerol with one or two
roles are considered in more detail.
linked galactose residues, and sulfolipids,
diacylglycerols with a linked sulfonated sugar
residue and thus a negatively charged head Phosphatidylinositols and Sphingosine Derivatives
group.
Act as Intracellular Signals
! Some archaea have unique membrane lipids, Phosphatidylinositol and its phosphorylated derivatives
with long-chain alkyl groups ether-linked to act at several levels to regulate cell structure and
glycerol at both ends and with sugar residues metabolism. Phosphatidylinositol 4,5-bisphosphate
and/or phosphate joined to the glycerol to provide (Fig. 10–16) in the cytoplasmic (inner) face of plasma
a polar or charged head group. These lipids are membranes serves as a reservoir of messenger molecules
stable under the harsh conditions in which that are released inside the cell in response to extracel-
these archaea live. lular signals interacting with specific surface receptors.
! The sphingolipids contain sphingosine, a long- Extracellular signals such as the hormone vasopressin
chain aliphatic amino alcohol, but no glycerol. activate a specific phospholipase C in the membrane,
Sphingomyelin has, in addition to phosphoric acid which hydrolyzes phosphatidylinositol 4,5-bisphosphate
and choline, two long hydrocarbon chains, one to release two products that act as intracellular messen-
contributed by a fatty acid and the other by gers: inositol 1,4,5-trisphosphate (IP3), which is water-
sphingosine. Three other classes of sphingolipids soluble, and diacylglycerol, which remains associated
are cerebrosides, globosides, and gangliosides, with the plasma membrane. IP3 triggers release of Ca21
which contain sugar components. from the endoplasmic reticulum, and the combination of
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10.3 Lipids as Signals, Cofactors, and Pigments 371

diacylglycerol and elevated cytosolic Ca21 activates the with injury or disease; in the formation of blood clots
enzyme protein kinase C. By phosphorylating specific and the regulation of blood pressure; in gastric acid
proteins, this enzyme brings about the cell’s response to secretion; and in various other processes important in
the extracellular signal. This signaling mechanism is human health or disease.
described more fully in Chapter 12 (see Fig. 12–10). All eicosanoids are derived from arachidonic acid
Inositol phospholipids also serve as points of nucle- (20:4(D5,8,11,14)) (Fig. 10–18), the 20-carbon polyun-
ation for supramolecular complexes involved in signal- saturated fatty acid from which they take their general
ing or in exocytosis. Certain signaling proteins bind name (Greek eikosi, “twenty”). There are three classes
specifically to phosphatidylinositol 3,4,5-trisphosphate of eicosanoids: prostaglandins, thromboxanes, and leu-
in the plasma membrane, initiating the formation of kotrienes.
multienzyme complexes at the membrane’s cytosolic Prostaglandins (PG) contain a five-carbon ring
surface. Formation of phosphatidylinositol 3,4,5- originating from the chain of arachidonic acid. Their
trisphosphate in response to extracellular signals there- name derives from the prostate gland, the tissue from
fore brings the proteins together in signaling complexes which they were first isolated by Bengt Samuelsson and
at the surface of the plasma membrane (see Fig. 12–16). Sune Bergström. Two groups of prostaglandins were
Membrane sphingolipids also can serve as sources originally defined: PGE (ether-soluble) and PGF (fosfat
of intracellular messengers. Both ceramide and sphin- (Swedish for phosphate) buffer–soluble). Each group
gomyelin (Fig. 10–13) are potent regulators of protein contains numerous subtypes, named PGE1, PGE2, PGF1,
kinases, and ceramide or its derivatives are involved in and so forth. Prostaglandins have an array of functions.
the regulation of cell division, differentiation, migration, Some stimulate contraction of the smooth muscle of the
and programmed cell death (also called apoptosis; see uterus during menstruation and labor. Others affect
Chapter 12). blood flow to specific organs, the wake-sleep cycle, and
the responsiveness of certain tissues to hormones such
as epinephrine and glucagon. Prostaglandins in a third
Eicosanoids Carry Messages to Nearby Cells group elevate body temperature (producing fever) and
Eicosanoids are paracrine hormones, substances cause inflammation and pain.
that act only on cells near the point of hormone The thromboxanes have a six-membered ring
synthesis instead of being transported in the blood to containing an ether. They are produced by platelets
act on cells in other tissues or organs. These fatty acid (also called thrombocytes) and act in the formation of
derivatives have a variety of dramatic effects on verte- blood clots and the reduction of blood flow to the site of
brate tissues. They are involved in reproductive func- a clot. As shown by John Vane, the nonsteroidal antiin-
tion; in the inflammation, fever, and pain associated flammatory drugs (NSAIDs)—aspirin, ibuprofen, and

O
8 5 1

O!
O O Arachidonate
8
11 14 O
O!
NSAIDs O!
12 O
HO OH
8
O!
Prostaglandin E1 (PGE1) Leukotriene A4
O
O
12
O
OH
Thromboxane A2

FIGURE 10–18 Arachidonic acid and some eicosanoid deriva-

tives. Arachidonic acid (arachidonate at pH 7) is the precursor
of eicosanoids, including the prostaglandins, thromboxanes, and leukotri-
enes. In prostaglandin E1, C-8 and C-12 of arachidonate are joined to form
the characteristic five-membered ring. In thromboxane A2, the C-8 and
C-12 are joined and an oxygen atom is added to form the six-membered
ring. Leukotriene A4 has a series of three conjugated double bonds.
Nonsteroidal antiinflammatory drugs (NSAIDs) such as aspirin and ibu-
profen block the formation of prostaglandins and thromboxanes from
arachidonate by inhibiting the enzyme cyclooxygenase (prostaglandin
H2 synthase). John Vane, Sune Bergström, and Bengt Samuelsson
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372 Lipids

meclofenamate, for example—inhibit the enzyme pros- tors, very low concentrations of hormones (nanomolar or
taglandin H2 synthase (also called cyclooxygenase, or less) are sufficient to produce responses in target tissues.
COX), which catalyzes an early step in the pathway The major groups of steroid hormones are the male and
from arachidonate to prostaglandins and thromboxanes female sex hormones and the hormones produced by the
(Fig. 10–18; see also Fig. 21–15). adrenal cortex, cortisol and aldosterone (Fig. 10–19).
Leukotrienes, first found in leukocytes, contain Prednisone and prednisolone are steroid drugs with
three conjugated double bonds. They are powerful bio- potent antiinflammatory activities, mediated in part by
logical signals. For example, leukotriene D4, derived from the inhibition of arachidonate release by phospholipase
leukotriene A4, induces contraction of the smooth muscle A2 and consequent inhibition of the synthesis of leukotri-
lining the airways to the lung. Overproduction of leuk- enes, prostaglandins, and thromboxanes. These drugs
otrienes causes asthmatic attacks, and leukotriene syn- have a variety of medical applications, including the
thesis is one target of antiasthmatic drugs such as treatment of asthma and rheumatoid arthritis. ■
prednisone. The strong contraction of the smooth muscle Vascular plants contain the steroidlike brassinolide
of the lungs that occurs during anaphylactic shock is part (Fig. 10–19), a potent growth regulator that increases
of the potentially fatal allergic reaction in individuals the rate of stem elongation and affects the orientation
hypersensitive to bee stings, penicillin, or other agents. ■ of cellulose microfibrils in the cell wall during growth.

Steroid Hormones Carry Messages between Tissues Vascular Plants Produce Thousands of Volatile Signals
Steroids are oxidized derivatives of sterols; they Plants produce literally thousands of different lipophilic
have the sterol nucleus but lack the alkyl chain compounds, volatile substances that are used to attract
attached to ring D of cholesterol, and they are more polar pollinators, to repel herbivores, to attract organisms that
than cholesterol. Steroid hormones move through the defend the plant against herbivores, and to communicate
bloodstream (on protein carriers) from their site of pro- with other plants. Jasmonate, for example (see Fig. 12–33),
duction to target tissues, where they enter cells, bind to derived from the fatty acid 18:3(D9,12,15) in membrane
highly specific receptor proteins in the nucleus, and trig- lipids, triggers the plant’s defenses in response to
ger changes in gene expression and thus metabolism. insect-inflicted damage. The methyl ester of jasmonate
Because hormones have very high affinity for their recep- gives the characteristic fragrance of jasmine oil, which is

O OH O
OH OH
OH
HO O OH

H H H
H H H H H H
O O O
Testosterone Cortisol Prednisone

OH O OH O
O OH
OH
HO HO
H H H
H H H H H H
HO O O
#-Estradiol Aldosterone Prednisolone

OH
H

FIGURE 10–19 Steroids derived from cholesterol. H OH

Testosterone, the male sex hormone, is produced in
H
the testes. Estradiol, one of the female sex hormones, is HO
produced in the ovaries and placenta. Cortisol and aldoste- H H
rone are hormones synthesized in the cortex of the adrenal
HO O
gland; they regulate glucose metabolism and salt excre- H
tion, respectively. Prednisone and prednisolone are syn- O
thetic steroids used as antiinflammatory agents. Brassi- Brassinolide
nolide is a growth regulator found in vascular plants. (a brassinosteroid)
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10.3 Lipids as Signals, Cofactors, and Pigments 373

widely used in the perfume industry. Many of the plant photochemical reaction driven by the UV component of
volatiles are derived from fatty acids, or from compounds sunlight (Fig. 10–20a). Vitamin D3 is not itself biologi-
made by the condensation of five-carbon isoprene units; cally active, but it is converted by enzymes in the liver
these include geraniol (the characteristic scent of gerani- and kidney to 1!,25-dihydroxyvitamin D3 (calcitriol), a
ums), "-pinene (pine trees), limonene (limes), menthol, hormone that regulates calcium uptake in the intestine
and carvone (see Fig. 1–24a), to name but a few. and calcium levels in kidney and bone. Deficiency of
CH3
vitamin D leads to defective bone formation and the dis-
ease rickets, for which administration of vitamin D pro-
CH2 C CH CH2 duces a dramatic cure (Fig. 10–20b). Vitamin D2 (ergo-
Isoprene calciferol) is a commercial product formed by UV
irradiation of the ergosterol of yeast. Vitamin D2 is struc-
Vitamins A and D Are Hormone Precursors turally similar to D3, with slight modification to the side
During the first third of the twentieth century, a chain attached to the sterol D ring. Both have the same
major focus of research in physiological chemistry biological effects, and D2 is commonly added to milk and
was the identification of vitamins, compounds that are butter as a dietary supplement. Like steroid hormones,
essential to the health of humans and other vertebrates the product of vitamin D metabolism, 1!,25-dihydroxyvi-
but cannot be synthesized by these animals and must tamin D3, regulates gene expression by interacting with
therefore be obtained in the diet. Early nutritional studies specific nuclear receptor proteins (pp. 1182–1183).
identified two general classes of such compounds: those Vitamin A (retinol), in its various forms, functions
soluble in nonpolar organic solvents (fat-soluble vitamins) as a hormone and as the visual pigment of the vertebrate
and those that could be extracted from foods with aque- eye (Fig. 10–21). Acting through receptor proteins in
ous solvents (water-soluble vitamins). Eventually the fat- the cell nucleus, the vitamin A derivative retinoic acid
soluble group was resolved into the four vitamin groups A, regulates gene expression in the development of epithelial
D, E, and K, all of which are isoprenoid compounds syn- tissue, including skin. Retinoic acid is the active ingredi-
thesized by the condensation of multiple isoprene units. ent in the drug tretinoin (Retin-A), used in the treatment
Two of these (D and A) serve as hormone precursors. of severe acne and wrinkled skin. Retinal, another vitamin
Vitamin D3, also called cholecalciferol, is nor- A derivative, is the pigment that initiates the response of
mally formed in the skin from 7-dehydrocholesterol in a rod and cone cells of the retina to light, producing a

(a) H 22 24 27 H
21
20 23 25 25
12 18 H H OH
17 26
11 16
13
H 22 24 26 9
14
15
21 8
20 23 25 H H
12 18 H 7
11 17 16 27 UV light 6
13
1 19 9 14
15 19
2 4 5
10 8 10
H H 2 steps (in skin) 1 step in the liver
3 7 3 1 step in the kidney 1
HO 5 HO 1 HO OH
4 6 2

7-Dehydrocholesterol Cholecalciferol (vitamin D3) 1!,25-Dihydroxyvitamin D3

(calcitriol)

FIGURE 10–20 Vitamin D3 production and metabolism.

(a) Cholecalciferol (vitamin D3) is produced in the skin by UV
irradiation of 7-dehydrocholesterol, which breaks the bond shaded light red.
In the liver, a hydroxyl group is added at C-25; in the kidney, a second
hydroxylation at C-1 produces the active hormone, 1!,25-dihydroxyvitamin D3.
This hormone regulates the metabolism of Ca21 in kidney, intestine, and
bone. (b) Dietary vitamin D prevents rickets, a disease once common in
cold climates where heavy clothing blocks the UV component of sunlight
necessary for the production of vitamin D3 in skin. In this detail from a large
mural by John Steuart Curry, The Social Benefits of Biochemical Research (1943),
the people and animals on the left show the effects of poor nutrition, includ-
ing the bowed legs of a boy with classical rickets. On the right are the peo-
ple and animals made healthier with the “social benefits of research,”
including the use of vitamin D to prevent and treat rickets. This mural is in
the Department of Biochemistry at the University of Wisconsin–Madison. (b)
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374 Lipids

Retinoic acid Hormonal

(d) signal to
oxidation
of aldehyde epithelial
to acid cells

2
6

7
visible
light

Neuronal
point of oxidation of signal
alcohol to to brain
cleavage 11
aldehyde
11 11

12 12

CH2OH C C
15 H O
H O
Vitamin A1 11-cis-Retinal all-trans-Retinal
(retinol) (visual pigment)
(b) (c) (e)

#-Carotene
(a)

FIGURE 10–21 Vitamin A1 and its precursor and derivatives. (a) #- spread in nature. In the dark, retinal of rhodopsin is in the 11-cis form (c).
Carotene is the precursor of vitamin A1. Isoprene structural units are set When a rhodopsin molecule is excited by visible light, the 11-cis-retinal
off by dashed red lines (see p. 373). Cleavage of #-carotene yields two undergoes a series of photochemical reactions that convert it to all-
molecules of vitamin A1 (retinol) (b). Oxidation at C-15 converts retinol trans-retinal (e), forcing a change in the shape of the entire rhodopsin
to the aldehyde, retinal (c), and further oxidation produces retinoic acid molecule. This transformation in the rod cell of the vertebrate retina
(d), a hormone that regulates gene expression. Retinal combines with sends an electrical signal to the brain that is the basis of visual transduc-
the protein opsin to form rhodopsin (not shown), a visual pigment wide- tion, a topic we address in more detail in Chapter 12.

neuronal signal to the brain. This role of retinal is unsaturated fatty acids from oxidation and preventing
described in detail in Chapter 12. oxidative damage to membrane lipids, which can cause
Vitamin A was first isolated from fish liver oils; liver, cell fragility. Tocopherols are found in eggs and vegeta-
eggs, whole milk, and butter are also good dietary sources. ble oils and are especially abundant in wheat germ.
In vertebrates, #-carotene, the pigment that gives car- Laboratory animals fed diets depleted of vitamin E
rots, sweet potatoes, and other yellow vegetables their develop scaly skin, muscular weakness and wasting, and
characteristic color, can be enzymatically converted to sterility. Vitamin E deficiency in humans is very rare;
vitamin A. Deficiency of vitamin A leads to a variety of the principal symptom is fragile erythrocytes.
symptoms in humans, including dryness of the skin, The aromatic ring of vitamin K (Fig. 10–22b)
eyes, and mucous membranes; retarded development undergoes a cycle of oxidation and reduction during the
and growth; and night blindness, an early symptom com- formation of active prothrombin, a blood plasma protein
monly used in diagnosing vitamin A deficiency. ■ essential in blood clotting. Prothrombin is a proteolytic
enzyme that splits peptide bonds in the blood protein
Vitamins E and K and the Lipid Quinones Are fibrinogen to convert it to fibrin, the insoluble fibrous
protein that holds blood clots together (see Fig. 6–39).
Oxidation-Reduction Cofactors
Henrik Dam and Edward A. Doisy independently dis-
Vitamin E is the collective name for a group of covered that vitamin K deficiency slows blood clotting,
closely related lipids called tocopherols, all of which can be fatal. Vitamin K deficiency is very uncom-
which contain a substituted aromatic ring and a long mon in humans, aside from a small percentage of infants
isoprenoid side chain (Fig. 10–22a). Because they are who suffer from hemorrhagic disease of the newborn, a
hydrophobic, tocopherols associate with cell mem- potentially fatal disorder. In the United States, new-
branes, lipid deposits, and lipoproteins in the blood. borns are routinely given a 1 mg injection of vitamin K.
Tocopherols are biological antioxidants. The aromatic Vitamin K1 (phylloquinone) is found in green plant
ring reacts with and destroys the most reactive forms of leaves; a related form, vitamin K2 (menaquinone), is
oxygen radicals and other free radicals, protecting formed by bacteria living in the vertebrate intestine.
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10.3 Lipids as Signals, Cofactors, and Pigments 375

CH3
HO CH3 CH3 CH3
(a)
Vitamin E: an antioxidant CH2 CH2 CH2 CH CH2 CH2 CH2 CH CH2 CH2 CH2 CH CH3
H3C O CH3
CH3

O
(b)
CH3 CH3 CH3 CH3
Vitamin K1: a blood-clotting
cofactor (phylloquinone) CH2 CH C CH2 "CH2 CH2 CH CH2 ! 2 CH2 CH2 CH CH3

O O
(c)
Warfarin: a blood
anticoagulant CH
OH
CH2 C CH3
O

O
(d) H3CO CH3
Ubiquinone: a mitochondrial CH3 CH3 CH3
electron carrier (coenzyme Q)
(n ! 4 to 8) H3CO CH2 CH C CH2 "CH2 CH C CH2 ! n CH2 CH C CH3
O

O
H 3C
(e)
CH3 CH3 CH3
Plastoquinone: a chloroplast
electron carrier (n ! 4 to 8) H3C CH2 CH C CH2 "CH2 CH C CH2 ! n CH2 CH C CH3
O

(f) CH3 CH3 CH3

Dolichol: a sugar carrier
(n ! 9 to 22) HO CH2 CH2 CH CH2 "CH2 CH C CH2 ! n CH2 CH C CH3

FIGURE 10–22 Some other biologically active isoprenoid compounds or 10 isoprene units. Dolichols of animals have 17 to 21 isoprene units (85
derivatives. Units derived from isoprene are set off by dashed red lines. to 105 carbon atoms), bacterial dolichols have 11, and those of plants
In most mammalian tissues, ubiquinone (also called coenzyme Q) has and fungi have 14 to 24.

Ubiquinone (also called coenzyme Q) and plasto-

quinone (Fig. 10–22d, e) are isoprenoids that function
as lipophilic electron carriers in the oxidation-reduction
reactions that drive ATP synthesis in mitochondria and
chloroplasts, respectively. Both ubiquinone and plasto-
quinone can accept either one or two electrons and
either one or two protons (see Fig. 19–3).

Dolichols Activate Sugar Precursors for Biosynthesis

During assembly of the complex carbohydrates of bac-
Henrik Dam, Edward A. Doisy,
1895–1976 1893–1986
terial cell walls, and during the addition of polysaccha-
ride units to certain proteins (glycoproteins) and lipids
Warfarin (Fig. 10–22c) is a synthetic compound (glycolipids) in eukaryotes, the sugar units to be added
that inhibits the formation of active prothrombin. It is are chemically activated by attachment to isoprenoid
particularly poisonous to rats, causing death by internal alcohols called dolichols (Fig. 10–22f). These com-
bleeding. Ironically, this potent rodenticide is also an pounds have strong hydrophobic interactions with
invaluable anticoagulant drug for treating humans at membrane lipids, anchoring the attached sugars to the
risk for excessive blood clotting, such as surgical membrane, where they participate in sugar-transfer
patients and those with coronary thrombosis. ■ reactions.
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376 Lipids

O Canthaxanthin
(bright red)

OH

HO
Zeaxanthin
(bright yellow)

FIGURE 10–23 Lipids as pigments in plants and bird feathers. Com- ments that color their feathers red or yellow by eating plant materials
pounds with long conjugated systems absorb light in the visible region of that contain carotenoid pigments, such as canthaxanthin and zeaxanthin.
the spectrum. Subtle differences in the chemistry of these compounds The differences in pigmentation between male and female birds are the
produce pigments of strikingly different colors. Birds acquire the pig- result of differences in intestinal uptake and processing of carotenoids.

Many Natural Pigments Are Lipidic Conjugated Dienes Polyketides Are Natural Products with Potent
Conjugated dienes have carbon chains with alternating Biological Activities
single and double bonds. Because this structural Polyketides are a diverse group of lipids with biosyn-
arrangement allows the delocalization of electrons, the thetic pathways (Claisen condensations) similar to
compounds can be excited by low-energy electromag- those for fatty acids. They are secondary metabolites,
netic radiation (visible light), giving them colors visible compounds that are not central to an organism’s
to humans and other animals. Carotene (Fig. 10–21) is metabolism but that serve some subsidiary function
yellow-orange; similar compounds give bird feathers that gives their producers an advantage in some eco-
their striking reds, oranges, and yellows (Fig. 10–23). logical niche. Many polyketides find use in medicine
Like sterols, steroids, dolichols, vitamins A, E, D, and K, as antibiotics (erythromycin), antifungals (amphoteri-
ubiquinone, and plastoquinone, these pigments are syn- cin B), or inhibitors of cholesterol synthesis (lova-
thesized from five-carbon isoprene derivatives; the bio- statin) (Fig. 10–24).
synthetic pathway is described in detail in Chapter 21.

O
OH
OH
O OH
HO OH
OH N(CH3)2 O OH OH OH OH O O
HO HO

O O O H OH

O O OH O O
H
OH
O HO OH
H
NH2
Erythromycin (antibiotic) Amphotericin B (antifungal)

HO O

O O
H
O
H H

FIGURE 10–24 Three polyketide natural products

Lovastatin (statin) used in human medicine.
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10.4 Working with Lipids 377

SUMMARY 10.3 Lipids as Signals, Cofactors, and Pigments Lipid Extraction Requires Organic Solvents
! Some types of lipids, although present in relatively Neutral lipids (triacylglycerols, waxes, pigments, and
small quantities, play critical roles as cofactors or so forth) are readily extracted from tissues with ethyl
signals. ether, chloroform, or benzene, solvents that do not
! Phosphatidylinositol bisphosphate is hydrolyzed to permit lipid clustering driven by hydrophobic interac-
yield two intracellular messengers, diacylglycerol tions. Membrane lipids are more effectively extracted
and inositol 1,4,5-trisphosphate. Phosphatidylinositol
Tissue (a) Cells
3,4,5-trisphosphate is a nucleation point for homogenize in
chloroform/methanol/water
supramolecular protein complexes involved in
biological signaling.
! Prostaglandins, thromboxanes, and leukotrienes
(the eicosanoids), derived from arachidonate, are
extremely potent hormones.
!
Methanol + water
Steroid hormones, such as the sex hormones, are
derived from sterols. They serve as powerful Chloroform + lipids
biological signals, altering gene expression in
target cells.
! Vitamins D, A, E, and K are fat-soluble compounds (b) separate major classes first (c) use “shotgun” approach
made up of isoprene units. All play essential roles
in the metabolism or physiology of animals. Adsorption Direct mass
Thin-layer
chromatography, spectrometry
Vitamin D is precursor to a hormone that regulates chromatography
gas chromatography, of total extract
calcium metabolism. Vitamin A furnishes the visual HPLC
pigment of the vertebrate eye and is a regulator of
gene expression during epithelial cell growth.
Vitamin E functions in the protection of membrane
lipids from oxidative damage, and vitamin K is
essential in the blood-clotting process.
! Ubiquinones and plastoquinones, also isoprenoid
derivatives, are electron carriers in mitochondria
and chloroplasts, respectively.
! Dolichols activate and anchor sugars to cellular
membranes; the sugar groups are then used in the
synthesis of complex carbohydrates, glycolipids,
and glycoproteins.
! Lipidic conjugated dienes serve as pigments in
flowers and fruits and give bird feathers their mass spectrometry of different types, conditions, and monitoring modes
striking colors.
! Polyketides are natural products widely used in
Lipidome
medicine.
FIGURE 10-25 Common procedures in the extraction, separation, and
identification of cellular lipids. (a) Tissue is homogenized in a chloroform/
10.4 Working with Lipids methanol/water mixture, which on addition of water and removal of
unextractable sediment by centrifugation yields two phases. (b) Major
Because lipids are insoluble in water, their extraction
classes of extracted lipids in the chloroform phase may first be separated
and subsequent fractionation require the use of organic by thin-layer chromatography (TLC), in which lipids are carried up a silica
solvents and some techniques not commonly used in gel–coated plate by a rising solvent front, less-polar lipids traveling farther
the purification of water-soluble molecules such as pro- than more-polar or charged lipids, or by adsorption chromatography on
teins and carbohydrates. In general, complex mixtures a column of silica gel, through which solvents of increasing polarity are
of lipids are separated by differences in polarity or solu- passed. For example, column chromatography with appropriate solvents
bility in nonpolar solvents. Lipids that contain ester- or can be used to separate closely related lipid species such as phosphati-
amide-linked fatty acids can be hydrolyzed by treat- dylserine, phosphatidylglycerol, and phosphatidylinositol. Once separ-
ment with acid or alkali or with specific hydrolytic ated, each lipid's complement of fatty acids can be determined by mass
enzymes (phospholipases, glycosidases) to yield their spectrometry. (c) Alternatively, in the “shotgun” approach, an unfrac-
components for analysis. Some methods commonly tionated extract of lipids can be directly subjected to high-resolution
used in lipid analysis are shown in Figure 10–25 and mass spectrometry of different types and under different conditions to
discussed below. determine the total composition of all the lipids: the lipidome.
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378 Lipids

by more polar organic solvents, such as ethanol or Gas-Liquid Chromatography Resolves Mixtures
methanol, which reduce the hydrophobic interactions
of Volatile Lipid Derivatives
among lipid molecules while also weakening the hydro-
gen bonds and electrostatic interactions that bind Gas-liquid chromatography separates volatile compo-
membrane lipids to membrane proteins. A commonly nents of a mixture according to their relative tendencies
used extractant is a mixture of chloroform, methanol, to dissolve in the inert material packed in the chroma-
and water, initially in volume proportions (1:2:0.8) that tography column or to volatilize and move through the
are miscible, producing a single phase. After tissue is column, carried by a current of an inert gas such as
homogenized in this solvent to extract all lipids, more helium. Some lipids are naturally volatile, but most must
water is added to the resulting extract and the mixture first be derivatized to increase their volatility (that is,
separates into two phases, methanol/water (top phase) lower their boiling point). For an analysis of the fatty
and chloroform (bottom phase). The lipids remain in acids in a sample of phospholipids, the lipids are first
the chloroform layer, and the more polar molecules transesterified: heated in a methanol/HCl or methanol/
such as proteins and sugars partition into the methanol/ NaOH mixture to convert fatty acids esterified to glyc-
water layer (Fig. 10–25a). erol into their methyl esters. These fatty acyl methyl
esters are then loaded onto the gas-liquid chromatogra-
phy column, and the column is heated to volatilize the
Adsorption Chromatography Separates Lipids compounds. Those fatty acyl esters most soluble in the
of Different Polarity column material partition into (dissolve in) that mate-
Complex mixtures of tissue lipids can be fractionated by rial; the less soluble lipids are carried by the stream of
chromatographic procedures based on the different inert gas and emerge first from the column. The order
polarities of each class of lipid (Fig. 10–25b). In adsorp- of elution depends on the nature of the solid adsorbant
tion chromatography, an insoluble, polar material such in the column and on the boiling point of the compo-
as silica gel (a form of silicic acid, Si(OH)4) is packed nents of the lipid mixture. Using these techniques, mix-
into a glass column, and the lipid mixture (in chloro- tures of fatty acids of various chain lengths and various
form solution) is applied to the top of the column. (In degrees of unsaturation can be completely resolved.
high-performance liquid chromatography, the column is
of smaller diameter and solvents are forced through the Specific Hydrolysis Aids in Determination
column under high pressure.) The polar lipids bind of Lipid Structure
tightly to the polar silicic acid, but the neutral lipids
Certain classes of lipids are susceptible to degradation
pass directly through the column and emerge in the first
under specific conditions. For example, all ester-linked
chloroform wash. The polar lipids are then eluted, in
fatty acids in triacylglycerols, phospholipids, and sterol
order of increasing polarity, by washing the column with
esters are released by mild acid or alkaline treatment,
solvents of progressively higher polarity. Uncharged but
and somewhat harsher hydrolysis conditions release
polar lipids (cerebrosides, for example) are eluted with
amide-bound fatty acids from sphingolipids. Enzymes
acetone, and very polar or charged lipids (such as glyc-
that specifically hydrolyze certain lipids are also useful in
erophospholipids) are eluted with methanol.
the determination of lipid structure. Phospholipases A, C,
Thin-layer chromatography on silicic acid employs
and D (Fig. 10–16) each split particular bonds in phos-
the same principle (Fig. 10–25b). A thin layer of silica
pholipids and yield products with characteristic solubili-
gel is spread onto a glass plate, to which it adheres. A
ties and chromatographic behaviors. Phospholipase C, for
small sample of lipids dissolved in chloroform is applied
example, releases a water-soluble phosphoryl alcohol
near one edge of the plate, which is dipped in a shallow
(such as phosphocholine from phosphatidylcholine) and
container of an organic solvent or solvent mixture; the
a chloroform-soluble diacylglycerol, each of which can be
entire setup is enclosed in a chamber saturated with
characterized separately to determine the structure of
the solvent vapor. As the solvent rises on the plate by
the intact phospholipid. The combination of specific
capillary action, it carries lipids with it. The less polar
hydrolysis with characterization of the products by thin-
lipids move farthest, as they have less tendency to bind
layer, gas-liquid, or high-performance liquid chromatog-
to the silicic acid. The separated lipids can be detected
raphy often allows determination of a lipid structure.
by spraying the plate with a dye (rhodamine) that fluo-
resces when associated with lipids, or by exposing the
plate to iodine fumes. Iodine reacts reversibly with the Mass Spectrometry Reveals Complete Lipid Structure
double bonds in fatty acids, such that lipids containing To establish unambiguously the length of a hydrocarbon
unsaturated fatty acids develop a yellow or brown chain or the position of double bonds, mass spectrometric
color. Several other spray reagents are also useful in analysis of lipids or their volatile derivatives is invaluable.
detecting specific lipids. For subsequent analysis, The chemical properties of similar lipids (for example,
regions containing separated lipids can be scraped two fatty acids of similar length unsaturated at different
from the plate and the lipids recovered by extraction positions, or two isoprenoids with different numbers of
with an organic solvent. isoprene units) are very much alike, and their order of
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10.4 Working with Lipids 379

100
371 M+
90 O
H
80 C O C
92 H
70 N 108 178 220 260 300 328 356
92 164 206 234 274 314 342
Abundance (%)

60

50 108 164

40

30 67
260 314
328
20 55 151 274
220 300
10 178 206
123 234
356
0
60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380
m/z

FIGURE 10–26 Determination of fatty acid structure by mass spec- The prominent ions at m/z 5 92, 108, 151, and 164 contain the pyridine
trometry. The fatty acid is first converted to a derivative that minimizes ring of the picolinol and various fragments of the carboxyl group, show-
migration of the double bonds when the molecule is fragmented by ing that the compound is indeed a picolinyl ester. The molecular ion, M1
electron bombardment. The derivative shown here is a picolinyl ester of (m/z 5 371), confirms the presence of a C18 fatty acid with two double
linoleic acid—18:2(D9,12) (Mr 371)—in which the alcohol is picolinol bonds. The uniform series of ions 14 atomic mass units (u) apart repre-
(red). When bombarded with a stream of electrons, this molecule is sents loss of each successive methyl and methylene group from the methyl
volatilized and converted to a parent ion (M1; Mr 371), in which the N end of the acyl chain (beginning at C-18; the right end of the molecule as
atom bears the positive charge, and a series of smaller fragments pro- shown here), until the ion at m/z 5 300 is reached. This is followed by a
duced by breakage of COC bonds in the fatty acid. The mass spec- gap of 26 u for the carbons of the terminal double bond, at m/z 5 274; a
trometer separates these charged fragments according to their mass/ further gap of 14 u for the C-11 methylene group, at m/z 5 260; and so
charge ratio (m/z). (To review the principles of mass spectrometry, see forth. By this means the entire structure is determined, although these data
pp. 100–102.) alone do not reveal the configuration (cis or trans) of the double bonds.

elution from the various chromatographic procedures example, all glycerophosphocholines are GP01; the sub-
often does not distinguish between them. When the elu- group of glycerophosphocholines with two fatty acids in
ate from a chromatography column is sampled by mass ester linkage is designated GP0101; with one fatty acid
spectrometry, however, the components of a lipid mixture ether-linked at position 1 and one in ester linkage at
can be simultaneously separated and identified by their position 2, this becomes GP0102. Specific fatty acids are
unique pattern of fragmentation (Fig. 10–26). With the designated by numbers that give every lipid its own
increased resolution of mass spectrometry, it is possible unique identifier, so that each individual lipid, including
to identify individual lipids in very complex mixtures with- lipid types not yet discovered, can be unambiguously
out first fractionating the lipids in a crude extract. This described in terms of a 12-character identifier. One fac-
“shotgun” method (Fig. 10–25c) avoids losses during pre- tor used in this classification is the nature of the biosyn-
liminary separation of lipid subclasses, and it is faster. thetic precursor. For example, prenol lipids (dolichols
and vitamins E and K, for example) are formed from
isoprenyl precursors. Polyketides include some natural
Lipidomics Seeks to Catalog All Lipids products, many toxic, with biosynthetic pathways relat-
and Their Functions ed to those for fatty acids. The eight chemical categories
In exploring the biological role of lipids in cells and tis- in Table 10–3 do not coincide perfectly with the divisions
sues, it is important to know which lipids are present and according to biological function that we have used in this
in what proportions, and to know how this lipid composi- chapter. For example, the structural lipids of mem-
tion changes with embryonic development, disease, or branes include both glycerophospholipids and sphingo-
drug treatment. As lipid biochemists have become aware lipids, separate categories in Table 10–3. Each method
of the thousands of different naturally occurring lipids, of categorization has its advantages.
they have proposed a new nomenclature system, with The application of mass spectrometric techniques
the aim of making it easier to compile and search data- with high throughput and high resolution can provide
bases of lipid composition. The system places each lipid quantitative catalogs of all the lipids present in a specific
in one of eight chemical groups (Table 10–3) designated cell type under particular conditions—the lipidome—
by two letters. Within these groups, finer distinctions and of the ways in which the lipidome changes with dif-
are indicated by numbered classes and subclasses. For ferentiation, disease such as cancer, or drug treatment.
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380 Lipids

TABLE 10–3 Eight Major Categories of Biological Lipids

Category Category code Examples
Fatty acids FA Oleate, stearoyl-CoA, palmitoylcarnitine
Glycerolipids GL Di- and triacylglycerols
Glycerophospholipids GP Phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine
Sphingolipids SP Sphingomyelin, ganglioside GM2
Sterol lipids ST Cholesterol, progesterone, bile acids
Prenol lipids PR Farnesol, geraniol, retinol, ubiquinone
Saccharolipids SL Lipopolysaccharide
Polyketides PK Tetracycline, erythromycin, aflatoxin B1

An animal cell contains more than a thousand different sterol 368 vitamin A (retinol) 373
lipid species, each presumably having a specific func- cholesterol 368 vitamin E 374
tion. These functions are known for a growing number of prostaglandin 371 tocopherol 374
lipids, but the still largely unexplored lipidome offers a thromboxane 371 vitamin K 374
rich source of new problems for the next generation of leukotriene 372 dolichol 375
biochemists and cell biologists to solve. vitamin 373 polyketide 376
vitamin D3 373 lipidome 379
SUMMARY 10.4 Working with Lipids cholecalciferol 373
! In the determination of lipid composition, the
lipids are first extracted from tissues with organic
solvents and separated by thin-layer, gas-liquid, or
high-performance liquid chromatography.
Further Reading
! Phospholipases specific for one of the bonds in a
phospholipid can be used to generate simpler General
compounds for subsequent analysis. Fahy, E., Subramaniam, S., Brown, H.A., Glass, C.K., Merrill,
A.H., Jr., Murphy, R.C., Raetz, C.R.H., Russell, D.W., Seyama,
! Individual lipids are identified by their Y., Shaw, W., et al. (2005) A comprehensive classification system
chromatographic behavior, their susceptibility to for lipids. J. Lipid Res. 46, 839–862.
hydrolysis by specific enzymes, or mass A new system of nomenclature for biological lipids, separating
spectrometry. them into eight major categories. The definitive reference on lipid
classification.
! High-resolution mass spectrometry allows the Gurr, M.I., Harwood, J.L., & Frayn, K.N. (2002) Lipid
analysis of crude mixtures of lipids without Biochemistry: An Introduction, 5th edn, Blackwell Science Ltd.,
prefractionation—the “shotgun” approach. Oxford.
A good general resource on lipid structure and metabolism, at
! Lipidomics combines powerful analytical the intermediate level.
techniques to determine the full complement of Lipid Maps. Nature Lipidomics Gateway, [Link].
lipids in a cell or tissue (the lipidome) and to Tutorials and lectures on lipid structure and function, lipidomics
assemble annotated databases that allow methods, and databases on lipid structures and properties.
comparisons between lipids of different cell types Vance, J.E. & Vance, D.E. (eds). (2008) Biochemistry of Lipids,
and under different conditions. Lipoproteins, and Membranes, 5th edn, Elsevier Science Publishing
Co., Inc., New York.
An excellent collection of reviews on various aspects of lipid
Key Terms structure, biosynthesis, and function.

Terms in bold are defined in the glossary. Lipids as Nutrients

fatty acid 357 plasmalogen 364 Angerer, P. & von Schacky, C. (2000) Omega-3 polyunsaturated
polyunsaturated fatty galactolipid 365 fatty acids and the cardiovascular system. Curr. Opin. Lipidol.
sphingolipid 366 11, 57–63.
acid (PUFA) 359
triacylglycerol 360 ceramide 366 Covington, M.B. (2004) Omega-3 fatty acids. Am. Fam. Physician
70, 133–140.
lipases 360 sphingomyelin 366
Succinct statement of the findings that omega-3 fatty acids
phospholipid 363 glycosphingolipid 366 reduce the risk of cardiovascular disease.
glycolipid 363 cerebroside 366 de Logeril, M., Salen, P., Martin, J.L., Monjaud, I., Delaye,
glycerophospholipid 363 globoside 366 J., & Mamelle, N. (1999) Mediterranean diet, traditional risk
ether lipid 364 ganglioside 366 factors, and the rate of cardiovascular complications after