PALAWAN POLYTECHNIC COLLEGE, INC.

DEPARTMENT OF NURSING

MC2 – Biochemistry

PART 4. Lipids

Lipids are a class of biological molecules defined by low solubility in water and high solubility
in nonpolar solvents. As molecules that are largely hydrocarbon in nature, lipids represent
highly reduced forms of carbon and, upon oxidation in metabolism, yield large amounts of
energy. Lipids are thus the molecules of choice for metabolic energy storage.

We have discussed that lipids are either hydrophobic (containing only nonpolar groups) or
amphipathic (possessing both polar and nonpolar groups). The hydrophobic nature of lipid
molecules allows membranes to act as effective barriers to more polar molecules. The
properties of lipids were previously discussed. In this part, we will discuss the structure,
chemistry, and biological function of lipids.

A. Fatty Acids
A fatty acid is composed of a long hydrocarbon chain ("tail") and a terminal carboxyl group
(or "head"). The carboxyl group is normally ionized under physiological conditions. Fatty
acids occur in large amounts in biological systems but only rarely in the free, uncomplexed
state. They typically are esterified to glycerol or other backbone structures. Most of the
fatty acids found in nature have an even number of carbon atoms (usually 14 to 24).
Certain marine organisms, however, contain substantial amounts of fatty acids with odd
numbers of carbon atoms. Fatty acids are either saturated (all carbon-carbon bonds are
single bonds) or unsaturated (with one or more double bonds in the hydrocarbon chain).
If a fatty acid has a single double bond, it is said to be monounsaturated, and if it has
more than one, polyunsaturated. Fatty acids can be named or described in at least three
ways, as listed in the table below:

For example, a fatty acid composed of an 18-carbon chain with no double bonds can be
called by its systematic name (octadecanoic acid), its common name (stearic acid), or its
shorthand notation, in which the number of carbons is followed by a colon and the number
of double bonds in the molecule (18:0 for stearic acid). Stearic acid (18:0) and palmitic
acid (16:0) are the most common saturated fatty acids in nature.

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 Free rotation around each of the carbon-carbon bonds makes saturated fatty acids
extremely flexible molecules. Owing to steric constraints, however, the fully extended
conformation is the most stable for saturated fatty acids. Nonetheless, the degree of
stabilization is slight, and (as will be seen) saturated fatty acid chains adopt a variety of
conformations.
Unsaturated fatty acids are slightly more abundant in nature than saturated fatty acids,
especially in higher plants. The most common unsaturated fatty acid is oleic acid, or
18:1(9), with the number in parentheses indicating that the double bond is between
carbons 9 and 10. The number of double bonds in an unsaturated fatty acid typically varies
from one to four, but in the fatty acids found in most bacteria, this number rarely exceeds
one.
The double bonds found in fatty acids are nearly always in the cis configuration. This
causes a bend or "kink" in the fatty acid chain. This bend has very important consequences
for the structure of biological membranes. Saturated fatty acid chains can pack closely
together to form ordered, rigid arrays under certain conditions, but unsaturated fatty acids
prevent such close packing and produce flexible, fluid aggregates.
Some fatty acids are not synthesized by mammals and yet are necessary for normal
growth and life. These essential fatty acids include linoleic and y-linolenic acids. These
must be obtained by mammals in their diet (specifically from plant sources). Arachidonic
acid, which is not found in plants, can be synthesized by mammals only from linoleic acid.
At least one function of the essential fatty acids is to serve as a precursor for the synthesis
of eicosanoids, such as prostaglandins, a class of compounds that exert hormonelike
effects in many physiological processes.

In addition to unsaturated fatty acids, several other modified fatty acids are found in
nature. Microorganisms, for example, often contain branched-chain fatty acids, such as
tuberculostearic acid. When these fatty acids are incorporated in membranes, the methyl
group constitutes a local structural perturbation in a manner similar to the double bonds in
unsaturated fatty acids. Some bacteria also synthesize fatty acids containing cyclic
structures such as cyclopropane, cyclopropene, and even cyclopentane rings.

B. Triacylglycerols
A significant number of the fatty acids in plants and animals exist in the form of
triacylglycerols (also called triglycerides). TriacyIglycerols are a major energy reserve

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 and the principal neutral derivatives of glycerol found in animals. These molecules consist
of a glycerol esterified with three fatty acids. If all three fatty acid groups are the same, the
molecule is called a simple triacylglycerol. Examples include tristearoylglycerol
(common name tristearin) and trioleoylglycerol (triolein). Mixed triacylglycerols contain
two or three different fatty acids. Triacylglycerols in animals are found primarily in the
adipose tissue (body fat), which serves as a depot or storage site for lipids.
Monoacylglycerols and diacylglycerols also exist, but they are far less common than the
triacylglycerols. Most natural plant and animal fat is composed of mixtures of simple and
mixed triacylglycerols.

Tristearin
(a simple triacylglycerol)

Acylglycerols can be hydrolyzed by heating with acid or base or by treatment with

lipases. Hydrolysis with alkali is called saponification and yields salts of free fatty acids
and glycerol. This is how our ancestors made soap (a metal salt of an acid derived from
fat). One method used potassium hydroxide (potash) leached from wood ashes to
hydrolyze animal fat (mostly triacylglycerols). (The tendency of such soaps to be
precipitated by Mg2+ and Ca2+ ions in hard water makes them less useful than modern
detergents.) When the fatty acids esterified at the first and third carbons of glycerol are
different, the second carbon is asymmetric. The various acylglycerols are normally soluble
in benzene, chloroform, ether, and hot ethanol. Although triacylglycerols are insoluble in
water, monoacylglycerols and diacylglycerols readily form organized structures in water,
owing to the polarity of their free hydroxyl groups.
Triacylglycerols are rich in highly reduced carbons and thus yield large amounts of
energy in the oxidative reactions of metabolism. Complete oxidation of 1 g of
triacylglycerols yields about 38 kJ of energy, whereas proteins and carbohydrates yield
only about 17 kJ/g. Also, their hydrophobic nature allows them to aggregate in highly
anhydrous forms, whereas polysaccharides and proteins are highly hydrated. For these
reasons, triacylglycerols are the molecules of choice for energy storage in animals. Body
fat (mainly triacylglycerols) also provides good insulation. Whales and Arctic mammals
rely on body fat for both insulation and energy reserves.

C. Glycerophospholipids
A 1,2-diacylglycerol that has a phosphate group esterified at carbon atom 3 of the glycerol
backbone is a glycerophospholipid, also known as a phosphoglyceride or a glycerol
phosphatide. These lipids form one of the largest and most important classes of natural
lipids. They are essential components of cell membranes and are found in small
concentrations in other parts of the cell. It should be noted that all glycerophospholipids
are members of the broader class of lipids known as phospholipids.

Phosphatidic acid, the parent compound for glycerophospholipids.

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 The numbering and nomenclature of glycerophospholipids present a dilemma in that
the number 2 carbon of the glycerol backbone of a phospholipid is asymmetric. It is
possible to name these molecules either as D- or L-isomers. Thus, glycerol phosphate
itself can be referred to either as D-glycerol-1-phosphate or as L-glycerol-3-phosphate.
Instead of naming the glycerol phosphatides in this way, biochemists have adopted the
stereospecific numbering or sn-system. In this system, the pro-S position of a prochiral
atom is denoted as the 1-position, the prochiral atom as the 2-position, and so on. When
this scheme is used, the prefix sn- precedes the molecule name (glycerol phosphate in
this case) and distinguishes this nomenclature from other approaches. In this way, the
glycerol phosphate in natural phosphoglycerides is named as sn-glycerol-3-phosphate.

The absolute configuration of sn-glycerol-3-phosphate. The pro-R and pro-S positions of the parent glycerol are also indicated.

Glycerophospholipids Are the Most Common Phospholipids

Phosphatidic acid, the parent compound for the glycerol-based phospholipids, consists
of sn-glycerol-3-phosphate, with fatty acids esterified at the 1- and 2-positions.
Phosphatidic acid is found in small amounts in most natural systems and is an important
intermediate in the biosynthesis of the more common glycerophospholipids. In these
compounds, a variety of polar groups are esterified to the phosphoric acid moiety of the
molecule. The phosphate, together with such esterified entities, is referred to as a "head"
group. Phosphatides with choline or ethanolamine are referred to as phosphatidylcholine
(known commonly as lecithin) or phosphatidylethanolamine, respectively. These
phosphatides are two of the most common constituents of biological membranes. Other
common head groups found in phosphatides include glycerol, serine, and inositol. Another
kind of glycerol phosphatide found in many tissues is diphosphatidylglycerol. First
observed in heart tissue, it is also called cardiolipin. In cardiolipin, a phosphatidylglycerol
is esterified through the C-1 hydroxyl group of the glycerol moiety of the head group to the
phosphoryl group of another phosphatidic acid molecule.

Phosphatides exist in many different varieties, depending on the fatty acids esterified
to the glycerol group. As we shall see, the nature of the fatty acids can greatly affect the
chemical and physical properties of the phosphatides and the membranes that contain
them. In most cases, glycerol phosphatides have a saturated fatty acid at position 1 and
an unsaturated fatty acid at position 2 of the glycerol. Thus, 1-stearoyl-2-oleoyl-
phosphatidylcholine is a common constituent in natural membranes, but 1-linoleoyl-2-
palmitoylphospha-tidylcholine is not.
Both structural and functional strategies govern the natural design of the many different
kinds of glycerophospholipid head groups and fatty acids. Certain phospholipids, including
phosphatidylinositol and phosphatidylcholine, participate in complex cellular signaling
events. These roles, appreciated only in recent years.

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Ether Glycerophospholipids Include PAF and Plasmalogens
Ether glycerophospholipids possess an ether linkage instead of an acyl group at the C-
1 position of glycerol. One of the most versatile biochemical signal molecules found in
mammals is platelet-activating factor, or PAE, a unique ether glycerophospholipid. The
alkyl group at C-1 of PAF is typically a 16-carbon chain, but the acyl group at C-2 is a 2-
carbon acetate unit. By virtue of this acetate group, PAF is much more water soluble than
other lipids, allowing PAF to function as a soluble messenger in signal transduction.

A 1-alkyl 2-acyl-phosphatidylethanolamine
(an ether glycerophospholipid).

Plasmalogens are ether glycerophospholipids in which the alkyl moiety is cis-a,b-

unsaturated. Common plasmalogen head groups include choline, ethanolamine, and
serine. These lipids are referred to as phosphatidal choline, phosphatidal ethanolamine,
and phosphatidal serine.

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 The structure and a space-filling model of a choline plasmalogen.

D. Sphingolipids
Sphingolipids represent another class of lipids frequently found in biological membranes.
An 18-carbon amino alcohol, sphingosine, forms the backbone of these lipids rather than
glycerol. Typically, a fatty acid is joined to a sphingosine via an amide linkage to form a
ceramide. Sphingomyelins represent a phosphorus-containing subclass of sphingolipids
and are especially important in the nervous tissue of higher animals. A sphingomyelin is
formed by the esterification of a phosphorylcholine or a phosphorylethanolamine to the 1-
hydroxy group of a ceramide.

Formation of an amide linkage between a fatty acid and sphingosine produces a ceramide.

A structure and a space-filling model of a choline The structure of a cerebroside.

sphingomyelin formed from stearic acid. Note the sphingosine backbone. 6
 There is another class of ceramide-based lipids that, like the sphingomyelins, are
important components of muscle and nerve membranes in animals. These are the
glycosphingolipids, and they consist of a ceramide with one or more sugar residues in
a B-glycosidic linkage at the 1-hydroxyl moiety. The neutral glycosphingolipids contain
only neutral (uncharged) sugar residues. When a single glucose or galactose is bound in
this manner, the molecule is a cerebroside. Another class of lipids is formed when a
sulfate is esterified at the 3-position of the galactose to make a sulfatide. Gangliosides
(Figure 8.14) are more complex glycosphingolipids that consist of a ceramide backbone
with three or more sugars esterified, one of these being a sialic acid such as N-
acetylneuraminic acid. These latter compounds are referred to as acidic
glycosphingolipids, and they have a net negative charge at neutral pH.

The structures of several important gangliosides. Also shown is a space-filling model of ganglioside GM1

The glycosphingolipids have a number of important cellular functions, despite the fact
that they are present only in small amounts in most membranes. Glycosphingolipids at cell
surfaces appear to determine, at least in part, certain elements of tissue and organ
specificity. Cell-cell recognition and tissue immunity appear to depend on specific
glycosphingolipids. Gangliosides are present in nerve endings and appear to be important
in nerve impulse transmission. A number of genetically transmitted diseases involve the
accumulation of specific glycosphingolipids due to an absence of the enzymes needed for
their degradation. Such is the case for ganglioside Gm2 in the brains of Tay-Sachs disease
victims, a rare but fatal disease characterized by a red spot on the retina, gradual
blindness, and loss of weight, especially in infants and children.

E. Waxes
Waxes are esters of long-chain alcohols with long-chain fatty acids.
The resulting molecule can be viewed (in analogy to the
glycerolipids) as having a weakly polar head group (the ester
moiety itself) and a long, nonpolar tail (the hydrocarbon chains).
Fatty acids found in waxes are usually saturated. The alcohols
found in waxes may be saturated or unsaturated and may include
sterols, such as cholesterol. Waxes are water insoluble due to the
weakly polar nature of the ester group. As a result, this class of An example of a wax. Oleoyl alcohol is
esterified to stearic acid in this case.

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 molecules confers water repellant character to animal skin, to the leaves of certain plants,
and to bird feathers. The glossy surface of a polished apple results from a wax coating.
Carnauba wax, obtained from the fronds of a species of palm tree in Brazil, is a particularly
hard wax used for high gloss finishes, such as in automobile wax, boat wax, floor wax, and
shoe polish. Lanolin, a component of wool wax, is used as a base for pharmaceutical and
cosmetic products because it is rapidly assimilated by human skin.

F. Terpenes
The terpenes are a class of lipids formed from combinations of two or more molecules of
2-methyl-1,3-butadiene, better known as isoprene (a five-carbon unit that is abbreviated
Cs). A monoterpene (C10) consists of two isoprene units, a sesquiterpene (C15) consists
of three isoprene units, a diterpene (C20) has four isoprene units, and so on. Isoprene
units can be linked in terpenes to form straight-chain or cyclic molecules, and the usual
method of linking isoprene units is head to tail. Monoterpenes occur in all higher plants,
whereas sesquiterpenes and diterpenes are less widely known. Several examples of these
classes of terpenes are shown below. The triterpenes are C30 terpenes and include
squalene and lanosterol, two of the precursors of cholesterol and other steroids.
Tetraterpenes (C40) are less common but include the carotenoids, a class of colorful
photosynthetic pigments. b-Carotene is the precursor of vitamin A, whereas lycopene,
similar to b-Carotene but lacking the cyclopentene rings, is a pigment found in tomatoes.

The structure of isoprene (2-methyl-1,3-butadiene) and the structure of head-to-tail and head-to-tail linkages.
Isoprene itself can be formed by distillation of natural rubber, a linear head-to-tail polymer of isoprene units.

Many monoterpenes are readily recognized by their characteristic flavor or odor (limonene in lemons, citronellal in roses, geraniums, and
some perfumes; pinene in turpentine; and menthol from peppermint, used in cough drops and nasal inhalers). The diterpenes, which are
C20 terpenes, include retinal (the essential light-absorbing pigment in rhodopsin, the photoreceptor protein of the eye), phytol (a constituent
of chlorophyll), and the gibberellins (potent plant hormones). The triterpene lanosterol is a constituent of wool fat. Lycopene is a carotenoid
found in ripe fruit, especially tomatoes.

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 Long-chain polyisoprenoid molecules with a terminal alcohol moiety are called
polyprenols. The dolichols, one class of polyprenols, consist of 16 to 22 isoprene units
and, in the form of dolichyl phosphates, function to carry carbohydrate units in the
biosynthesis of glycoproteins in animals. Polyprenyl groups serve to anchor certain
proteins to biological membranes.

Dolichol phosphate is an inhibition point for the synthesis of carbohydrate polymers in animals. The analogous alcohol in bacterial systems,
undecaprenol, also known as bactoprenol, consists of 11 isoprene units. Undecaprenyl phosphate delivers sugars from the cytoplasm for the
synthesis of cell wall components such as peptidoglycans, lipopolysaccharides, and glycoproteins. Polyprenyl compounds also serve as he side
chains of vitamin K, the ubiquinones, plastoquinones, and tocopherols (such as vitamin E).

G. Steroids

Cholesterol
A large and important class of terpene-based lipids is the steroids. This molecular family,
whose members effect an amazing array of cellular functions, is based on a common
structural motif of three 6-membered rings and one 5-membered ring all fused together.
Cholesterol is the most common steroid in animals and the precursor for all other animal
steroids. The numbering system for cholesterol applies to all such molecules. Many
steroids contain methyl groups at positions 10 and 13 and an 8- to 10-carbon alkyl side
chain at position 17. The polyprenyl nature of this compound is particularly evident in the
side chain. Many steroids contain an oxygen at C-3, either a hydroxyl group in sterols or
a carbonyl group in other steroids. Note also that the carbons at positions 10 and 13 and
the alkyl group at position 17 are nearly always oriented on the same side of the steroid
nucleus, the b-orientation. Alkyl groups that extend from the other side of the steroid
backbone are in an a-orientation.
Cholesterol is a principal component of animal cell plasma membranes, and much
smaller amounts of cholesterol are found in the membranes of intracellular organelles. The
relatively rigid fused ring system of cholesterol and the weakly polar alcohol group at-the
C-3 position have important consequences for the properties of plasma membranes.
Cholesterol is also a component of lipoprotein complexes in the blood, and it is one of the
constituents of plaques that form on arterial walls in atherosclerosis.

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 Steroid Hormones Are Derived from Cholesterol
Steroids derived from cholesterol in animals include five families of hormones (the
androgens, estrogens, progestins, glucocorticoids, and mineralocorticoids) and bile acids.
Androgens such as testosterone and estrogens such as estradiol mediate the
development of sexual characteristics and sexual function in animals. The progestins
such as progesterone participate in control of the menstrual cycle and pregnancy.
Glucocorticoids (cortisol, for example) participate in the control of carbohydrate, protein,
and lipid metabolism, whereas the mineralocorticoids regulate salt (Na+, K+, and CI-)
balances in tissues. The bile acids (including cholic and deoxycholic acid) are detergent
molecules secreted in bile from the gallbladder that assist in the absorption of dietary lipids
in the intestine.

The structures of several important sterols derived from cholesterol.

Reference:
Garrett, R., & Grisham, C. M. (2005). Biochemistry (3rd ed.). Brooks/Cole Publishing Company.

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