LIPIDS
Carbohydrates are defined in terms of the organic functional groups present on the molecule. They are
polyhydroxyl aldehydes or ketones. Carbohydrates are very polar molecules because there is a large
difference in electronegativity between oxygen and carbon and between oxygen and hydrogen. They are
very water soluble because the hydroxyl groups and carbonyl groups can form numerous hydrogen bonds
with water.
LIPIDS are not defined in terms of the functional groups present on the molecule, rather they are defined on
the basis of their physical properties. Lipids are the non-polar, hydrophobic, water insoluble components of
the cell. Lipids are soluble in non-polar solvents such as ether, benzene, the liquid alkanes, or the
halogenated alkanes. They cannot form dipole-dipole interactions nor hydrogen bonds with water. They
interact with each other and the non-polar solvents by very weak London forces or hydrophobic interactions.
Lipids are a diverse group of biological molecules. There are numerous different classes of lipids each with
slightly different chemical, physical, and biological properties.
Saponification
When animal fat (lipids) are treated with a strongly basic solution (50% solution of NaOH or KOH) and
heat, some of the lipids leave the oily mass of animal fat floating on the surface and enter the water phase.
The hot NaOH has catalyzed the hydrolysis of some of the lipids in the sample into smaller more water
soluble molecules. Hydrolysis {hydro - water; lysis - to break} is the breaking of chemical bonds by adding
water across them.
Question - What types of chemical bonds, what organic functional groups, are hydrolyzed by hot strongly
basic solutions; e.g., 50% NaOH, KOH or LiOH?
Hot sodium hydroxide catalyzes the hydrolysis of Ester Bonds, Amide Bonds, and some Glycosidic (Acetal
or Ketal) Bonds. The base catalyzed hydrolysis of esters and amides is termed SAPONIFICATION and the
group of lipids that are hydrolyzed into smaller more water soluble molecules by hot base are called the
SAPONIFIABLE LIPIDS. Saponifiable lipids are large water insoluble molecules composed of smaller water
soluble and/or slightly water soluble precursors covalently linked by ester, amide, and/or glycosidic bonds.
Those lipids that did not react with the hot NaOH or KOH solution are called the NONSAPONIFIABLE LIPIDS,
they remain floating on the top of the pot.
The “Small Molecules” Produced by the Saponification of Lipids
or
The Precursors of the Saponifiable Lipids
The Fatty Acids
The largest group of molecules produced by lipid saponification are the Fatty Acids. Fatty acids are long
chain monocarboxylic acids containing a minimum of eight carbon atoms. Eight carbons is the dividing line
with respect to solubility; carboxylic acids with less than 8 carbon atoms are relatively water soluble, those
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with 8 or more are only slightly water soluble. Some of the fatty acids are saturated, containing only
carbon-carbon single bonds and a maximum amount of hydrogen. Others are unsaturated, containing one or
more carbon-carbon double bonds. Fifteen (15) fatty acids make up the majority (≈65%) of the fatty acids
found in human cells. These 15 common fatty acids are:
# C’s
#
double
bonds
Location of Double Bonds
Shorthand
Notation
Caprate
10
0
—
10:0
Lauric acid
Laurate
12
0
—
12:0
Myristic acid
Myristate
14
0
—
14:0
Palmitic acid
Palmitate
16
0
—
16:0
Stearic acid
Stearate
18
0
—
18:0
Arachidic acid
Arachidate
20
0
—
20:0
Behenic Acid
Behenate
22
0
—
22:0
Lignoceric acid
Lignocerate
24
0
—
24:0
Cerotic Acid
Cerotate
26
0
—
26:0
Palmitoleic acid
Palmitoleate
16
1
between 9 & 10
16:1 Δ9
Oleic acid
Oleate
18
1
between 9 & 10
18:1 Δ9
Linoleic acid
Linoleate
18
2
between 9 & 10 and 12 & 13
α-Linolenic acid
α-Linolenate
18
3
between 9 & 10, 12 & 13
and 15 & 16
18:3 Δ9,12,15
γ-Linolenic acid
γ-Linolenate
18
3
between 6 & 7, 9 & 10 and
12 & 13
18:3 Δ6,9,12
Arachidonic acid
Arachidonate
20
4
between 5 & 6, 8 & 9, 11 &
12, and 14 & 15
20:4 Δ5,8,11,14
Name when
Unionized
Name when
Ionized
Capric acid
18:2 Δ9,12
Nine of the 15 common fatty acids are saturated fatty acids, the other six fatty acids are unsaturated.
Palmitoleate & Oleate are monounsaturated fatty acids since they contain one carbon-carbon double bond.
Linoleate, α-Linolenate, γ-Linolenate, & Arachidonate are polyunsaturated fatty acids, they contain two or
more double bonds. {Note: The structure of the common fatty acids are given in Figure 2a & Figure 2b of
the Lipids Objectives & Figures Document. It is necessary to be able to identify the structure of these
molecules.}
Things to note about the common fatty acids:
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1. They all contain an even number of carbon atoms.
2. At physiological pH, pH 7.4, the carboxylic acid group of the fatty acid is ionized. They have
donated a hydrogen ion to water or some other proton acceptor forming a negative carboxylate ion.
The charged forms are named with the “ate” suffix used for carboxylate ions. Since the charged
forms are the only form present at physiological pH the fatty acids will always be named as ions.
The ionized forms are the ones given on the Lipids Objectives & Figures Document.
3. The double bonds in the common unsaturated fatty acids are all in the “cis” configuration. The “cis”
double bond puts a “kink” in the molecule.
4. The unsaturated fatty acids have lower melting points and boiling points that the saturated fatty
acids. The “kink” in the unsaturated fatty acids makes it more difficult for these molecules to pack
in an orderly array necessary for forming a solid. Likewise, the kinks weaken the interactions in the
liquid phase making it easier for the molecules to enter the gaseous phase.
5. Two fatty acids; Linoleate and α-Linolenate; are essential fatty acids. These fatty acids cannot be
synthesize by the human animal but they are necessary for its normal growth, development, and
maintenance. They must be obtained from the diet either from plants that can synthesize them or
from other animals that have eaten plants. {Note: γ-Linolenate can be synthesized from Linoleate.}
6. The sodium or potassium salts of the fatty acids, the products of saponification, are the soaps
(saponification = soap forming).
“Trans Fats” have been deemed unfit for human consumption. “Trans Fats” are formed when the double
bonds of unsaturated fatty acids in polyunsaturated triacylglycerols (see below) are reduced with a less than
stoichiometric amount of H2 (partially hydrogenated). The conditions of this industrial reaction reduces
some of the double bonds in the unsaturated fatty acids to single bonds. However, since there is a limiting
amount of H2 some of the double bonds, rather than undergoing reduction, undergo a change in
configuration from cis to trans. The three trans fatty acids most often found in “Trans Fats” are Figure 2c
of the Lipids Objectives & Figures Document. Note: these fatty acids are the trans isomers of the naturally
occurring cis forms.
Not all fatty acids with trans double bonds are harmful to human health. A variety of naturally occurring
fatty acids containing trans double bonds have been identified and have been shown to be beneficial for
human health. These naturally occurring “good” trans fatty acids make up only small percentage of the
fatty acids, they are all polyunsaturated, and they contain a mixture of “cis” and “trans” double bonds.
These are Figure 2d of the Lipids Objectives & Figures Document.
Question - How do soaps work?
When fats are saponified the fatty acids are
converted into their sodium or potassium
salts. The carboxylate ions are weakly
AMPHIPATHIC. Molecules that are
AMPHIPATHIC contain a polar region, the
charged carboxylate group and a non-polar
region, the hydrocarbon “tail” of the fatty
acid. When soaps are placed in water they
coalesce to form spherical structures called
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MICELLES. The surface of the micelle is composed of the charged carboxylate ions of the soap molecules.
These charged groups interact with the polar water. The interior of the spherical micelle particle contains
the non-polar hydrocarbon “tails” of the soap molecules. These non-polar hydrocarbon tails interact with
each other by hydrophobic interactions and avoid water as much as possible. Dirt and odors are held to your
body and clothing by bodily oils (lipid molecules) that we naturally secrete to maintain skin integrity. The
hydrocarbon tails of the soap molecules dissolves the body oil into the micelle releasing the dirt (remember
like dissolves like). The polar head of the soap allows it to interact with water and the water can wash the
oils and dirt away.
Polar Alcohols
The second most abundant molecule in the products of saponification mixture, in the group of precursors of
the saponifiable lipids, is the molecule glycerol. Glycerol is a three carbon tri-alcohol, hence it is very polar.
Its IUPAC name is 1,2,3-propanetriol. Glycerol is used commercially as a skin softener and as a laxative.
Also present in the products of saponification, albeit to a lesser extent, are several other very polar alcohols.
These polar alcohols include: ethanolamine, choline, serine, and inositol. Ethanolamine contains a polar
alcohol group as well as a polar primary amine group. Choline contains a polar alcohol group as well as a
positively charged quaternary ammonium ion. Serine contains a polar alcohol group, a primary amine
group, and a carboxylic acid group. Serine is an amino acid. Inositol is a cyclic six carbon hexa-alcohol, it
has six hydroxyl groups. Although it may be confused with a monosaccharide, inositol is not a sugar.
Ethanolamine, choline, and serine are charged molecules at physiological pH, pH 7.4. At this pH the amino
groups on ethanolamine, choline, and serine accept a proton to become positively charged ammonium ions.
The carboxylic acid group on serine will also ionize, it will donate a proton to become a negatively charged
carboxylate ion. The structures of these small molecules are given on Figure 3 of the Lipids Objectives &
Figures Document. The structures of ethanolamine, choline, and serine are given in the ionized forms, since
only the ionized form exists in the cell. {It is necessary to be able to identify the structures of these small
molecules that act as precursors for the saponifiable lipids.}
Long chain alcohols are also precursors for some of the saponifiable lipids. These alcohols all have the
hydroxyl group on carbon 1 and can contain from 16 to 34 carbon atoms. Some of the alcohols found in
lipids are vinyl alcohols. A vinyl alcohol contains the hydroxyl group on carbon 1 and a carbon-carbon
double bond between carbon 1 and carbon 2.
Sphingosine
Sphingosine is an eighteen carbon molecule. There are polar hydroxyl groups on carbons 1 and 3 and a
polar amino group on carbon 2. A carbon-carbon double bond in the “trans” configuration is present
between carbon 4 and 5. The remainder of the molecule is hydrocarbon. Sphingosine is an AMPHIPATHIC
molecule. Amphipathic molecules have a very polar region and a very non-polar region. The first three
carbons of sphingosine contain three very polar groups, two hydroxyl groups and the positively charged
amino group. The last 15 carbons are very non-polar, they are hydrophobic hydrocarbons. {Note: The
structure of sphingosine is given in Figure 3 of the Lipids Objectives & Figures Document. It is necessary
to be able to identify the structure of this molecule.}
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Monosaccharides
Monosaccharides are present in the mixture of compounds produced when saponifiable lipids are treated
with hot NaOH. The monosaccharides found most often are glucose, galactose, and mannose. Modified
monosaccharides such as glucosamine, galactosamine, N-acetylglucosamine, N-acetylgalactosamine, and Nacetylneuraminic acid (sialic acid), are also found in the products of saponification.
Last but not least, the PHOSPHATE ION (PO4–3) is found in the saponification mixture.
The Precursors of the Saponifiable Lipids - Summary
(The Small Molecules that Make-Up the Saponifiable Lipids)
•Fatty Acids
•Saturated & Unsaturated
•Polar Alcohols
•Glycerol, Serine, Ethanolamine, Choline, & Inositol
•Sphingosine
•Long Chain Alcohols
•Saturated and Vinyl
•Monosaccharides & Modified Monosaccharides
The Saponifiable Lipids
Up to this point;
1. Lipids have been defined as the non-polar, water insoluble components of the cell.
2. Lipids have been classified as either saponifiable or nonsaponifiable.
3. Saponifiable lipids are composed of smaller molecules covalently linked by ester, amide, or
glycosidic bonds.
4. The small molecules that make up the saponifiable lipids have been examined (see above).
5. Nonsaponifiable lipids do not react with hot NaOH solutions implying that this group does not
contain chemical bonds that can be hydrolyzed under basic conditions.
It is now time to take the small molecules that are the precursors of the saponifiable lipids and put them
together in a variety of ways in order to assemble the various types of saponifiable lipids. The saponifiable
lipids are broken down into classes and subclasses, the precursor small molecules that they are composed of
will be described, and then the structure and function of each of the intact lipids will be examined. As the
structure of the classes and subclasses of saponifiable lipids are described, contemplate the small precursor
molecules that are used to build the complex molecule and look for / focus on the one or two unique
characteristic(s) that distinguish one class of lipid molecules from another.
There are three major classes of saponifiable lipids; the WAXES, the GLYCEROL LIPIDS, and the
SPHINGOLIPIDS (Figure 4). As their names imply, the glycerol lipids all contain at least one molecule of
glycerol and the sphingolipids all contain at least one molecule of sphingosine. Within the class of glycerol
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lipids, there are three subclasses; the TRIACYLGLYCEROLS, the PHOSPHOGLYCERIDES, and the ETHER LIPIDS.
A subclass of the ETHER LIPIDS are the PLASMALOGENS. The name Triacylglycerol describes the makeup of
these molecules; there are three acids (triacyl) and a glycerol present. The name Phosphoglyceride
describes the molecule as containing a phosphate and a glycerol. Other groups are present, but the subclass
name doesn’t indicated what other groups. Ether Lipid indicates that this subclass contains an ether
functional group. Again other groups are present, but the name doesn’t indicate what groups. The
sphingolipid class contains two subclasses; the SPHINGOMYELINS and the GLYCOSPHINGOLIPIDS.
Sphingomyelin denotes that this subclass contains sphingosine and it bespeaks to the source of first
isolation; the Myelin of the nervous system. “Glycos” is a prefix meaning sweet or sugar, hence the
glycosphingolipids contain a sugar or sugars as part of their structures. The glycosphingolipids are further
divided into the CEREBROSIDES and the GANGLIOSIDES. These terms, Cerebroside and Ganglioside,
indicates from where they were first isolated, the nervous tissue.
^]^]^]^]^]^]^]^]^]^]^]^]^]^]^]^]^]^]^]^]^]^]
Waxes
Waxes are the simplest group of saponifiable lipids. Structurally, waxes are long chain alcohols 16 to 34
carbons in length in ester linkage with long chain fatty acids 14 to 36 carbons long (Figure 5). The ester
linkage joining the long chain acid and alcohol makes a wax saponifiable. Waxes function primarily as
water proofing agents. Plants use waxes to prevent the loss of water from leaves, seeds, stems, and fruit.
Bees use wax to prevent their honey from drying out and crystallizing. Aquatic and marine animals and
birds use waxes to prevent the “wetting” of their fur and feathers. Whale oil is primarily a wax. Humans
produce and secrete a wax in SEBUM, an oily substance secreted by the sebaceous glands that lubricates the
hair and helps to keep skin moist and supple.
O
O
Triacylglycerols
Moving up in complexity the next class of lipids is the Triacylglycerols. Triacylglycerols are composed of
three fatty acids (triacyl) in ester linkage to one molecule of glycerol. The fatty acids attached to glycerol
can be any combination of the 15 fatty acids previously described as well as any of the “minor” fatty acids;
fatty acids shorter, longer or the “good” trans fatty acids. A SATURATED TRIACYLGLYCEROL (SATURATED
FAT) is formed when three saturated fatty acids are esterified to glycerol. Saturated fats are greasy solids at
room temperature. A MONOUNSATURATED TRIACYLGLYCEROL (MONOUNSATURATED FAT) contains one
unsaturated fatty acid and two saturated fatty acids. The number of double bonds in the unsaturated fatty
acid does not matter, rather it is the presence of one unsaturated fatty acid that makes the triacylglycerol a
monounsaturated fat. Monounsaturated fats are usually viscous liquids at room temperature, but some can
be semisolids. A triacylglycerol containing two or more unsaturated fatty acids is a POLYUNSATURATED
TRIACYLGLYCEROL (POLYUNSATURATED FAT). These compounds are oily liquids at room temperature. In
triacylglycerols as the length of the fatty acids increase the melting point increases and as the number of
carbon-carbon double bonds increase the melting point decreases.
This class of lipids serves three functions in the body:
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1. They are the major energy storage depot in animals. The majority of excess energy in animals and
humans is stored as triacylglycerols. An unlimited supply can be stored.
2. They serve as insulators against heat and cold.
3. They serve as shock absorbers. The internal organs are surrounded by a layer of triacylglycerol and
this fat protects the internal organs from friction and/or trauma.
Polyunsaturated fats can be converted to monounsaturated fats and saturated fats by the process of
HYDROGENATION. Remember alkenes can be hydrogenated in an addition reaction where hydrogen is added
across the carbon-carbon double bond forming a carbon-carbon single bond. This same reaction can be
performed with polyunsaturated triacylglycerols. When hydrogenation is performed the liquid
polyunsaturated fat is converted into a semisolid monounsaturated or a solid saturated fat. MARGARINE is
formed by this process and so are the “bad” trans fatty acids. {Note: The structure of a triacylglycerol was
given in Figure 6 of the Lipids Objectives & Figures Document. It is necessary to be able to identify the
structure of this lipid when seen or when described in words.}
Phosphoglycerides
Moving up in complexity, the next group of glycerol lipids is the Phosphoglycerides. As their name implies
these molecules contain a molecule of glycerol and a phosphate ion. The phosphate is in ester linkage to the
hydroxyl group on carbon three of glycerol. All the molecules in this class also contain two fatty acids in
ester linkage to carbon one and two of glycerol. This molecule (glycerol, two fatty acids, and phosphate) is
called Phosphatidate (Figure 7a), the simplest phosphoglyceride. The cell contains very little
Phosphatidate. Phosphatidate is the precursor for the synthesis of the other phosphoglycerides. The cell
converts the Phosphatidate into the other phosphoglycerides by adding one of the polar alcohols to the
phosphate group. An ester linkage is formed between the hydroxyl group on the polar alcohol and the
phosphate group.
From phosphatidate the cell synthesizes five major phosphoglycerides:
1. When choline is esterified (linked) to the phosphate of phosphatidate the resulting phosphoglyceride
is Phosphatidylcholine. This molecule is also known a Lecithin (Figure 7b).
2. When ethanolamine is linked to the phosphate of phosphatidate the resulting phosphoglyceride is
Phosphatidylethanolamine (Figure 7c).
3. When serine is linked to phosphatidate the resulting phosphoglyceride is Phosphatidylserine (Figure
7d).
4. When inositol is linked to phosphatidate the resulting phosphoglyceride is Phosphatidylinositol
(Figure 7e).
5. A glycerol molecule can be esterified between two phosphatidate molecules forming
Diphosphatidylglycerol also known as Cardiolipin (Figure 7f).
The phosphoglycerides are VERY AMPHIPATHIC molecules. They have a very polar region, a polar “head”,
consisting of the phosphate ion and the polar alcohol, and they have a very non-polar, very hydrophobic
region, or a non-polar “tail”composed of the hydrocarbon chains of the two fatty acids. This unique
structural feature makes these molecules uniquely suitable for the task they perform. The
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phosphoglycerides are components of cellular membranes. Cell membranes are composed primarily of lipid
and protein and the phosphoglycerides comprise a large portion of the lipids present in cellular membranes.
Phosphoglycerides are not used for energy storage, rather they are part of the structures that keep the outside
out, the inside in, and the various organelles separated. In addition to lipids and protein, Eukaryotic cell
membranes also contain some carbohydrate. When the structure of cell membranes is discussed the
importance of the amphipathic nature of theses molecules will become apparent. Cardiolipin was first
isolated from the heart. It is a major component of mitochondrial membranes and it was first isolated from
heart muscle because this organ is very rich in mitochondria. {Note: The structures of the
phosphoglycerides are Figure 7a - 7f in the Lipids Objectives & Figures Document. It is necessary to be
able to identify the structures of these lipids when seen or when described in words.}
Ether Lipids / Plasmalogens
Ether lipids contain a long chain alcohol bonded to the hydroxyl group on carbon three (3) of glycerol by an
ether bond (Figure 8). Ether lipids are synthesized from the phosphoglycerides by an exchange reaction.
The fatty acid on the last carbon is exchanged for a long chain alcohol. The alcohol is covalently linked to
the glycerol by an ether bond. Choline or ethanolamine is the polar alcohol usually present on ether lipids.
The PLASMALOGENS are a subset of the ether lipids. The plasmalogens contain an alcohol with a double
bond between carbon 1 and carbon 2. The PLASMALOGENS contain a VINYL ALCOHOL. The ether lipids /
plasmalogens are also components of cellular membranes. About 50% of the membrane lipids of heart
muscle are either ether lipids or plasmalogens. Some of the ether lipids and plasmalogens have signal
molecule / hormone like activity. For example PLATELET ACTIVATING FACTOR is an ether lipid with potent
signaling activity. When released from the membranes of activated basophils, it stimulates platelet
aggregation and the release of serotonin, a vasoconstrictor, from platelets. {Note: The structures of the ether
lipids and plasmalogens are Figure 8 in the Lipids Objectives & Figures Document. It is necessary to be
able to identify the structures of these lipids when seen or when described in words.}
Spingolipids
The sphingolipids are the next group of saponifiable lipids. These molecules do not contain glycerol. The
backbone of this group of lipids is a molecule of sphingosine.
Ceramides
The Ceramides are the simplest subgroup of sphingolipids. The ceramides contain a single fatty acid
covalently linked to a molecule of sphingosine. The covalent bond joining the fatty acid to the sphingosine
is an amide bond formed between the carboxyl group of the fatty acid and the amino nitrogen on carbon two
of sphingosine. The cell contains very little ceramide since it is used as a precursor for the other
sphingolipids. The small amount present in the cell is part of the lipids of the plasma membrane.
Sphingomyelin
The Sphingomyelins subclass of sphingolipids is synthesized from ceramide. A phosphate is covalently
linked by an ester bond to the hydroxyl group on carbon one of sphingosine and then either choline or
ethanolamine is covalently linked to the phosphate by a second ester bond. These groups along with the
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fatty acid in amide linkage to the nitrogen on carbon two are present on the molecule. The Sphingomyelins
are very amphipathic molecules, they have a polar head; the phosphate, the choline or ethanolamine, the
amide functional group, and the hydroxyl group on carbon 3. The non-polar region of these molecules is the
hydrocarbon part of the fatty acid and the last 15 carbons of sphingosine. Sphingomyelins, as the name
implies, were first isolated from the myelin of the brain and spinal cord. These lipids are particularly rich in
nervous tissue, but are found to a greater or lesser extent in the plasma membrane of all cells.
Cerebrosides
Along with the fatty acid in amide linkage on carbon two of sphingosine, the Cerebroside subclass of
sphingolipids contain a single monosaccharide, either glucose or galactose in glycosidic linkage to the
hydroxyl group on carbon one of sphingosine. The anomeric carbon (C1) of the sugar is made to react with
the –OH group on C-1 of sphingosine. The sugar is present along with the fatty acid in amide linkage to the
nitrogen on carbon two. The Cerebrosides are amphipathic molecules, they have a polar head; the glucose
or galactose, the amide functional group, and the hydroxyl group on carbon 3 and a non-polar region; the
fatty acid and the last 15 carbons of sphingosine. The Cerebrosides, as the name implies, were first isolated
from the cerebrum of the brain. They are particularly rich in nervous tissue, but they are present to a greater
or lesser extent in all cell membranes.
Gangliosides
In the Ganglioside subclass of sphingolipids a hetero-oligosaccharide containing 3 to 15 sugar residues is
attached to carbon one of ceramide by glycosidic bonds. The heteropolysaccharide can contain glucose,
galactose, mannose, glucosamine, galactosamine, N-acetylglucosamine, and/or N-acetylgalactosamine. The
terminal (last) sugar(s) of the heteropolysaccharide is usually one or more sialic acid residues. The
Gangliosides are very amphipathic molecules, they have a very polar head; the hetero-oligosaccharide, the
amide functional group, and the hydroxyl group on carbon 3 and a non-polar region; the fatty acid and the
last 15 carbons of sphingosine. The Gangliosides, as the name implies, were first isolated from the ganglia
of the brain and spinal cord. They are particularly rich in nervous tissue, but they are present to a greater or
lesser extent in all plasma membranes. For example, the three heteropolysaccharides that determine
whether an individual has blood type A, blood type B, or blood type O are examples of the types of
heteropolysaccharides that are attached to ceramide to form a ganglioside. Hence, the presence of one or
more specific ganglioside(s) on the cell membrane of red blood cells determines whether an individual has
type A, type B, type AB, or type O blood. Specific Gangliosides on other tissues need to be matched before
tissue transplantation. {Note: The structures of the sphingolipids are given in Figure 9a & 9b of the Lipids
Objectives & Figures Document. It is necessary to be able to identify the structures of these lipids when
seen or when described in words.}
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Nonsaponifiable Lipids
The nonsaponifiable lipids cannot be hydrolyzed, broken down into smaller molecules. They do not contain
ester, amide, or glycosidic bonds. The nonsaponifiable lipids are large non-polar hydrophobic molecules.
There are three major classes of nonsaponifiable lipids; the fat soluble vitamins (vitamins A, D, E, and K),
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the eicosanoids, and the cholesterol based lipids. The cholesterol based lipids include cholesterol itself, the
bile acids, salts, and esters, and the steroid hormones (Figure 10).
Fat Soluble Vitamins
The fat soluble vitamins are the simplest group of nonsaponifiable
lipids. The fat soluble vitamins belong to a class of molecules called
ISOPRENES or TERPENES. These molecules are synthesized from an
unsaturated five carbon precursor, ISOPRENE (2-methyl-1,3butadiene). There are four fat soluble vitamins; Vitamin A, Vitamin
D, Vitamin E, and Vitamin K.
Isoprene
Vitamin A
There are three active forms of Vitamin A; Retinol, Retinal, and Retinoic Acid. Retinal is necessary for
vision. In the retina of the eye it is covalently linked to a light sensitive protein, opsin or rhodopsin. Retinol
plays a role in the regulation of gene expression during cell differentiation especially during embryonic and
fetal development. Retinoic Acid helps to maintain the integrity of the skin. Vitamin A can also used by
cells as an antioxidant. It reacts with strong oxidizing agents produced in the cell from molecular oxygen
and prevents these very reactive oxidizing agents from destroying cell membranes and other necessary
cellular components. The antioxidant role is a minor function. Vitamin A can be obtained from animal
sources directly or from the hydrolysis of the 40 carbon molecule, β-carotene, obtained from yellow/orange
vegetables. The lack of Vitamin A in the diet first results in Night Blindness, followed by other Vision
Abnormalities and a “Failure to Thrive”.
Vitamin D
Vitamin D is a group of related lipids. Vitamin D3, also known as cholecalciferol, is formed
nonenzymatically by sunlight reacting with the cholesterol derivative, 7-dehydrocholesterol, present in the
skin. The active form of vitamin D, 1,25-Dihydroxycholecalciferol, is formed from vitamin D3 by two
hydroxylation reactions, by the addition of two hydroxyl groups to the molecule. The active vitamin plays a
role in maintaining normal plasma Ca+2 levels. It stimulates the uptake of Ca+2 from the intestine, the
reabsorption of Ca+2 by the kidney, and the uptake of Ca+2 from bone. (Note: Vitamin D is one of many
biomolecules that can be classified in more than one way. It is a fat soluble vitamin and it is a derivative of
cholesterol. Hence, it could be placed with cholesterol and the lipids derived from cholesterol.)
Vitamin E
Vitamin E, or α-Tocopherol is believed to function as a scavenger of strong oxidizing agents, as an
antioxidant. Its antioxidant action prevents damage to unsaturated fatty acids in biological membranes.
Vitamin K
Vitamin K is a lipid vitamin obtained from plants. It is required for the normal synthesis of some of the
proteins involved in the blood coagulation system. It is the only fat soluble vitamin that has cofactor
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activity. A cofactor is a molecule necessary for the normal function of an enzyme. A deficiency in Vitamin
K results in abnormal blood clotting. The affected individual bleeds an abnormally long time and in
extreme cases could exsanguinate (bleed to death). The anticoagulant drug Coumadin is given to
individuals that have had thrombotic events. A thrombotic event occurs when the blood clots abnormally,
causing pathological states such as a heart attack or a stroke. Coumadin antagonizes the action of Vitamin
K, it inhibits the vitamin from acting as a cofactor during the synthesis of the blood coagulation factors.
Individuals on this drug are tested regularly to insure that they do not bleed excessively.
Eicosanoids
EICOSA means 20. All the Eicosanoids are derived from the 20 carbon fatty acid, Arachidonate.
Arachidonate is the precursor for the Eicosanoids. The Eicosanoids are local hormones, autocrine or
paracrine. They are synthesized by a certain cell type, released from that cell, and they evoke a specific
response in neighboring cells or in a very localized region of the body. Their effect is much more short
range than endocrine hormones which produce an effect throughout the body. The Eicosanoids are divided
into three groups depending upon common structural characteristics. The three groups of eicosanoids are
the Prostaglandins, Thromboxanes, and Leukotrienes. The eicosanoids produce a variety of biological
effects. They:
1. cause smooth muscle contractions.
2. cause smooth muscle relaxation.
3. inhibit the secretion of HCl by the stomach.
4. inhibit the use of fatty acids for energy.
5. inhibit blood clotting.
6. stimulate blood clotting.
7. regulate the synthesis of steroids
8. regulate nervous transmission.
9. mediate (increase or decrease) the sensation of pain.
10. mediate (increase or decrease) the inflammatory response.
For example endothelial cells, the cells that line the blood vessels, continually produce a group of
Prostaglandins that prevent blood coagulation. When a “boo-boo” happens these cells are damaged or
destroyed and the production of these compounds in a localized region drops to zero. The lack of these
compounds at the site of a wound allows platelets to bind to the site, forming a platelet plug that initially
stops blood loss. Platelets produce Thromboxanes that simulate the blood coagulation system. A blood clot
(scab) forms sealing the wound until healing occurs.
Cholesterol
Cholesterol and the biomolecules synthesized from Cholesterol are the last group of non saponifiable lipids.
Like the fat soluble vitamins Cholesterol is an isoprene. Cholesterol is an important component of cell
membranes, without it cell membranes would not function properly. Cholesterol is also converted into a
variety of important biomolecules. It is converted into the Bile Acids, Bile Salts, Bile Esters, and it is
converted into the Steroid Hormones. The Bile Acids, Bile Salts, and Bile Esters are important and
necessary for the normal digestion and absorption of lipids.
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There are three classes of Steroid Hormones that utilize Cholesterol as precursor. The first group of steroid
hormones synthesized from cholesterol are the Progestins. The Progestins (e.g. progesterone) readies the
female uterus for pregnancy, stimulates ovulation, and maintains pregnancy during the early stages. The
Progestins are the precursors for the other classes of steroid hormones. They are converted into the
Glucocorticoids (e.g. cortisol). The Glucocorticoids are one of several hormones that helps maintain blood
glucose level and they modulate the inflammatory response to injury. The progestins are also converted into
the Mineralocorticoids (e.g. aldosterone). The Mineralocorticoids helps to control the monovalent ion (Na+,
K+, HCO3–, and Cl–) concentrations in the body. Glucocorticoids and mineralocorticoids are synthesized
and secreted by the cortex of the Adrenal Gland. Finally, the progestins can be converted into the
Androgens (e.g. testosterone). These hormones stimulate/mediate sexual maturation in both sexes, but
especially the male. The androgens are the precursors to the Estrogens (e.g., β-estradiol). These hormones
stimulate/mediate sexual maturation in both sexes, but especially the female. The androgens and estrogens
are classified as anabolic steroids. {Note: The structures of the nonsaponifiable lipids are given in Figures
11, 12, & 13 of the Lipids Objectives & Figures Document. It is NOT necessary to be able to identify the
structures of these lipids. Know their functions}
The French Paradox (FYI)
OH
A diet high in saturated fats (saturated
triacylglycerols) has been implicated as a cause for
cardiovascular disease. It has been suggested that
Americans limit the amount of fat in their diets. The
French diet is as rich or richer in saturated fats when
HO
compared to the American diet and yet the French
have a lower incidence of cardiovascular disease –
OH
The French Paradox. Biochemists, nutritionists, and
Resveratrol
physicians looked closely at the French diet and
noted that one of the major differences between their
diet and the American diet is the amount of red wine consumed by the French. When the red wine was
examined it was found to contain relatively high concentrations of a groups of compounds called
Polyphenols, the most abundant of these polyphenols is the molecule Resveratrol. Resveratrol can be found
in high concentrations in the skins of red wine grapes, peanuts, mulberries, chocolate and several other fruits
and nuts. The plant produces this compound as a fungicide, it destroys fungi that invade the fruit and cause
it to rot. In animals Resveratrol, and the other polyphenols, have been shown to be antioxidants,
anticoagulants, anti-inflammatory agents, to have anticancer effects and to increase high-density lipoprotein
(HDL), the “good cholesterol”. It has been difficult to isolate and purify these compounds because they are
easily oxidized and destroyed by the oxygen in the air. Resveratrol has become available on the internet and
in “health food stores” as a dietary supplement. However, its potency and effectiveness is open to question.
Membranes - THE FLUID MOSAIC MODEL OF MEMBRANES
Membranes surround and delineate the cell. In eukaryotic cells membranes also surround and delineate the
subcellular organelles. They function to keep the inside in and the outside out. Membranes are
supramolecular complexes of phosphoglycerides, sphingolipids, cholesterol and proteins. How the lipid
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components of the membrane are assembled into the complex structure will be examined now. Proteins will
be discussed shortly. Once the structure of proteins has been discussed the structure and organization of
membranes will be revisited to look at how membrane proteins control the flow materials and information
into and out of the cell.
Four biological macromolecules are assembled into the supramolecular complex of the cell membrane. The
four macromolecules are the Phosphoglycerides, Sphingolipids, Cholesterol and Proteins.
How are the lipids assembled into a membrane?
The phosphoglyceride and sphingolipid part will be examined first. What would happen if a mixture of
phosphoglycerides and sphingolipids were placed in/on water or in/on a buffer? The molecules in this
mixture would align themselves on the surface of the water or buffer such that the polar head of these
molecules would interact with the polar water or buffer as well as with each other, and the non-polar ends,
the non-polar tails would interact with each other and the nonpolar air. Non-polar regions of the molecule
(the non-polar tails) would arrange themselves to get as far away from the polar water as possible (Figure
14a).
The lipid and water mixture is now rapidly agitated and then allowed to settle. What has agitation done to
this mixture of lipids?
Some of the lipids will remain at the water / air interface with their polar heads interacting with water and
their tails interacting with air.
Some of the lipids will form micelles similar in structure to the micelles formed by soaps (see section-How
do soaps work?).
Some of the lipids will form a two layered structures enclosing some of the water/buffer. The polar heads of
the outer layer of lipids interacts with the exterior water and the polar heads of the inner layer of lipids
interacts with the water/buffer trapped inside the structure. The non-polar tails of the two lipid layers
interact with each other in the middle of this two layered structure. This two layered structure is called a
LIPID BILAYER and it is a major part of a cell membrane (Figure 14b).
Lipid Bilayer
Lets look at the structure of the lipid bilayer as it is found in cellular membranes. All membranes contain
phosphoglycerides, sphingolipids, and cholesterol. Both layers, both leaflets of the membrane contain
phosphoglycerides and cholesterol. Only the outer layer of the lipid bilayer, the outer leaflet, the outside
surface of the cell contains sphingolipids (Figure 15).
Sidedness - Telling the Outside from the Inside
The cellular membrane, the plasma membrane, is a lipid bilayer. The outside layer of the lipid bilayer, the
layer in contact with extracellular water is termed the outer leaflet. The layer in contact with intracellular
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water, the inner layer of the bilayer is called the inner leaflet. Plasma membranes have a definite sidedness,
a definite orientation. The the outer leaflet can be distinguished from the inner leaflet based upon
phospholipid composition. All of the Cerebrosides and Gangliosides and the majority of the
Sphingomyelins are found in the outer leaflet of the membrane. The monosaccharide molecule attached to
the cerebrosides and the hetero-oligosaccharides attached to the gangliosides orient these molecules
correctly in the membrane. The polysaccharide is directed extracellularly, directed toward the outside of the
cell. (Remember, one of the functions of heteropolysaccharides is to orient molecules correctly in cellular
membranes.) For most mammalian cells, the outer leaflet has a higher proportion (> than 50% of the total)
of Phosphatidylcholine, whereas the inner leaflet is rich (> than 50% of the total) in Phosphatidylserine,
Phosphatidylinositol, and Phosphatidylethanolamine. (Table 1)
Forces
Weak intermolecular interactions hold the lipids of the membrane together. Three forces stabilize the
membrane structure. The first force is hydrogen bonding and/or dipole-dipole interactions between the
polar ends of the lipids and the polar water molecules inside and outside of the cell. The second force is
hydrogen bonding and/or dipole-dipole interacts between the polar heads of the amphipathic lipids within an
individual layer; i.e., within the inner layer or within the outer layer, not across the layers. The third force is
the London forces between the non-polar hydrophobic tails of these amphipathic lipid molecules. These
London forces are HYDROPHOBIC INTERACTIONS because the molecules interacting with each other are all
non-polar hydrophobic molecules. The hydrophobic interactions between the non-polar “tails” contribute
the largest force toward stabilizing and maintaining the lipid bilayer structure.
Fluidity
Cellular membranes are fluid in nature. Lipids in the individual layers migrate within that layer and the
outer layer migrates, flows (moves) over the inner leaflet. For example a lipid molecule in the outer leaflet
migrates rapidly throughout the outer leaflet. It can move from one end of the cell to the other in a few
seconds. Lipid molecules rarely move between layers, a lipid molecule in the outer layer rarely “flip-flops”
into the inner layer and/or visa versa.
Cellular membranes must be fluid to perform their function. Since life forms are found over a wide range of
temperatures, membranes must be fluid over this wide range of temperatures. The fluidity of cellular
membranes is controlled by two factors. First, it is controlled by the ratio of saturated to unsaturated fatty
acids in the membrane lipids. Increasing the amount of saturated fatty acids decreases the fluidity, whereas
increasing the concentration of unsaturated fatty acids increases the fluidity. The “cis” double bonds in the
unsaturated fatty acids puts a “kink” in the molecule and the “kinky” unsaturated fatty acids do not allow the
lipid molecules to pack together well. Bacteria and animals that live in cold climates have membrane lipids
(phosphoglycerides and sphingolipids) with a high proportion of unsaturated fatty acids; the “kinky” fatty
acids have low melting points and therefore the membranes remain fluid. The bacteria and animals that live
in hot climates have membrane lipids with a high proportion of saturated fatty acids; the “straight” fatty
acids have high melting points. Second, it is controlled by the amount of cholesterol “dissolved” in the
membrane. Increasing the amount of cholesterol in the membrane increases membrane fluidity by
broadening the temperature at which a membrane undergoes the transition from fluid state to solid state.
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Barrier Properties
The lipid layer of the membrane is a very effective barrier against molecules entering or leaving a cell. The
polar surfaces on the exterior and interior of the membrane prevents the movement of non-polar molecules
into or out of the cell. Non-polar molecules do not interact (well) with the polar heads of the membrane
lipids. The non-polar middle region of the membrane prevents the movement of polar molecules. Polar
molecules do not interact (well) with the non-polar tails of the membrane lipids. A few small non-polar
molecules can freely diffuse across a cell membrane. N2, O2, CO2, and urea, can freely pass across the cell
membrane. A small amount of water can pass into and out of the cell through the membrane. The
movement of water across the cell membrane is called OSMOSIS; the movement of solute molecules such as
N2 O2, CO2, and urea across the membrane is called DIFFUSION.
Question - If the membrane is such an effective barrier against molecular movement into or out of the cell,
how do important biomolecules enter and/or leave the cell? How does information enter and/or leave the
cell?
The cell has to get large polar and non-polar molecules in and out. It needs glucose, lipids, and amino acids
for energy and growth, yet these molecules are too large or too polar to cross the cell membrane and enter
the cell. These molecules enter the cell using the membrane proteins. {The mechanism of to how molecules
and information get into and out of the cell will be discussed after proteins are examined.}
There are three types of proteins associated with or present in the cell membrane. EXTRINSIC or
PERIPHERAL membrane proteins are bound to and interact with only one surface of the membrane. These
proteins bind to and interact with the polar heads of the membrane lipids by hydrogen bonding and/or
dipole-dipole interactions. Cytoskeleton proteins, antigenic determinants, and cell-cell contact molecules
are examples of extrinsic (peripheral) proteins (Figure 16).
The second type of membrane proteins are the INTRINSIC, INTEGRAL, or TRANSMEMBRANE proteins. These
proteins are embedded within the membrane and extend completely through it. Parts of the protein are
exposed on both the inside and outside of the cell. The parts of the protein that interact with the polar
surfaces of the membrane interact by dipole-dipole interactions and/or hydrogen bonding. The parts of the
protein that interact with the non-polar regions of the membrane do so by hydrophobic interactions.
Molecular transporters and hormone receptors are examples of intrinsic (integral) proteins. They can also
be antigenic determinants, cell-cell contact molecules, and anchors for the cytoskeleton.
The third type of proteins associated with the cell membrane are LIPID LINKED proteins. These proteins are
covalently linked to a fatty acid, a phosphoglyceride, or a complex isoprene. The lipid moiety is inserted
into either the inner leaflet or the outer leaflet of the membrane and the protein is tethered to the surface of
the cell by this lipid molecule. Lipid linked protein have the most freedom of movement of all the
membrane associated proteins.
The extrinsic membrane proteins associated with the outer leaflet (the outside of the cell) and many intrinsic
membrane proteins are usually GLYCOPROTEINS. GLYCOPROTEINS are protein molecules with one or more
hetero-oligosaccharides or heteropolysaccharides covalently attached. The sugar part of the molecule
signals to the cell that these proteins are to be embedded in the cell membrane and they orient the protein
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correctly in the cell membrane. The heteropolysaccharide is always on the exterior of the cell (pointing out)
where it can interact, form hydrogen bonds, with extracellular water.
Since the proteins are embedded in the membrane and interact with the membrane lipids these embedded
proteins move along the cell surface as the membrane lipids move. The membrane is a mosaic of lipids and
proteins in constant motion.
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