BCH301:

INTRODUCTION TO
BIOCHEMISTRY

Ralph Abi-Habib, Ph.D.

Chapter 6: Lipids
 What are lipids?

• Lipids are a heterogeneous and complex class of mostly

hydrophobic macromolecules that show a very wide array
of structures and functions.

• The simplest lipids are fatty acids, which have the general
formula R - COOH, where R represents a hydrocarbon
chain.

• Fatty acids are components of more complex types of lipids

including triacylglycerols, glycerophospholipids and
sphingolipids.
• On the other hand, steroids, lipid vitamins and terpenes are
synthesized from isoprene, a 5-carbon ring molecule, and
are, therefore, called isoprenoids.

• Some types of lipids contain phosphate groups and are

called phospholipids, while others contain both sphingosine
and carbohydrate groups and are called glycosphingolipids.
 Fatty Acids

• Fatty acids differ from each other by the length of their

hydrocarbon tail, the number and position of carbon-carbon
double bonds and the number of branches.

• Most fatty acids have a pKa of 4.5 to 5 and are, therefore,

deprotonated at physiological pH.

• Fatty acids are a form of detergent since they have a long

hydrophobic tail and a polar head, hence, the concentration of
free fatty acids in cells is very low (because of their ability to
disrupt membranes) with most being components of more
complex lipids.

• Fatty acids that do not contain carbon-carbon double bonds are

called saturated, while those containing at least 1 double bond are
called unsaturated (mono or polyunsaturated).
• Fatty acids are referred to by either the International Union of
Pure and Applied Chemistry (IUPAC) names or the common
names.

• The number of carbon atoms in the most abundant fatty acids

ranges from 12 to 20 and is always even since fatty acids are
synthesized by the sequential addition of 2 carbon units.

• In IUPAC nomenclature, the carboxyl carbon is labeled C-1 with

the remaining carbons numbered sequentially.
• In common nomenclature, the carbons are designated using
Greek letters with the second carbon (C-2 in IUPAC) designated
a and the subsequent carbons b, d, e, etc.

• The carbon farthest from the carboxyl group is designated w,

regardless of the length of the hydrocarbon chain.
• The configuration of the double bonds in unsaturated fatty
acids is generally cis.

• In IUPAC nomenclature, the positions of the double bonds

are indicated by the symbol Dn, where n indicates the lower-
numbered carbon atom of each double bonded pair.

• A shorthand notation for identifying fatty acids uses two

numbers separated by a colon (referring to the number of
carbons and the number of double bonds) followed by the
symbol indicating the position of the double bonds.

• For example, palmitate is 16:0, oleate is 18:1 D9 and

arachidonate is 20:4 D5,8,11,14.
• Unsaturated fatty acids can also be described by the
location of the last double bond relative to the w carbon.

• The last double bond is usually found three, six or nine

carbon atoms from the end of the chain.

• These fatty acids are called w-3 (e.g. 18:3 D9,12,15), w-6 (e.g.
18:2 D9,12) and w-9 (e.g. 18:1 D9).

• We are unable to synthesize w-3 fatty acids, hence the

importance of dietary sources.
• At room temperature, saturated fatty acids are waxy solids
while unsaturated fatty acids are liquids.

• The melting point of fatty acids is determined by the length

of the hydrocarbon chain and the degree of unsaturation.

• Laurate (12:0), myristate (14:0) and palmitate (16:0), for

example, are saturated fatty acids with increasing
hydrocarbon tail lengths.

• The melting points of these fatty acids increase from

Laurate to palmitate since the increase in chain length
increases the number of Van der Walls interactions and
extent of hydrophobic interactions between molecules.
• The melting point of unsaturated fatty acids is significantly
lower than that of saturated fatty acids since the presence of
a cis double bond restricts rotation around a carbon pair and
produces a pronounced kink in the hydrocarbon chain.

• The presence of this kink prevents the close packing of

fatty acid molecules and results in a far lower number of
Van der walls interactions between molecules.

• This in turn leads to the energy needed to disrupt these

interactions (hence the melting point) being lower in
saturated fatty acids compared to tightly packed (extensive
Van der walls) saturated FAs.
• For example stearate (18:0), oleate (18:1) and linolenate
(18:3) have the same length hydrocarbon chain but
different degrees of saturation from fully saturated to mono
and poly-unsaturated.

• As the degree of unsaturation increases the molecules

become more fluid and the melting point decreases.

• The melting points of stearate, oleate and linolenate are,

therefore, 70oC, 13oC and -17oC, respectively.

• At body temperature, therefore, stearate is solid while

oleate and linolenate are in liquid forms.
 Fatty acid esters: Triacylglycerols

• Free fatty acids occur only in trace amounts in living cells.

Hence, most fatty acids are esterified to glycerol or other
backbone compounds to form more complex lipid
molecules.

• In esters, as well as in other derivatives of carboxylic acids,

the RC = O moiety contributed by the acid is called the acyl
group.

• In common nomenclature, complex lipids that contain

specific fatty acyl groups are named after the parent fatty
acid. e.g., esters of the fatty acid laurate are lauryl esters
and esters of linoleate are linoeyl esters.
• Fatty acids are generally found in cells as neutral lipids
called triacylglycerols (triglycerides).

• These are composed of three fatty acids esterified to

glycerol, a three-carbon sugar alcohol.

• Triacylglycerols are very hydrophobic and are stored in

cells in an anhydrous form

• Because the carbon atoms of fatty acids are more reduced

than those in proteins or carbohydrates, the oxidation of
fatty acids yields more energy (37 kJ/g) compared to
carbohydrates (16 kJ/g).

• This is, in part, why fatty acids are the quintessential

energy storage molecules in living organisms.
• Fats and oils are mixtures of triacylglycerols.

• The most abundant fatty acids in animal triacylglycerols are

oleate (18;1), palmitate (16:0) and stearate (18:0).

• Mammals require certain dietary polyunsaturated fatty

acids such as linoleate (18:2) and linolenate (18:3). Hence,
these fatty acids are called essential fatty acids.

• Most fatty acids present in animals are linear while

branched fatty acids occur mainly in bacterial membranes.

• Triacylglycerols containing only saturated, long-chain, fatty

acyl groups are solid at room and body temperature, e.g.
triplamitin, while those containing unsaturated fatty acids
are liquid at room and body temperature, e.g. triolein.
• Most lipids in the average human diet are triacylglycerols, which are
digested in the small intestine by lipases.

• Lipases are synthesized in the pancreas as zymogens and secreted in

the small intestine where they are activated.

• Pancreatic lipase catalyzes hydrolysis of the primary esters at C-1 and

C-3 of triacylglycerols releasing fatty acids and generating
monoacylglycerols.

• Lipid digestion occurs in the presence of strong detergents called bile

salts, which are amphipathic derivatives of cholesterol synthesized in
the liver and stored in the gall bladder.
• Micelles of bile salts solubilize triacylglycerides and orient
the ester bonds of the molecules towards the surface of the
micelle where they are easily accessed by lipases.

• These micelles also solubilize fatty acids and

monoacylglycerols which allows them to diffuse through
and be absorbed by the cells of the intestinal wall.

• If the production of bile salts is inadequate due to liver

disease, large amounts of fat are not absorbed by the
intestine and are excreted in the feces (up to 30 g/day).

• This condition is called steatorrhea.

• In most cells triacylglycerols coalesce as fat droplets,
which are sometimes seen near mitochondria in cells with
high energetic needs.

• In mammals, most fat is stored in adipose tissue, which is

composed of specialized cells called adipocytes.

• Each adipocyte contains a large fat droplet that accounts for

nearly the entire volume of the cell.

• Most adipose tissue occur under the skin and in the

abdominal cavity and serves both as energy storage depot
and as thermal insulation.
 Fatty acid esters: Glycerophospholipids

• Glycerophospholipids are the most abundant lipids in

biological membranes.

• Glycerophospholipids are amphipathic molecules that

consist of 2 fatty acyl groups esterified to the C-1 and C-2
carbons of a glycerol molecule to which at least a
phosphate group is attached at C-3.

• The distinguishing feature of glycerophospholipids is the

presence of the phosphate group on the C-3 of the glycerol
backbone.

• The simplest glycerophospholipids are called phosphatides

and only have a phosphate group at C-3 of glycerol.
• Phosphatidates are present in small amounts as
intermediates in the biosynthesis or breakdown of more
complex glycerophospholipids.

• In most glycerophospholipids, the phosphate group is

esterified to both glycerol and another compound bearing a
hydroxyl group.

• The most common compounds attached to the C-3

Phosphate group of glycerol 3-phosphate in phospholipids
are choline, ethanolamine, serine, glycerol and inositol.
• The resulting corresponding glycerophospholipids are
phosphatidylcholine, phosphatidylethanolamine,
phosphatidylserine, phosphatidylglycerol and
phosphatidylinositol.

• Each of the glycerophospholipids mentioned above

represents a whole family of molecule with different fatty
acyl chains at positions C-1 and C-2 of glycerol.

• For example, the cell membranes of erythrocytes contain at

least 21 different species of phosphatidylcholine that differ
from one another in the fatty acyl chains esterified at C-1
and C-2.

• In general, glycerophospholipids have saturated fatty acids

esterified to C-1 and unsaturated fatty acids esterified to C-
2.
• Glycerophospholipids are hydrolyzed through the catalytic action of
phospholipases.

• Phospholipases A1 and A2 catalyze the hydrolysis of the ester bonds at

C-1 and C-2 of glycerol, respectively.

• Phospholipase C catalyzes the hydrolysis of the bond between the C-3

hydroxyl of glycerol and the phosphate group, while Phospholipase D
converts glycerphospholipids to phosphatidates.
• The other major type of glycerophospholipids is called
plasmalogen and it differs from phosphatidates in having
the hydrocarbon substituent on the C-1 hydroxyl group of
glycerol attached by a vinyl-ether linkage rather than an
ester linkage.

• Ethanolamine or choline are commonly esterified to the

phosphate group of plasmalogens.

• Plasmalogens account for about 23% of the

glycerophospholipids in the human central nervous system
and are also found in the membranes of peripheral nerves.

• An example of plasmalogens is the platelet activating factor

(PAF).
• PAF is a 1-alkyl-2-acetyl ether analog of
phosphatidylcholine that induces blood platelet
aggregation, smooth muscle contraction and the activation
of certain immune cells.
 Sphingolipids

• Sphingolipids are the second most abundant lipid in cell

membranes after glycerophospholipids.

• The structural backbone of sphingolipids is sphingosine, an

unbranched, C18 alcohol with a trans double bond between
C-4 and C-5, an amino group at C-2 and hydroxyl groups at
C-1 and C-3.

• Ceramide consists of a fatty acyl group linked to the C-2

amino group of sphingosine by an amide bond.

• Ceramides are the metabolic precursors of all

sphingolipids, which are subdivided into three major
families: sphingomyelins, cerebrosides and gangliosides.
• Of the 3 major families of sphingolipids, only
sphingomyelins contain phosphate and are classified as
phospholipids.

• Cerebrosides and gangliosides contain carbohydrate

residues and are classified as glycosphingolipids.

• In sphingomyelins, phosphocholine is attached to the C-1

hydroxyl group of a ceramide.

• Sphingomyelin resembles phosphatidylcholine with a

phosphocholine polar head and 2 long hydrophobic tails.

• They’re both zwiterions and present abundantly in cell

membranes.
• Cerebrosides are glycosphingolipids that contain one monosaccharide
residue attached by a b-glycosidic bond to C-1 of a ceramide.

• Galactocerebrosides, also known as galactosylceramides, have a single

b-D-galactosyl residue as a polar head group.

• Galactocerebrosides are abundant in nerve tissue and account for about

15% of the lipids of myelin sheaths.

• Glucocerebrosides, ceramides with a b-D-glucosyl head group, are also

present in several other tissues.
• Gangliosides are more complex glycosphingolipids in
which oligosaccharide chains containing N-
acetylneuraminic acid (NeuNac) are attached to a ceramide.

• The presence of NeuNac renders the head group of

gangliosides anionic.

• More than 60 varieties of gangliosides have been

characterized all resulting from variations in the
composition and sequence of the sugar residues.

• In all gangliosides, the ceramide is linked through its C-1 to

a b-glucosyl residue, which in turn is bound to a b-
galactosyl residue.
• Gangliosides are present in cell membranes and form part
of the cell surface repertoire of diverse oligosaccharides
along with glycoproteins.

• Collectively, they provide cells with distinguishing cell

surface markers that serve in cell recognition and cell-to-
cell communication.

• For example, the oligosaccharide components of the ABO

blood group antigens on the surface of human cells can be
contributed by glycosphingolipids in addition to
glycoproteins.

• The composition of membrane glycosphingolipids changes

dramatically during tumorigenesis.
• Genetically inherited defects in ganglioside metabolism
lead to debilitating and sometimes lethal diseases.

• For example, in Tay-Sachs disease, there is a deficiency in

the hydrolase that catalyses the removal of N-
acetylgalactosamine from GM2 in the lysosomes of neuronal
cells

• This leads to an accumulation of GM2 in the lysosomes of

neuronal cells, which subsequently swell leading to
neuronal cell death.

• This genetically inherited disease is characterized by

blindness, mental retardation and death.
Ganglioside M2
 Steroids

• Steroids are a third class of lipids found in eukaryotic cell

membranes.

• Steroids, along with vitamins and terpenes, are classified as

isoprenoids because their structure is related to the five
carbon molecule, isoprene.

• Steroids contain 4 fused rings: 3 six-carbon rings

designated A, B and C and a five-carbon D ring.

• The characteristic ring structure of steroids is derived from

squalene the common precursor of this family of
molecules.
• The steroid cholesterol is an important component of
animal plasma membranes but is absent from plants,
prokaryotes, protists and fungi.

• Cholesterol is actually a sterol because it carries a hydroxyl

group at C-3.
• Other steroids includes the sterols of plants, fungi and yeast,
mammalian steroid hormones (estrogens, androgens, progestins
and adrenal corticosteroids) and bile salts.

• These sterols differ from each other in the length of the side-
chain attached to C-17 and in the number and placement of
methyl groups, double bonds, hydroxyl groups and, in some
cases, keto groups.
• Cholesterol often accumulates in lipid deposits (plaques) on
the walls of blood vessels in a condition called
atherosclerosis.

• Atherosclerosis is one of the main risk factors for

cardiovascular diseases such as heart attacks and strokes.

• Despite its implication in cardiovascular diseases,

cholesterol plays an essential role in mammalian
biochemistry and is the precursor of other steroids, such as
bile salts and steroid hormones and non-steroid lipid
hormones (Vitamin D).

• The fused ring system of cholesterol makes it less flexible

than other lipids allowing it to regulate the fluidity of cell
membranes.
• Since the hydroxyl group at C-3 of cholesterol is the only polar
substituent, cholesterol is far more hydrophobic than
glycerophospholipids and sphingolipids.

• Esterification of a fatty acid to the C-3 hydroxyl group of

cholesterol forms a cholesteryl ester.

• Because the 3-acyl group of the ester is non-polar, a cholesteryl

esters are more hydrophobic than cholesterol.

• Cholesterol is converted to cholesteryl esters for storage in cells

or for transport through the bloodstream.

• Cholesterol and its esters are transported in serum in

lipoproteins.
• There are many additional types of lipids that are not found
in membranes such as waxes, eicosanoids and isoprenoids.

• Waxes are non-polar esters of long-chain fatty acids and

long-chain monohydroxylic alcohols.

• For example, myricyl palmitate, a major component of

beeswax, is the ester of palmitate (16:0) and the 30-carbon
myricyl alcohol.

• Myricyl palmitate is, therefore, very hydrophobic and

accounts for the high melting temperature of beeswax.

• Waxes play important protective and lubrication functions

in many organisms.
• Eicosanoids are oxygenated derivatives of C20
polyunsaturated fatty acids such as arachidonic acid that
participate in a variety of physiological processes.

• Prostaglandins are eicosanoids that have a cyclopentane

ring.

• Prostaglandin E2 has major vasoconstricting effects while

Thromboxane A2 plays a role in coagulation.
• Leukotriene D4 is a mediator of smooth muscle cell
contraction, which plays a role in bronchial constriction
seen in asthmatics.

• Several anti-inflammatory drugs inhibit the synthesis of

prostaglandins.