Lipids & Membranes: Structure and Functions

Lipids & Membranes
Biochemistry of Metabolism

Introduction
• Definition: water insoluble compounds
• Most lipids are fatty acids or ester of fatty acid
• They are soluble in non-polar solvents such as petroleum ether,
benzene, chloroform
• Functions
• Energy storage
• Structure of cell membranes
• Thermal blanket and cushion
• Precursors of hormones (steroids and prostaglandins)
• Types:
• Fatty acids
• Neutral lipids
• Phospholipids and other lipids

Lipids are non-polar (hydrophobic) compounds,
soluble in organic solvents.
Most membrane lipids are amphipathic, having a
non-polar end and a polar end.
Fatty acids consist of a hydrocarbon chain with a
carboxylic acid at one end.
A 16-C fatty acid: CH3(CH2)14-COO-
Non-polar polar
A 16-C fatty acid with one cis double bond between
C atoms 9-10 may be represented as 16:1 cis D9.

Some fatty acids and their common names:
14:0 myristic acid; 16:0 palmitic acid; 18:0 stearic acid;
18:1 cisD9 oleic acid
18:2 cisD9,12 linoleic acid
18:3 cisD9,12,15 a-linonenic acid
20:4 cisD5,8,11,14 arachidonic acid
20:5 cisD5,8,11,14,17 eicosapentaenoic acid (an omega-3)
Double bonds in fatty
acids usually have the
cis configuration.
Most naturally
occurring fatty acids
have an even number
of carbon atoms.
C
O
O
1
2
3
4
a


fatty acid with a cis-D9
double bond

There is free rotation about C-C bonds in the fatty acid
hydrocarbon, except where there is a double bond.
Each cis double bond causes a kink in the chain.
Rotation about other C-C bonds would permit a more
linear structure than shown, but there would be a kink.
C
O
O
1
2
3
4
a


fatty acid with a cis-D9
double bond

Saturated and Unsaturated Acyl Chains have
Different Shapes
• Double bonds are usually in cis configuration.
This results in a kink in the acyl chain
C=C
H H
CH2 CH2

Lipid composition of cell membranes
• Phospholipids (the major
lipids, 50-90% of total lipid content
• Most phospholipids are derivatives of
diacyl-glycerol-3-phosphate,
phosphatide)
• Sterols (5-25% of membrane content,
sterols are usually more concentrated in
the plasma membrane)
• Glycolipids (the least abundant,
usually less than 5%)

Topic 3 8
• Chemical composition
– Membranes are lipid-protein assemblies
• Held together by non-covalent bonds
• Core – a sheet of lipids – bimolecular layer
– A structural backbone
– Barrier
• Proteins – specific functions
– Carbohydrates
• Glycolipids
Membrane Structure

Glycerophospholipids
Glycerophospholipids
(phosphoglycerides), are common
constituents of cellular membranes.
They have a glycerol backbone.
Hydroxyls at C1 & C2 are esterified
to fatty acids.
C OH
H
CH2OH
CH2OH
glycerol
An ester forms
when a hydroxyl
reacts with a
carboxylic acid,
with loss of H2O.
Formation of an ester:
O O
R'OH + HO-C-R" R'-O-C-R'' + H2O

Phosphatidate
In phosphatidate:
 fatty acids are esterified to hydroxyls on C1 & C2
 the C3 hydroxyl is esterified to Pi.
O P O
O
O
H2C
CH
H2C
O
C
R1
O O C
O
R2
phosphatidate

In most glycerophospholipids (phosphoglycerides),
Pi is in turn esterified to OH of a polar head group (X):
e.g., serine, choline, ethanolamine, glycerol, or inositol.
The 2 fatty acids tend to be non-identical. They may differ
in length and/or the presence/absence of double bonds.
O P O
O
O
H2C
CH
H2C
O
C
R1
O O C
O
R2
X
glycerophospholipid

The Structure of a Phospholipid Molecule

Phosphatidylinositol, with inositol as polar head group,
is one glycerophospholipid.
In addition to being a membrane lipid,
phosphatidylinositol has roles in cell signaling.
O P
O
O
H2C
CH
H2C
O
C
R1
O O C
O
R2
OH
H
OH
H
H
OH
H
OH
H
O
H OH
phosphatidyl-
inositol

Phosphatidylcholine, with choline as polar head
group, is another glycerophospholipid.
It is a common membrane lipid.
O P O
O
O
H2C
CH
H2C
O
C
R1
O O C
O
R2
CH2 CH2 N CH3
CH3
CH3
+
phosphatidylcholine

polar
non-polar
"kink" due to
double bond
O P O
O
O
H2C
CH
H2C
O
C
R1
O O C
O
R2
X
glycerophospholipid
Each glycerophospholipid
includes
 a polar region:
glycerol, carbonyl O
of fatty acids, Pi, & the
polar head group (X)
 non-polar hydrocarbon
tails of fatty acids (R1, R2).

Sphingosine may be reversibly
phosphorylated to produce the signal
molecule sphingosine-1-phosphate.
Other derivatives of sphingosine are
commonly found as constituents of
biological membranes.
H2C
H
C
OH
CH
N+ CH
C
CH2
CH3
H
H3
OH
( )12
sphingosine
Sphingolipids are derivatives of
the lipid sphingosine, which has a
long hydrocarbon tail, and a polar
domain that includes an amino group.
sphingosine-1-P
H2C
H
C
O
CH
N+
CH
C
CH2
CH3
H
H3
OH
( )12
P O
O

O

In the more complex sphingolipids,
a polar “head group" is esterified
to the terminal hydroxyl of the
sphingosine moiety of the ceramide.
H2C
H
C
OH
CH
N+ CH
C
CH2
CH3
H
H3
OH
( )12
sphingosine
H2C
H
C
OH
CH
NH CH
C
CH2
CH3
H
OH
( )12
C
R
O
ceramide
The amino group of sphingosine can
form an amide bond with a fatty acid
carboxyl, to yield a ceramide.

Sphingomyelin, with a phosphocholine head group, is
similar in size and shape to the glycerophospholipid
phosphatidyl choline.
Sphingomyelin has
a phosphocholine or
phosphethanolamine
head group.
Sphingomyelins are
common constituent
of plasma membranes
H2C
H
C
O
CH
NH CH
C
CH2
CH3
H
OH
( )12
C
R
O
P
O O
O
H2
C
H2
C
N
+
CH3
H3C
CH3
Sphingomyelin
phosphocholine
sphingosine
fatty acid


head group that is a complex oligosaccharide, including
the acidic sugar derivative sialic acid.
Cerebrosides and gangliosides, collectively called
glycosphingolipids, are commonly found in the outer
leaflet of the plasma membrane bilayer, with their sugar
chains extending out from the cell surface.
cerebroside with
-galactose head group
H2C
H
C CH
NH CH
C
CH2
CH3
OH
C
R
O
OH O
H H
H
OH
H
OH
CH2OH
H
O
H
( )12
A cerebroside is a
sphingolipid
(ceramide) with a
monosaccharide
such as glucose or
galactose as polar
head group.
A ganglioside is a
ceramide with a polar

Topic 3 21
• Chemical
composition
– Lipid Types
• Cholesterol
Membrane Structure

Topic 3 22
• Chemical
composition
– Lipid Types
Membrane Structure

Cholesterol is largely
hydrophobic.
But it has one polar group,
a hydroxyl, making it
amphipathic.
Cholesterol
HO
Cholesterol, an
important constituent
of cell membranes,
has a rigid ring
system and a short
branched
hydrocarbon tail.
cholesterol
PDB 1N83

Fatty Acids Melting Points and Solubility in Water
Solubility in H O
Fatty Acid Chain Length
2
Melting Point
z
x
x
x
x
x
x
x
x

C4 - 8 -
C6 - 4 970
C8 16 75
C10 31 6
C12 44 0.55
C14 54 0.18
C16 63 0.08
Fatty Acids M.P.(C) mg/100 ml in H2O*
C18 70 0.04
Characteristics of Fatty Acids
* Solubility

Effects of Double Bonds on the Melting Points
16:0 60
16:1 1
18:0 63
18:1 16
18:2 -5
18:3 -11
20:0 75
F. A. M. P. (0C)
20:4 -50
M.P.
# Double bonds

Analytical Methods for The
Determination of Characteristics of
Fats and Oils

1. Acid Value
2. Saponification Value
3. Iodine Value
4. Gas Chromatographic Analysis for Fatty Acids
5. Liquid Chromatography
6. Cholesterol Determination
Analytical Methods

Glycerides
H2C OH
HC OH
H2C O
O
C (CH2)16CH3
H2C O
HC OH
H2C O
O
C (CH2)16CH3
C (CH2)16CH3
O
H2C O
HC O
H2C O
O
C (CH2)16CH3
C (CH2)16CH3
O
O
C (CH2)14CH3
( C18)
(C16)
(C18)

Saponification Value
Saponification - Hydrolysis of ester (triglycerider)
under alkaline condition.
O
C R
O
O
C R
C R
O
H2C O
HC O
H2C O
KOH
H
H
H
H2C O
HC O
H2C O
R C O
-
K
+
+ 3 + 3
Heat
Definition : mgs of KOH required to saponify 1 g of fat

CH2 O C
O
(CH2)6 CH3
CH O C
O
(CH2)6 CH3
CH2 O C
O
(CH2)6 CH3
CH2 O C
O
(CH2)16 CH3
CH O C
O
(CH2)16 CH3
CH2 O C
O
(CH2)16 CH3
Tricaprylin (MW=
450)
Tristearin (MW= 890)
1Gram of Oils A and B
B
A

Definition : mgs of KOH required to saponify 1 g
of fat
A B
:Large molecular triacylglycerols : Small molecular triacylglycerols

• The molecular weights of tributyrin and tristearin
are 300 and 900, respectively. If the numbers of
tributyrin in 1 gram is 21 x 1020, what are the
approximate numbers of tristearin in 1 gram?
• If the saponification value is tristearin is 190, what
is the approximate saponification value of
tributyrin?

Milk Fat 210-233
Coconut Oil 250-264
Cotton Seed Oil 189-198
Soybean Oil 189-195
Fat Saponification #
Lard 190-202
Saponification Values of Fats and Oils

Fatty Acids (%) of Fats and Oils
4 3
6 3
8 2 6
10 3 6
12 3 44
14 10 18 1
16 26 11 4 12
16:1 7 1
18:0 15 6 3 2
18:1 29 7 18 24
18:2 2 2 53 54
Fatty
Acids
Butter Cocon
ut
Cottonsee
d
Soybean
18:3 2 8

Iodine Value
Number of iodine (g) absorbed by 100 g of oil.
Molecular weight and iodine number can calculate the
number of double bonds. 1 g of fat adsorbed 1.5 g of
iodine value =150.

Iodine Value
Trilinolein
(MW= 878)
Triolein (MW=
884)
CH2 O C
O
(CH2)7 CH CH (CH2)7 CH3
CH3
(CH2)7
CH
CH
(CH2)7
O
C
O
CH
CH3
(CH2)7
CH
CH
(CH2)7
O
C
O
CH2
CH2 O C
O
(CH2)7 CH CH CH2 CH
CH
CH
(CH2)7
O
C
O
CH
CH
CH
(CH2)7
O
C
O
CH2
CH (CH2)4 CH3
CH3
(CH2)4
CH
CH
CH2
CH3
(CH2)4
CH
CH
CH2
A
B

CH2 O C
O
(CH2)7
CH CH
CH
CH
(CH2)7
O
C
O
CH
(CH2)14
O
C
O
CH2
CH3
(CH2)4
CH
CH
CH2
(CH2)7
CH3
CH3
C H 2 O C
O
(C H 2)7
(C H 2)14
O
C
O
C H
(C H 2)14
O
C
O
C H 2 C H 3
C H 3
C H 3
(C H 2)7
C H
C H
A
B

ICl KI KCl
I2
I2
Na2S2O3 Na2S4O6 NaI
+
+ 2 2
+
+
Excess unreacted ICl
Iodine Value Determination
CH CH CH CH
Cl I
ICl
Iodine chloride
+
_
_

Iodine Values of Triglycerides
Palmitoleic
Acid
1 95
Oleic Acid 1 86
Linoleic Acid 2 173
Linolenic Acid 3 261
Fatty Acids # of Double-bonds Iodine #
Arachidonic
Acid
4 320

Compositions (%) of Fatty Acids of Fats
1 5 5 20 40 30
2 20 35 40 5
3 10 50 40
4 20 40 40
5 10 20 20 10 20 20
Fat C4 C6 C10 C16C18 C18:
1
C18:
2
C18:
3
C20:
4
6 10
0

Structure of Cholesterol
Fundamental framework of steroids is the
tetracyclic unit shown.
A B
C D

Cholesterol has the fundamental steroid
skeleton modified as shown.
HO
CH3
H
H
H
CH3
CH3 CH3
CH3

Some parts of the cholesterol molecule are
isoprenoid. But other parts don't obey the
isoprene rule. Also, cholesterol has 27
carbons, which is not a multiple of 5.
HO
CH3
H
H
H
CH3
CH3 CH3
CH3

Terpenes
• Terpenes are natural products that
are structurally related to isoprene.
H2C C
CH3
CH CH2
or
Isoprene
(2-methyl-1,3-butadiene)

Terpenes
• Myrcene (isolated from oil of
bayberry) is a typical terpene.
CH2
CH3
CH3C CHCH2CH2CCH
CH2
or

The Isoprene Unit
• An isoprene unit is the carbon skeleton of
isoprene (ignoring the double bonds)
Myrcene contains two isoprene units.

The Isoprene Unit
• The isoprene units of myrcene are joined
"head-to-tail."
head tail
tail head

Terpenes
• Class Number of carbon atoms
• Monoterpene 10
• Sesquiterpene 15
• Diterpene 20
• Sesterpene 25
• Triterpene 30
• Tetraterpene 40
Classification of Terpenes

Terpenes
Representative Monoterpenes
a-Phellandrene
(eucalyptus)
Menthol
(peppermint)
Citral
(lemon grass)
O
H
OH

Terpenes
Representative Monoterpenes
a-Phellandrene
(eucalyptus)
Menthol
(peppermint)
Citral
(lemon grass)

Terpenes
Representative Sesquiterpenes
a-Selinene
(celery)
H

Terpenes
Representative Sesquiterpenes
a-Selinene
(celery)

Terpenes
Representative Diterpenes
Vitamin A
OH

Terpenes
Representative Diterpenes
Vitamin A

Common Terpenes
OH
Gerani
ol C
10
H
18
O
OH
Nerol C
10
H
18
O
OH
Terpineol C 10 H 18 O
O
H
Linalool C 10 H 18 O

Isoprene / Biosynthesis
O
P
O
P
O
O
O
O
O
Isopentenyl pyrophosphate
Isoprene

Formation of geranyl pyrophosphate
Terpene Biosynthesis

Formation of Squalene, the Precursor of
Cholesterol

Terpenes
Representative Triterpene
Squalene
(shark liver oil)
tail-to-tail linkage of isoprene units

Isoprene Links
Heads or Tails?

Squalene, a triterpene, is a precursor of steroids

• Many hormones are steroids
Steroids

Methyl groups at C-10 and C-13 are called angular
methyl groups
The B, C, and D rings are trans fused

Those on the opposite side of the plane of the ring
system are a-substituents
Substituents on the same side of the steroid ring system
as the angular methyl groups are -substituents
The A and B rings are also trans fused in most naturally
occurring steroids

TERPENE
BIOSYNTHESES
in detail
Isopentenyl
Pyrophosphate:
The Biological Isoprene
Unit

Unit
• The isoprene units in terpenes do not come
from isoprene.
• They come from isopentenyl pyrophosphate.
• Isopentenyl pyrophosphate (5 carbons) comes
from acetate (2 carbons) via mevalonate (6
carbons).

Unit
CH3COH
O
3 HOCCH2CCH2CH2OH
CH3
OH
O
Mevalonic acid
H2C CCH2CH2OPOPOH
CH3 O O

Isopentenyl Pyrophosphate
H2C CCH2CH2OPOPOH
CH3 O O
or OPP

Isopentenyl and Dimethylallyl
Pyrophosphate
Isopentenyl pyrophosphate is interconvertible with
2-methylallyl pyrophosphate.
OPP
OPP
• Dimethylallyl pyrophosphate has a leaving
group (pyrophosphate) at an allylic carbon;
it is reactive toward nucleophilic
substitution at this position.
Isopentenyl pyrophosphate Dimethylallyl pyrophosphate

Carbon-Carbon Bond
Formation in Terpene
Biosynthesis

Carbon-Carbon Bond
Formation
• The key process involves the double bond of
isopentenyl pyrophosphate acting as a
nucleophile toward the allylic carbon of
dimethylallyl pyrophosphate.
+
OPP
OPP

Carbon-Carbon Bond
Formation
+
OPP
OPP
–
+
OPP
OPP

After C—C Bond
Formation...
+
OPP
• The
carbocation
can lose a
proton to give
a double bond.

After C—C Bond
Formation...
+
OPP
OPP
• The
carbocation
can lose a
proton to give
a double bond.
H
–
+

After C—C Bond
Formation...
OPP
• This compound is called geranyl
pyrophosphate. It can undergo hydrolysis of its
pyrophosphate to give geraniol (rose oil).

After C—C Bond
Formation...
OPP
OH
Geraniol
H2O

Terpenes
O
P
O
P
O
O
O
O
O
Isoprene
• isoprenyl (C5) --> geranyl (C10)
• geranyl (C10) --> farnesyl (C15)
• farnesyl (C15) --> squalene (C30)
• Generic: C10 monoterpenes,
C15sesquiterpenes, C20 diterpenes,
C30 triterpenes, C40 tetraterpenes

From 10 Carbons to 15
+
OPP
OPP
Geranyl pyrophosphate
+
OPP

+
OPP
H
–
+
OPP

OPP
• This compound is called farnesyl
pyrophosphate.
• Hydrolysis of the pyrophosphate ester gives
the alcohol farnesol.

OPP
• Farnesyl pyrophosphate is extended by
another isoprene unit by reaction with
isopentenyl pyrophosphate.
OPP

Cyclization
• Rings form by intramolecular carbon-carbon
bond formation.
OPP
OPP
+
E double
bond
Z double
bond

+
OH
H
–
+
H2O
Limonene
a-Terpineol

Bicyclic Terpenes
+
+
+
-Pinene
+
a-Pinene

The Pathway from
Acetate to Isopentenyl
Pyrophosphate

Terpenes
CH3COH
O
3 HOCCH2CCH2CH2OH
CH3
OH
O
Mevalonic acid
H2C CCH2CH2OPOPOH
CH3 O O

Biosynthesis of Mevalonic
Acid
CH3CCH2CSCoA
O
O
S-Acetoacetyl
coenzyme A
• In a sequence analogous to the early steps
of fatty acid biosynthesis, acetyl coenzyme
A is converted to S-acetoacetyl coenzyme
A.

Acid
CH3CSCoA
O
+
CH3CCH2CSCoA
O
O
• In the next step, S-acetoacetyl coenzyme A
reacts with acetyl coenzyme A.
• Nucleophilic addition of acetyl coenzyme A
(probably via its enol) to the ketone
carbonyl of S-acetoacetyl coenzyme A
occurs.

Acid
CH3CSCoA
O
CH3CCH2CSCoA
CH2COH
HO O
O
+
CH3CCH2CSCoA
O
O

Acid
CH3CCH2CSCoA
CH2COH
HO O
O
• Next, the acyl coenzyme A function is
reduced.
• The product of this reduction is mevalonic
acid.

CH3CCH2CSCoA
CH2COH
HO O
O
CH3CCH2CH2OH
CH2COH
HO
O
Mevalonic
acid

Conversion of Mevalonic
Acid to Isopentenyl
Pyrophosphate
CH3CCH2CH2OH
CH2COH
HO
O
• The two hydroxyl groups of mevalonic acid
undergo phosphorylation.
CH3CCH2CH2OPP
CH2COH
O
OPO3
2–

Acid to Isopentenyl
Pyrophosphate
CH3CCH2CH2OPP
CH2
• Phosphorylation is followed by a novel
elimination involving loss of CO2 and PO4
3–
.
OPO3
3–
CH3CCH2CH2OPP
CH2
O
OPO3
2–
C O
••
••
•
•
–
O C O

Acid to Isopentenyl
Pyrophosphate
• The product of this elimination is
isopentenyl pyrophosphate.
CH3CCH2CH2OPP
CH2

Biosynthetic pathway is
based on experiments with
14C-labeled acetate
CH3COH
O
HOCCH2CCH2CH2OH
CH3
OH
O
Mevalonic acid
H2C CCH2CH2OPOPOH
CH3 O O

Biosynthetic pathway is
based on experiments with
14C-labeled acetate
CH3COH
O
• Citronellal biosynthesized using 14C-labeled
acetate as the carbon source had the labeled
carbons in the positions indicated.
H2C CCH2CH2OPOPOH
CH3 O O
O
H
•
• • •
•
•

Biosynthesis of
Cholesterol
Cholesterol is biosynthesized from the
triterpene squalene. In the first step, squalene
is converted to its 2,3-epoxide.

Biosynthesis of
Cholesterol
Cholesterol is biosynthesized from the
triterpene squalene. In the first step, squalene
is converted to its 2,3-epoxide.
O
O2, NADH, enzyme

Biosynthesis of
Cholesterol
To understand the second step, we need to
look at squalene oxide in a different
conformation, one that is in a geometry
suitable for cyclization.
O

Biosynthesis of
Cholesterol
To understand the second step, we need to
look at squalene oxide in a different
conformation, one that is in a geometry
suitable for cyclization.
O
O

Biosynthesis of
Cholesterol
Cyclization is triggered by epoxide ring
opening.
O
H
+

Biosynthesis of
Cholesterol
Cyclization is triggered by epoxide ring
opening.
O
H
+
HO
+

Biosynthesis of
Cholesterol
Loss of a proton is accompanied by a series of
hydride shifts and methyl migrations.
HO
+
OH2
••
•
•
H
H
H
HO
H
H

Biosynthesis of
Cholesterol
The product of this rearrangement is a
triterpene called lanosterol. A number of
enzyme-catalyzed steps follow that convert
lanosterol to cholesterol.
HO
H
H

Cholesterol
Cholesterol is the biosynthetic precursor to a
large number of important steroids:
Bile acids
Vitamin D
Corticosteroids
Sex hormones

Cholesterol
HO
CH3
H
H
H
CH3
CH3 CH3
CH3
Cholesterol is the precursor to vitamin D.
Enzymes dehydrogenate cholesterol to introduce a second double
bond in conjugation with the existing one. The product of this
reaction is called 7-dehydrocholesterol.

7-Dehydrocholesterol
HO
CH3
H H
CH3
CH3 CH3
CH3
Sunlight converts 7-dehydrocholesterol on the
skin's surface to vitamin D3.

Vitamin D3
HO
H
CH3
CH3 CH3
CH3
Insufficient sunlight can lead to a deficiency
of vitamin D3, interfering with Ca2+ transport
and bone development. Rickets can result.

Cholesterol
HO
CH3
H
H
H
CH3
CH3 CH3
CH3
Oxidation in the liver degrades the cholesterol side chain and
introduces OH groups at various positions on the steroid skeleton.
Cholic acid is the most abundant of the bile acids.

Cholic Acid
Salts of cholic acid amides (bile salts), such as sodium
taurocholate, act as emulsifying agents to aid digestion.
HO
CH3
H
H
H
CH3
CH3
H
OH
HO
O
OH

Sodium Taurocholate
HO
CH3
H
H
H
CH3
CH3
H
OH
HO
O
NHCH2CH2SO3Na

Cholesterol
HO
CH3
H
H
H
CH3
CH3 CH3
CH3
Enzymatic degradation of the side chain and oxidation of various
positions on the steroid skeleton convert cholesterol to
corticosteroids.

Cortisol
Cortisol is the most abundant of the corticosteroids. Enzyme-
catalyzed oxidation of cortisol gives cortisone.
O
CH3
H
H
H
CH3
OH
HO
O
OH

Cortisone
Corticosteroids are involved in maintaining electrolyte levels,
in the metabolism of carbohydrates, and in mediating the
allergic response.
O
CH3
H
H
H
CH3
OH
O
O
OH

Testosterone
Testosterone is the main male sex hormone.
O
H
H
H
H3C
H3C
OH

Estradiol
Estradiol is a female sex hormone involved in
regulating the menstrual cycle and in
reproduction.
HO
H
H
H
H3C
OH

Progesterone
Supresses ovulation during pregnancy.
O
H
H
H
H3C
H3C
O

Lipids & Membranes: Structure and Functions

Lipids & Membranes: Structure and Functions

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