Chapter 8

Lipids and Proteins Are

Associated in Biological
Membranes

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Chapter Outline
(8-1) The definition of a lipid
(8-2) The chemical natures of the lipid types
(8-3) Biological membranes
(8-4) Membrane proteins
(8-5) The functions of membranes
(8-6) Lipid-soluble vitamins and their functions
(8-7) Prostaglandins and leukotrienes

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Lipids
• Heterogeneous class of naturally occurring organic
compounds classified together on the basis of
common solubility properties
• Examples - Fats and oils
• Insoluble in water but soluble in aprotic organic
solvents including diethyl ether, chloroform,
methylene chloride, and acetone
• Amphipathic in nature
• Amphipathic: Molecule that has one end with a polar,
water-soluble group and another end with a nonpolar
hydrocarbon group that is insoluble in water

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Classification of Lipids

Open-chain Fused-ring
compounds compounds
• Fatty acids • Cholesterol
• Triacylglycerols • Steroid hormones
• Sphingolipids • Bile acids
• Phosphoacylglycerols
• Glycolipids

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Fatty Acids
• Unbranched chain carboxylic acids
• 12–20 carbons long
• Derived from hydrolysis of animal fats, vegetable oils,
or phosphodiacylglycerols of biological membranes
• Amphipathic compounds
• Types
• Unsaturated fatty acids - Contain carbon–carbon
double bonds
• Saturated fatty acids - Contain only single bonds

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Figure 8.1 - The Structures of Some Typical
Fatty Acids

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Table 8.1 - Typical Naturally Occurring Saturated
Fatty Acids

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Table 8.2 - Typical Naturally Occurring Unsaturated
Fatty Acids

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Unsaturated Fatty Acids
• cis isomer predominates and the trans isomer is rare
• cis double bond puts a kink in the long-chain
hydrocarbon tail
• Shape of a trans fatty acid is like that of a saturated
fatty acid in its fully extended conformation
• Double bonds are isolated by several singly bonded
carbons
• Have lower melting points than their saturated
counterparts
• Greater the degree of unsaturation, lower the melting
point

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Fatty Acid Notation
• Indicates the number of carbon atoms and the
number of double bonds separated by a colon
• Examples
• 18:0 denotes an 18-carbon saturated fatty acid with no
double bonds
• 18:1 denotes an 18-carbon fatty acid with one double
bond

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Triacylglycerols (Triglycerides)
• Lipids formed by the esterification of three fatty acids
to glycerol
• Ester groups form the polar part of the molecule, and
the tails are nonpolar
• Accumulated in adipose tissues and provide a means
of storing fatty acids
• Ester linkages are hydrolyzed by lipases when fatty
acids are used by organisms
• Serve as concentrated stores of metabolic energy

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Figure 8.2 - Triacylglycerols are Formed from Glycerol
and Fatty Acids

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Saponification
• Reaction of glyceryl
ester with NaOH or KOH
to produce glycerol and
respective Na or K salts
(soaps)
• Soaps form water-
insoluble salts when used
in hard water, which
contains Ca(II), Mg(II),
and Fe(III) ions
• Glycerol is used in
creams and in the
manufacture of
nitroglycerin
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Phosphatidic Acid
• Compound in which two fatty acids and phosphoric
acid are esterified to the three hydroxyl groups of
glycerol
• Phosphoric acid is triprotic in nature
• One molecule can form ester bonds to glycerol and to
some other alcohol to create phosphatidyl esters

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Phosphatidyl Esters
• Classed as phosphoacylglycerols
• Classification depends on nature of the second alcohol
that is esterified to the phosphoric acid
• Nature of fatty acids in a molecule varies widely
• Structure
• Long, nonpolar, hydrophobic tails
• Polar, highly hydrophilic head groups
• Amphipathic in nature

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Phosphoacylglycerols
• Polar head group is
charged
• Phosphate group is
ionized at neutral pH
• Positively charged
amino group is
contributed by an amino
alcohol esterified to the
phosphoric acid

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Waxes
• Complex mixtures of esters of long-chain carboxylic
acids and long-chain alcohols
• Serve as protective coatings for plants and animals

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Sphingolipids
• Contain sphingosine, a
long-chain amino
alcohol
• Found in plants and
animals and are
abundant in the nervous
system
• Sphingomyelin
• Primary alcohol of
sphingosine is esterified
to phosphoric acid, which
is esterified to choline

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Glycolipids
• Lipid to which a sugar moiety
is bonded
• Ceramides
• Parent compounds for
glycolipids
• Glycosidic bond is formed
between the primary alcohol
group of the ceramide and a
sugar residue (glucose or
galactose)
• Resulting compound is
called a cerebroside
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Example of Glycolipids: Gangliosides
• Glycolipids with a
complex carbohydrate
moiety that contains
more than three sugars
• One is always a sialic
acid
• Called acidic
glycosphingolipids
because of their net
negative charge at
neutral pH

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Figure 8.8 - Structures of Several Important
Gangliosides

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Steroids
• Lipids with a characteristic fused-ring structure
• Three six-membered rings (the A, B, and C rings)
• One five-membered ring (the D ring)
• Important steroids include sex hormones and
cholesterol
• Cholesterol: Occurs in cell membranes
• Highly hydrophobic
• Acts as a precursor of other steroids
• Plays a role in the development of atherosclerosis

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Figure 8.9 - Structures of Some Steroids

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Biological Membranes
• Every cell has a cell (plasma) membrane
• Eukaryotic cells also have membrane-enclosed
organelles (nuclei and mitochondria)
• Molecular basis of membrane structure lies in its lipid
and protein components
• Separate cells from the external environment and
transport specific substances into and out of cells
• Interaction between lipid bilayers and membrane
proteins determines membrane function
• Contain many important enzymes whose function
depends on the membrane environment

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Biological Membranes (continued)
• Major force driving the formation of lipid bilayers is
hydrophobic interaction
• Differ from lipid bilayers as they contain proteins as
well as lipids

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Lipid Bilayer
• Aggregate of a lipid molecule
in which the polar head
groups are in contact with
water and the hydrophobic
parts are not
• Polar surface contains charged
groups
• Hydrocarbon interior consists
of saturated and unsaturated
fatty acid chains and the fused-
ring system of cholesterol

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Lipid Bilayer (continued)
• Arrangement is held
together by noncovalent
interactions
• van der Waals and
hydrophobic interactions
• Both inner and outer
layers contain mixtures
of lipids
• Bulkier molecules tend to
occur in the outer layer
• Smaller molecules tend
to occur in the inner layer

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Table 8.3 - Lipid Composition of Membranes in Rat
Liver Cells, in Weight Percent

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Membrane Fluidity
• Arrangement of hydrocarbon interior of the bilayer
can be ordered and rigid or disordered and fluid
• Depends on composition of the bilayer
• Saturated fatty acids
• Linear arrangement of hydrocarbon chains leads to
rigidity
• Unsaturated fatty acids
• Kink in the hydrocarbon chain causes disorder in its
packing and leads to greater fluidity

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Figure 8.12 - Effect of Double Bonds on the
Conformations of Hydrocarbon Tails of Fatty Acids

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Membrane Fluidity and Cholesterol
• Presence of cholesterol can enhance order and
rigidity
• Fused-ring structure of cholesterol is rigid
• Stabilizes extended straight-chain arrangement of
saturated fatty acids by van der Waals interactions

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Membrane Fluidity in Plants and Animals
• Animal membranes are less fluid and more rigid than
plant membranes
• Plant membranes have a higher percentage of
unsaturated fatty acids than animal membranes
• Presence of cholesterol is characteristic of animal,
rather than plant, membranes
• Membranes of prokaryotes are the most fluid
• Contain no appreciable amounts of steroids

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Phase Transition in Lipid Bilayer
• Ordered bilayers become less ordered in the
presence of heat
• Cooperative transition occurs at a characteristic
temperature
• Transition temperature is higher for more rigid
membranes and is lower for less rigid membranes
• Mobility of the lipid chains increases dramatically

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Types of Membrane Proteins
• Peripheral proteins: Loosely bound to the outside of
a membrane
• Bound by polar interactions, electrostatic interactions,
or both and can be removed by raising the ionic
strength of the medium
• Example - Heterotrimeric G protein
• Integral proteins: Embedded in a membrane
• Can be removed by treatment with detergents or
extensive sonication, which may lead to denaturation
of the protein
• Example - Rhodopsin

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Figure 8.18 - Integral and Peripheral Proteins

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Anchoring Proteins to Membranes
• Proteins span across the membrane in the form of an
α-helix or a β-sheet
• Structures minimize the contact of polar parts with the
nonpolar lipids
• Proteins can be anchored to the lipids via covalent
bonds from cysteines or free amino groups on the
protein to one of the several lipid anchors

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Anchoring Proteins to Membranes (continued)
• N-myristoyl and S-palmitoyl are the anchoring motifs
• Anchors can be via N-terminal Gly
• Form a thioester linkage with Cys

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Figure 8.19 - Certain Proteins Are Anchored to
Biological Membranes by Lipid Anchors

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Functions of Membrane Proteins

Transport proteins

• Mediate the entry of specific substances

into a cell

Receptor proteins

• Contain specific binding sites for

extracellular substances

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Fluid-Mosaic Model
• Model in which proteins and a lipid bilayer exist side
by side without covalent bonds between them
• Basic structure of the biological membranes is that of
a lipid bilayer, with proteins embedded in the bilayer
structure
• Lipids are sorted into assemblages called rafts, which
serve as fundamental building blocks on which
membrane specificity is based
• Fluid mosaic
• Term that implies that there is lateral motion of
components in the membrane

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Figure 8.20 - Fluid-Mosaic Model of Membrane
Structure

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Membrane Imaging Methods
• Electron microscopy
• Depends on scattering a beam of electrons from the
surface of the sample
• Freeze-fracture technique - Membrane is frozen and
then fractured along the interface between the layers
• Atomic force microscopy
• Sample surface is scanned using a cantilever with a
sharp tip
• Electrical measurements determine the force
generated between the tip and the surface, which
generates the image

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Figure 8.21 - Freeze-Fracture Technique

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Membrane Transport: Passive Transport
• Process by which a substance enters a cell without
expenditure of cell energy
• Driven by concentration gradient
• Categories
• Simple diffusion: Process by which a molecule or an
ion moves through an opening or pore in a membrane
without requirement for a carrier or an expenditure of
energy
• Facilitated diffusion: Process by which substances
enter a cell by binding to a carrier protein
• Does not require energy

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Figure 8.22 - Passive Diffusion

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Figure 8.23 - Facilitated Diffusion

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Plot for Passive and Facilitated Diffusion
• Simple diffusion
• Rate of movement is
controlled by difference in
concentration across the
membrane
• Facilitated diffusion
• Plotting the rate of
transport against S gives
a hyperbolic curve similar
to that seen in Michaelis–
Menten enzyme kinetics

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Membrane Transport: Active Transport
• Substance is moved against a concentration gradient
• Involves a carrier protein and requires an energy
source to move solutes against a gradient
• Primary active transport
• Transport is directly linked to the hydrolysis of a high-
energy molecule, such as ATP
• Sodium–potassium ion pump (Na+/K+ ion pump)
• Secondary active transport
• Driven by H+ gradient
• Proton pumps: Active transporters that create H+
gradients

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Figure 8.25 - Sodium–Potassium Ion Pump

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Figure 8.26 - Mechanism for Na+/K+ ATPase (the
Sodium–Potassium Ion Pump)

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Figure 8.27 - Example of Secondary Active Transport

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Membrane Receptors
• Large oligomeric proteins with molecular weights on
the order of hundreds of thousands
• Examples - Receptors for G proteins, low-density
lipoprotein (LDL), and human growth hormone (hGH)
• Binding of a biologically active substance to a
receptor initiates an action within the cell
• Requirements
• Presence of essential functional groups that have the
correct 3-D conformation
• Ability of binding sites to provide a good fit for the
substrate
• Action can be inhibited by an inhibitor or a poison

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Low-Density Lipoprotein (LDL)
• Principal carrier of
cholesterol in the
bloodstream
• Consists of various
lipids and a protein
• Cholesterol portion is
used by the cell
• Protein portion binds to
the LDL receptor of a cell
• Forms a complex that is
pinched off into the cell via
endocytosis

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Figure 8.30 - Mechanism of Action of Human
Growth Hormone and its Receptor

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Lipid-Soluble Vitamins and Their Functions
• Lipid-soluble vitamins are hydrophobic

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Vitamin A
• -carotene: Extensively unsaturated hydrocarbon
• Precursor of vitamin A
• Found in the plant world in the form of a provitamin in
a group of pigments called carotenes
• Retinol: Alcohol form of vitamin A
• Enzymatically oxidized to an aldehyde group to form
retinal
• Aldehyde group forms an imine with a side-chain group
of the protein opsin to form the visual pigment called
rhodopsin

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Reactions of Vitamin A
• Enzyme-catalyzed cleavage of β-carotene followed
by reduction gives two molecules of vitamin A

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Reactions of Vitamin A (continued)
• Primary chemical event of
vision in rod cells is
absorption of light by
rhodopsin followed by
isomerization of the 11-cis
double bond to the 11-trans
double bond

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Figure 8.32 - Formation of Rhodopsin from 11-cis-
Retinal and Opsin

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Vitamin D
• Group of structurally related compounds involved in
the regulation of calcium and phosphorus metabolism
• Most abundant form in the circulatory system is
vitamin D3 (cholecalciferol)
• Further processed in the body to form hydroxylated
derivatives
• Presence leads to increased synthesis of Ca2+-binding
protein, which increases dietary calcium intake
absorption
• Deficiency leads to rickets

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Figure 8.34 - Reactions of Vitamin D

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Vitamin E
• Most active from of vitamin E is α-tocopherol
• Contains antioxidant properties
• Antioxidants: Strong reducing agents, which are
easily oxidized and thus prevent the oxidation of other
substances
• Traps free radicals (HOO• and ROO•)
• Highly reactive molecules that have at least one
unpaired electron
• Formed as a result of oxidation of unsaturated
hydrocarbon chains in membrane phospholipids

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Figure 8.35 - Most Active Form of Vitamin E Is α-
Tocopherol

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Vitamin K
• Plays an important role
in the blood-clotting
process
• Bicyclic ring system
contains two carbonyl
groups, the only polar
groups on the molecule
• Long unsaturated
hydrocarbon side chain
consists of repeating
isoprene units

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Figure 8.37 - Role of Vitamin K in the
Modification of Prothrombin

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Prostaglandins
• Derived from fatty acids
• First detected in seminal fluid, which is produced by
the prostate gland
• Arachidonic acid
• Metabolic precursor of all prostaglandins
• Fatty acid that has 20-carbon skeleton of prostanoic
acid
• Contains four double bonds, which are not conjugated
• Have five-membered rings
• Differ from one another in numbers and positions of
double bonds and oxygen-containing functional
groups
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Figure 8.38 - Arachidonic Acid and Some
Prostaglandins

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Functions of Prostaglandins
• Control of blood pressure
• Stimulation of smooth-muscle contraction
• Induction of inflammation
• Aspirin, cortisone, and other steroids possess anti-
inflammatory effects
• Inhibition of the aggregation of platelets
• Possess therapeutic value by preventing formation of
blood clots

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Leukotrienes
• Compounds derived from arachidonic acid
• Found in white blood cells (leukocytes)
• Consist of three conjugated double bonds
• Help in the constriction of smooth muscle, especially
in the lungs
• May have inflammatory properties and may be
involved in rheumatoid arthritis

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Thromboxanes
• Third class of derivatives of arachidonic acid
• Structure contains cyclic ethers
• Thromboxane A2 (TxA2)
• Induces platelet aggregation and smooth-muscle
contraction

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