Lipids

Philip L Yeagle, Rutgers University, Newark, New Jersey, USA

Lipids are molecular building blocks for the most fundamental structures in biology,
includingtheserumlipoproteins, the membranes of cells andcellular organelles andthe
membranes of enveloped viruses. Lipids provide a form of energy storage, like an
electrical battery for an organism. Lipids are the metabolic precursors of hormones and
signalling molecules in cells. Lipids regulate, often in specific ways, the functionality of
biological membranes. A nearly uncountable catalogue of lipid molecules is found in
nature, their individual structures imparting a wide variety of properties essential to the
structures and functions of lipids in life.
Introduction
The lipids of life govern many biological structures and
functions through their wide array of chemical structures
and corresponding physical properties. Although the cat-
alogue of chemical structures is vast, unifying principles
assist the student of lipids in organizing lipid properties,
and their corresponding roles, into an understandable text.
In the following, the relationship between lipid chemical
structure and lipid fundamental properties will be
explored. With this information in hand, many of the roles
of lipids in biology can be more readily understood (His-
tory of lipid science, http://www.cyberlipid.org/history/
history1.htm).
Properties Arising from Lipid
Structures
The structures of lipids in large part determine their prop-
erties. For example, the lipids of cell membranes are amp-
hipathic: one portion is largely hydrocarbon, and thus
hydrophobic, and another portion is polar and hydrophilic.
Lipids in the interior of lipoproteins are nearly entirely hy-
drocarbon and thus nearly fully hydrophobic. Because these
properties, hydrophobicity, hydrophilicity and amphipathi-
city, are critical to an understanding of lipids in nature, they
deserve some consideration before moving on.
The hydrophobic effect
The hydrophobic eect is the most important inuence in
the structures of biology outside the covalent bond. It
reects the thermodynamically unfavourable encounter
between water and hydrocarbon. Hydrocarbons are built
around carbon backbones, with direct bonds fromcarbons
to either hydrogen or another carbon. Since the electron-
egativity dierence between hydrogen and carbon is small,
the electrons in these bonds of the hydrocarbon are not
polarized and there is little if any separation of charge un-
der most circumstances. Hydrocarbons consequently can-
not form hydrogen bonds. Consequently, hydrocarbon
structures cannot participate in the structure of the water
because to do so, an ability to form hydrogen bonds is
required. Therefore water must become more structured in
response to the intrusion of a hydrocarbon molecule,
forming, for example, a clathrate-type structure of hydro-
gen-bonded water molecules around the hydrocarbon.
This ordering of the water molecules is achievedthroughan
entropy cost and is thermodynamically unfavourable.
Therefore oil and water do not mix because the water must
become structured to accommodate a hydrocarbon mol-
ecule (of the oil). Interestingly, one of the rst experiments
recorded that revealed this principle is the famous calming
of the waters by Benjamin Franklin. In 1773, Mr. Franklin,
using an English pond, observed the ability of a small
amount of oil to coat the surface of a pond, probably with a
molecular monolayer of the oil, but not to penetrate
the water phase (A Letter from Benjamin Franklin to
William Brownrigg, 1773, http://jcbmac.chem.brown.edu/
scissorsHtml/chem/Avogadro/BenFranklin.html).
Molecules that have chemical structures that can accept
or donate hydrogen bonds can participate in the structure
of liquid water and are generally soluble in water. These
molecules are referred to as hydrophilic or polar. Mole-
cules that have structures that are like hydrocarbons that
cannot participate in the water structure are generally in-
soluble in water. These molecules are referred to as hydro-
phobic and separate from water when encountering
aqueous environments.
The same principle applies when one portion of a given
molecule is hydrophobic and other portion is hydrophilic.
The hydrophilic portion interacts with water and the hy-
drophobic portion is excluded fromwater. These are called
amphipathic molecules.
Introductory article
Article Contents
. Introduction
. Properties Arising from Lipid Structures
. Overview of Lipid Classes
. Structural Roles of Lipids in Cells
. Biological Roles of Lipids in Cells
. Summary
Online posting date: 15
th
September 2009
ELS subject area: Biochemistry
How to cite:
Yeagle, PhilipL (September 2009) Lipids. In: Encyclopedia of Life Sciences
(ELS). John Wiley & Sons, Ltd: Chichester.
DOI: 10.1002/9780470015902.a0000711.pub2
ENCYCLOPEDIA OF LIFE SCIENCES & 2009, John Wiley & Sons, Ltd. www.els.net 1
The lipids of cell membranes are amphipathic molecules.
One end of the molecule consists of a polar, or hydrophilic,
chemical structure. That portion orients towards the aque-
ous phase. The remainder of the molecule often looks very
much like a hydrocarbon. The latter part of the molecule
must, in general, be excluded from the aqueous phase.
See also: Water: Structure and Properties
How hydrophobicity drives biological
structure
Lipid amphipathic structure and the hydrophobic eect
govern how lipid molecules behave in water. Figure 1 shows
the chemical structure of a common cell membrane lipid,
phosphatidylcholine. The portion on the right is polar, or
hydrophilic, and will interact well with water by accepting
hydrogen bonds from water on the phosphate oxygens.
The portion on the left is hydrocarbon and is thus hydro-
phobic. The hydrophobic portion must be excluded from
water, according to the hydrophobic eect. Therefore
phosphatidylcholine is an amphipathic molecule.
One can, in simplest form, approximate the geometry of
this molecule (e.g. see http://www.nyu.edu/pages/mathmol/
library/lipids/dppc.gif), as a cylinder as shown in Figure 2.
Here a ball represents the polar end and two wavy lines
represent the hydrophobic portion. Because of the
hydrophobic eect, the polar (headgroup) region of the
lipids can interact with water and the hydrophobic (tails) of
the lipids must be sequestered from the water. These re-
quirements are uniquely achieved with the lipid bilayer
structure shown in Figure 3 (for a more realistic model,
see http://www.umass.edu/microbio/rasmol/all3t.gif). Thus
the structure of a lipid bilayer is driven by the chemical
structure of the lipid molecules and the corresponding
physical properties manifested in the hydrophobic eect.
See also: Lipid Bilayers
It is this bilayer structure that constitutes the fundamen-
tal architecture of all cell membranes and viral envelopes.
Amphipathic membrane lipids in an aqueous environment
spontaneously form a bilayer structure. If isolated biolog-
ical lipids or pure synthetic lipids are placed in water,
liposomes, containing concentric layers of lipid bilayer,
result. In cells, newly synthesized lipids are added to exist-
ing bilayers by a biosynthetic apparatus, the last stages of
which are localized to the endoplasmic reticulum mem-
brane. See also: Membrane Lipid Biosynthesis
Lipids are not limited to forming bilayers. Their
chemical structures and properties lead to a set of interest-
ing structures. Amphipathic lipid molecules, including
phospholipids and cholesterol, form lipid monolayers
on the surface of serum lipoproteins (http://www.
ncbi.nlm.nih.gov/books/bv.fcgi?rid=cooper.ggrp.2023),
surrounding a hydrophobic core of neutral lipids or lipids
with few hydrophilic chemical features (e.g. triglycerides
(http://themedicalbiochemistrypage.org/lipid-synthesis.
html#triglycerides) and cholesterol esters http://www.
lipidlibrary.co.uk/Lipids/cholest/index.htm).
Another biologically important structure is the micelle
(http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.
ggrp.1902). Detergents form micelles. Molecules that
form micelles usually have a cross-sectional area per head-
group signicantly larger than the cross-sectional area
of the hydrophobic part of the lipid. A cone can approxi-
mate the overall geometry of a detergent molecule, and
packing of cones to sequester the hydrocarbon chains away
from the water leads to the formation of a spherical struc-
ture, or micelle (though not all micelles are perfect spheres).
A biological example of micelles is found in the dige-
stive tract. Micelles composed of bile salts solubilize
C
O
O C H
C
O
O C
H
H
C
H
O P
O
O
O
C
C
N
C
C
C
+
H

Figure 1 The chemical structure of phosphatidylcholine.
Figure 2 The geometry of some phospholipids may be approximated to a
cylinder. Figure 3 The lipid bilayer structure.
Lipids
ENCYCLOPEDIA OF LIFE SCIENCES & 2009, John Wiley & Sons, Ltd. www.els.net 2
hydrophobic molecules (such as triglyceride (fat)) in the gut
from the diet. Phospholipids with only one hydrocarbon
chain also satisfy the structural requirements for forming
micelles.
Lipids can form nonlamellar structures when the
polar lipid headgroups are small, only modestly polar
and poorly hydrated. An example is provided by phos-
phatidylethanolamine that can undergo a transition to
nonlamellar structures like hexagonal II phase. This struc-
ture is inverted in that the lipids are organized in tubes,
headgroups pointing inwards towards a small water chan-
nel. This structure is not generally found in biology, but
certain membrane events, like membrane fusion, likely
involve transient nonlamellar structures as intermedi-
ates (http://www.brocku.ca/researchers/peter_rand/lipid/
default.html).
Since no portion of the structure of neutral lipids can
interact with the structure of water, they are completely
excludedfromthe aqueous phase. They may be sequestered
in the interior of serum lipoproteins. Neutral lipids may
form droplets within cells. Neutral lipids may sequester
into the midplane of lipid bilayers.
Properties of lipid bilayers
It is the lipid bilayer structure that constitutes the funda-
mental architecture of all cell membranes and viral enve-
lopes. The lipid bilayer is not a gene product but is a
macromolecular assembly, stabilized by noncovalent in-
teractions, and consisting of thousands of individual spe-
cies of lipids each of which are the result of complex
metabolic pathways in the cell. Although this is a very
complex system, lipid bilayers exhibit some fundamental
properties. See also: Lipid Bilayers
Amphipathic membrane lipids in an aqueous environ-
ment spontaneously form a bilayer structure. If isolated
biological lipids or pure synthetic lipids are placed in water,
liposomes, containing concentric layers of lipid bilayer,
result. In cells, newly synthesized lipids are added to exist-
ing bilayers by a biosynthetic apparatus, the last stages of
which are localized to the endoplasmic reticulum mem-
brane. See also: Membrane Lipid Biosynthesis
This molecular assembly has unique structural and dy-
namic properties, many of which are important to mem-
brane function. The extensive interaction among the
molecular units leads to long-range structural order, very
unlike a liquid. The liquid crystal state of lipidbilayers is the
predominant form found in biological membranes. In the
liquidcrystal state, the lipid molecules (and other molecules
included in the membrane) are free to diuse laterally in the
plane of the membrane, but not to leave the bilayer for the
aqueous phase. Therefore, while two dimensions are disor-
dered in the liquid crystal state, the third dimension is not.
For this reason, the bilayer has some order.
As a consequence, the lipid bilayer can undergo a phase
transitions from a gel state to a liquid crystal state. This is
particularly notable in the case of lipids with saturated (no
double bonds) hydrocarbon chains for the hydrophobic
portion of the molecule. Extensive van der Waals interac-
tions among the chains can stabilize the gel state. Only
substantially elevated temperatures can introduce su-
cient thermal motion to induce the rapid lateral diusion
characteristic of the liquid crystal state in a saturated lipid
bilayer.
Unsaturation (or double bonds) in the hydrocarbon
chains of the lipids inhibits packing of the lipids, favour-
ing the liquidcrystal state of the bilayer. It is essential tolive
cells that their membranes exist in the liquid crystal state.
Membrane proteins that penetrate the lipid bilayer (e.g.
transmembrane proteins) must undergo conformational
changes necessary to their function. A transition to the gel
state inhibits conformational changes in these membrane
proteins, inhibiting their function. Therefore in most bio-
logical membranes of mammals, for example, lipids with
unsaturated hydrocarbon chains predominate.
It is the profusion of double bonds in the hydrocarbon
chains of the lipids that keeps the membranes in the liquid
crystal state. The double bonds introduce a kink into the
conformation of the hydrocarbon chain. This kink inter-
feres with the packing of chains side by side, and thus de-
stabilizes the gel state of the lipids. Therefore one of the
roles of unsaturated membrane lipids in membranes is both
a structural role and a biological role, necessary for cell
viability.
The lipid bilayer is relatively impermeable to solutes and
to hydrogen ions. Therefore the lipid bilayer seals the
membrane to the passive transport of such solute and al-
lows a clear dierentiation in composition fromone side of
the membrane to the other. This feature forces transport
across membranes to occur through membrane proteins,
where it can be elegantly regulated.
Overview of Lipid Classes
Thousands of dierent species of lipids are found in bio-
logical membranes. As it is not possible to describe themall
in detail, it is useful to classify them into groups according
to their structure. This section will introduce a useful clas-
sication of membrane lipids that also reveals the com-
plexity of membrane lipid composition.
Phospholipids
Anexample of the chemical structure of a phospholipidcan
be seen in Figure 1 (see also http://www.nyu.edu/pages/
mathmol/library/lipids/). Characteristic of membrane lip-
ids, a phospholipid is an amphipathic molecule. The polar
headgroup on the right of the gure carries charges and can
interact withthe water well. The polar headgroupis bonded
to a glycerol to which are esteried two fatty acids (other
structural possibilities include ether links, amide links and
carboncarbon links). Phospholipids get their name from
the phosphate group that is part of the polar headgroup.
The phosphate is bonded directly to the same glycerol to
which the fatty acids are esteried.
Lipids
ENCYCLOPEDIA OF LIFE SCIENCES & 2009, John Wiley & Sons, Ltd. www.els.net 3
The structure of the polar headgroup provides the basis
for a further classication (see http://www.chem.qmul.
ac.uk/iupac/lipid/). In Figure 1, the polar headgroup is
choline. Thus this phospholipid is named phosphatidyl-
choline. Other chemical groups can be found bound to the
phosphate, including serine, glycerol, ethanolamine and
inositol, giving phosphatidylserine, phosphatidylglycerol,
phosphatidylethanolamine and phosphatidylinositol.
These phospholipids have charges in the structure of the
headgroup. In the case of phosphatidylcholine, there is a
negative charge on the phosphate and a positive charge on
the choline. Thus phosphatidylcholine is zwitterionic. The
same can be said for phosphatidylethanolamine. However,
phosphatidylglycerol and phosphatidylinositol carry a net
negative charge. For example, phosphatidylserine has a
negative charge on the phosphate, a negative charge on the
serine carboxyl and a positive charge on the serine amino
group, for an overall net negative charge. Phospholipids
like phosphatidylserine and diphosphatidylglycerol, or
cardiolipin (four hydrocarbon chains and two phosphate
groups), give the surface of the membrane a negative
charge.
The structure of the hydrocarbon chains can vary in the
phospholipids. A variety of fatty acids can be found acy-
lated (or ether links, amide links and carbon-carbon links)
to the glycerol. These fatty acids can vary in length (in
nature) from 12 to 26 carbon atoms in length, and can
contain from0 to 6 double bonds. Interestingly, the double
bonds are rarely found conjugated. A common nomencla-
ture for these fatty acids is x:y, where x is the number of
carbon atoms and y is the number of double bonds. There-
fore 18:1 is a fatty acid with 18 carbon atoms and one
double bond. In nature, the double bond in an 18:1 fatty
acid is almost always between carbons 9 and 10, due to the
biosynthetic pathway. Some membranes seemto specialize
in unusual phospholipids, based on their fatty acid con-
tent. For example, in retinal membranes, 22:6 (or docosa-
hexenoic acid) is in high natural abundance as a fatty acid
component of the major phospholipids. In addition, some
lipids in bacteria can exhibit cyclopropane derivatives as
part of the hydrocarbon chains. See also: Fatty Acids:
Structures and Properties
These fatty acids also have common names that can also
be used to describe a phospholipid. For example, a
phosphatidylcholine with one 16:0 fatty acid and one 18:1
fattyacidcanbe calledpalmitoyloleoylphosphatidylcholine.
The 16:0 fatty acid is palmitic acid and the 18:1 fatty acid is
oleic acid.
Quite a variety of fatty acids can be found esteried to
phospholipids. Usually the saturated fatty acids are found
in position 1 of the glycerol, unsaturated fatty acids in po-
sition 2 of the glycerol and the phosphate in position 3 of
the glycerol (isomers are found in minor amounts). There-
fore many dozens of species of just phosphatidylcholine
can be found in biological membranes. Most, though not
all, of these species will form bilayers in water spontane-
ously phosphatidylethanolamine is one example of a lipid
that is generally unstable in a bilayer structure when pure
phospholipid is introduced into water. See also: Phospho-
lipases: Degradation of Membrane Phospholipids
Other lipid species
Many other classes of lipids are found in cell membranes
besides the phospholipids. Among the strongly amp-
hipathic lipids are the sphingolipids and the glycolipids.
In the sphingolipids, one of the hydrocarbon chains is
bonded to the lipid via an amide bond (Figure 4). One
example is sphingomyelin, which is similar to phos-
phatidylcholine except that one of the chains is attached
to the lipid by an amide bond and the other by a carbon
carbon bond.
Glycolipids are amphipathic lipids that carry sugars for
headgroups (Figure 4). These can be simple, such as in dig-
alactosyldiglyceride, which has two galactoses in the head-
group. Glycolipids can also be complex, as in the case of
the gangliosides that have a number of sugars in their
headgroups, including amino sugars and sugar acids. In
addition to the structural variety in the headgroups, these
lipids can also exhibit complexity in the composition of
their hydrocarbonchains. Thus there are perhaps hundreds
of structurally distinct glycolipids in biological mem-
branes. Many of these lipids will form bilayers spontane-
ously in water, just like the phospholipids, since they have a
similar amphipathic chemical structure (though some will
not as in monogalactosyldiglyceride which is not stable in a
bilayer conguration). See also: Glycolipids: Animal;
Glycolipids: Distribution and Biological Function
Cholesterol
Membranes also contain neutral lipid species that do not
carry any charged moieties. Most prominent among these
lipids is the sterol family. In mammalian systems the best-
known member of this family is cholesterol. This is a fused
four-ring (steroid ring) compound with only a hydroxyl for
a polar headgroup. This lipidcanplay botha structural and
a regulatory role incell membranes. The molecule is amphi-
pathic; the hydroxyl inserts into the interface between the
hydrocarbon interior and the aqueous phase surrounding
the membrane. The sterold ring and the small hydrocarbon
tail orient parallel to the (phospho)lipid hydrocarbon
chains of the lipid bilayer. The at rigid steroid ring of
cholesterol induces ordering in the adjacent lipid hydro-
carbon chains in a bilayer. Cholesterol binds to some
transmembrane proteins and will modulate the activity of
those proteins. Cholesterol is found in mammalian organ-
isms largely in the plasma membrane. A storage form of
cholesterol, cholesterol ester, is found in vacuoles and in
lipid storage structures within cells and in serum, choles-
terol esters are largely found in the interior of serum lipo-
proteins. In other life forms, sterols with dierent chemical
structures are found, often in a species-specic distribu-
tion. For example, sitosterols are found in plants and
ergosterol is found in yeast. See also: Cholesterol, Steroid
and Isoprenoid Biosynthesis
Lipids
ENCYCLOPEDIA OF LIFE SCIENCES & 2009, John Wiley & Sons, Ltd. www.els.net 4
Structural Roles of Lipids in Cells
Membrane dynamics
The lipids of cell membranes play a variety of structural
roles. The lipid bilayer is a nearly two-dimensional world
with interesting structure and dynamics. The lipid hydro-
carbon chains enjoy only limited conformational exibil-
ity. The most conformationally exible portion of the lipid
hydrocarbon chain is found in the middle of the lipid
bilayer. Moving from the middle of the bilayer towards
the surface one nds increasing motional order. The
hydrocarbon chains experience less and less conformatio-
nal freedom (primarily rotational conformers around the
carbon-carbon bonds of the hydrocarbon chain). As an
example, the most rigid portion of a phospholipid bilayer is
near the glycerol that connects the hydrocarbon chains to
the phosphate-containing headgroup. As one moves into
the headgroup region conformational motility increases
again. This behaviour suggests a highly anisotropic struc-
ture, with respect to molecular dynamics, that is a direct
product of the bilayer structure, which in turn is a direct
product of lipid structure and the hydrophobic eect.
Cholesterol can increase this anisotropy. Since cholesterol
consists of a rigid fused ring system, its presence in the mem-
brane will damp conformational motility of the constituent
lipid hydrocarbon chains. Cholesterol is located in the mem-
brane with its steroid ring intercalated between lipid hydro-
carbonchains inwhat is the most orderedregionof the bilayer
(between carbons 1 and 9 of the hydrocarbon chain), even in
the absence of the sterol. The presence of cholesterol therefore
enhances the highly anisotropic structure of the bilayer.
The dynamics of lipids in membranes provide an impor-
tant part of the properties of lipid bilayers conferred by the
CH
CH
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CH
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OH

CH
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P O O
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N(CH
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C
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(a)
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Galactose
N-acetylgalactosamine Galactose Glucose
HO
HOOC
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CHOH
NHAc
CHOH
CH
2
OH
HO
HOOC
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NHAc
CHOH
CH
2
OH
CHOH
Sialic acid
Sialic acid
O
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OH
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NH
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(b)
Figure 4 The structure of (a) a sphingomyelin and (b) a glycolipid.
Lipids
ENCYCLOPEDIA OF LIFE SCIENCES & 2009, John Wiley & Sons, Ltd. www.els.net 5
lipids and their structures. Double bonds (or cyclopropane
rings) introduce packing defects into the bilayer because
the rigidity of such structures is the source of imperfections
of the ability of two hydrocarbon chains to pack adjacent
to each other. Furthermore the lipid hydrocarbon chains
are dynamic, with carboncarbon bond rotations (around
single bonds) continually contributing a variety of con-
formers to the overall structure of the hydrocarbon chains.
Molecular dynamics calculations can reveal this confor-
mational motility (http://www.umass.edu/microbio/
rasmol/all3t.gif). These packing defects provide pathways
for passive diusion of small nonlipid molecules through a
lipid bilayer. Any reduction in these packing defects, for
example, by substituting saturated hydrocarbon chains for
unsaturated hydrocarbon chains or by inducing a gel state
through decreasing the temperature, will correspondingly
reduce passive permeability.
Defects in packing of the lipid hydrocarbon chains can
be very important to membrane protein function as well.
Defects arising in particular from the presence of double
bonds in the hydrocarbon chains can be recruited to
the lipidprotein interface. These packing defects can pro-
vide volume elements for expansion of an integral mem-
brane protein in the plane of a membrane, allowing protein
conformational changes necessary for protein function. As
might be expected, cholesterol at high levels in the mem-
brane caninhibit the functionof certainintegral membrane
proteins by reducing the conformational motility of the
proteins. See also: Membrane Dynamics
Membrane fusion
Membrane fusion is required by receptor-mediated end-
ocytosis, enveloped viral infection and vesicle transport
between endoplasmic reticulum and Golgi. Membrane fu-
sion describes the event by which two membranes become
one, or one membrane becomes two. The lipid bilayer is a
stable structure. For membrane fusion to occur, some
transient perturbation of the bilayer structure is required.
Membrane lipids that can adopt nonlamellar structures
and/or highly curved structures may facilitate the devel-
opment of the transient bilayer defects necessary for mem-
brane fusion. Such lipids have small headgroups or poorly
hydrated headgroups. A small headgroup will lead to an
inverted cone shape for the lipid and, instead of packing
into bilayers, such lipids adopt curved structures with the
headgroups on the inside of a concave surface. Likewise
poorly hydrated headgroups will sequester themselves
from water by packing on the inside of highly curved sur-
faces in which they have minimal exposure to bulk water.
Such highly curved surfaces constitute the stalk structures
that have been suggested to be intermediates in the fusion
event, connecting the outer monolayers of the two mem-
branes destined to fuse (Figure 5). See also: Clathrin-coated
Vesicles and Receptor-mediated Endocytosis; Endoplas-
mic Reticulum to Golgi Transport: Methods; In Vivo
Analysis of Membrane Fusion; Synaptic Vesicle Fusion
Membrane lipids cancarrycharges as part of the chemical
structure of their headgroups. For example, as noted earlier,
phosphatidylserine carries a net negative charge on its head-
group. Because of the chemical structure of the headgroup
and the location of that headgroup in the surface of the
bilayer, phospholipids with net charges on the headgroups
confer a net charge at the surface of the cell membrane.
Sometimes this charge is asymmetrically distributed, as in
the case of the mammalian erythrocyte membrane. The
negatively charged lipids of the red cell plasma membrane
(phosphatidylserine and phosphatidylinositol) are located
primarily on the cytoplasmic face of the membrane, whereas
zwitterionic lipids (phosphatidylcholine andsphingomyelin)
dominate the exterior surface of the bilayer.
The other major component of cell membranes is pro-
tein. The proteins of cell membranes are discussed in more
detail elsewhere. Many of these membrane proteins are in-
tegral to the lipid bilayer and therefore contact the lipids of
the membrane. Lipidprotein interactions are therefore an
important element of cell membrane structure. There are
examples of the preferential interaction of certain mem-
brane lipids with the integral membrane protein, through a
binding of specic lipids to the membrane protein. One
example is found in one of the major proteins of the human
erythrocyte membrane, glycophorin. Phosphatidylinosi-
tol, while a relatively minor component of the total lipid of
the erythrocyte membrane, is found bound to glycophorin
preferentially over all the other lipids of the membrane. In
additiontophospholipids, cholesterol canalsobe boundto
membrane proteins. An example can be found in the bind-
ing of one molecule of cholesterol to the mammalian rho-
dopsin, the G-protein coupled receptor in the retinal rod
cell. Finally, some lipids can be covalently attached to pro-
teins. One type of attachment is in the covalent attachment
of proteins to a derivative of phosphatidylinositol. These
proteins then are anchored to the membrane through this
covalent link to a membrane lipid that itself is part of the
lipid bilayer. Another type of attachment is by acylation of
a fatty acid or an isoprenyl group to the protein. Acylation,
Figure 5 Diagram showing the stalk structure which is thought to form the
intermediate in a fusion event between two lipid bilayers.
Lipids
ENCYCLOPEDIA OF LIFE SCIENCES & 2009, John Wiley & Sons, Ltd. www.els.net 6
for example, can take place through a cysteine on the
protein. The eects of such lipidprotein interactions on
membrane function will be discussed in the next section.
See also: Membrane Proteins; Protein Translocation
Across Membranes
Biological Roles of Lipids in Cells
Lipid biochemical functionality in cell
membranes
Membrane lipids play a variety of important biochemical
roles in cells. Among the most important is the ability of
lipids to modulate membrane protein functionality. Some
membrane proteins require specic lipids for activity.
Active transport of calcium by the Ca
2+
adenosine trip-
hosphatase (ATPase) is strongly dependent on the lipid
composition of the membrane. In particular, lipids such as
phosphatidylethanolamine appear to play an important
role in governing the transport activity of this enzyme.
Another example can be found in the transport of mono-
valent cations across the plasma membrane by the Na
+
/K
+
ATPase. The mammalian enzyme transport function re-
quires cholesterol in the membrane. The requirement is
specically for cholesterol; other sterols cannot substitute
for cholesterol. This observation may be the fundamental
source for the cholesterol requirement for mammalian cells
to support cell growth and development. Cholesterol also
regulates its own synthesis by regulating the activity of
the enzyme catalysing the rate-limiting step of cholesterol
biosynthesis. Another example can be found in the
phosphatidylinositol binding to glycophorin of the human
erythrocyte membrane. Glycophorin is connected to the
structure of the membrane skeleton of the erythrocyte.
That connection is regulated by the state of phosphoryla-
tion of the phosphatidylinositol bound to the glycophorin.
See also: Ion Channels
Lipids play a role in protein function through covalent
attachment to proteins. Acylation or prenylation of pro-
teins canrender themmore hydrophobic and cause themto
transfer to the membrane through integration of the lipid
component into the lipid bilayer of the cell membrane.
Localization of such proteins to the membrane can induce
functionality that did not exist for the protein in solution.
Therefore this kind of covalent modication of proteins
by lipids plays a regulatory role in the cell. See also:
Regulation by Covalent Modication
Phospholipids are asymmetrically distributed across the
plasma membrane of some mammalian cells. How is this
asymmetry established and maintained? Because of the
polar nature of the phospholipid headgroup it cannot pass
readily through the hydrophobic interior of the membrane.
Therefore in pure phospholipid bilayers, ip-op (or the
translocation of lipids from one side of the bilayer to
the other) does not occur at a measurable rate. However, in
the plasma membrane of the human erythrocyte, enzymes
exist that, at the expense of hydrolysis of adenosine
triphosphate (ATP), will translocate phospholipids from
one side of the bilayer to the other. In particular, amino
phospholipids, like phosphatidylethanolamine and phos-
phatidylserine, are translocated to the cytoplasmic face of
the lipid bilayer. This is the source of the asymmetry of that
membrane with respect to the lipid component. This proc-
ess has an important biological role. The mammalian
platelet has a similar phospholipid asymmetry across its
plasma membrane. When a platelet is activated, phospha-
tidylserine is transiently exposed on the exterior (among
many other events). This transient exposure of phospha-
tidylserine facilitates the activation of thrombin on the
surface of the platelet. Because of the potentially cata-
strophic nature of the blood clotting process, to which
thrombin activation is central, this process must be tightly
regulated. After this transient exposure of phosphatidyl-
serine during platelet activation, the ATP-dependent
enzymes in the plasma membrane translocate the phos-
phatidylserine back to the inner face of the bilayer, thus
terminating the ability of the phosphatidylserine to facil-
itate the activation of thrombin. See also: Platelets
Membrane lipid metabolism
Membrane lipids are the synthetic result of an interesting
set of metabolic pathways in the cell, and membrane lipids
themselves are substrates for further metabolic pathways.
The details of these pathways can be found in the works
listed in Further Reading. (http://themedicalbiochemistry-
page.org/lipid-synthesis.html; http://www.cyberlipid.org/
cyberlip/links.htm) See also: Membrane Lipid Bio-
synthesis
One pathway with direct relevance to principles dis-
cussed earlier is the remodelling of phospholipids by the
exchange of fatty acids. Phospholipase A
2
cleaves the ester
bond at the 2 position of the glycerol and removes one of
the fatty acids. AcylCoAis the substrate for reacylationof
that position on the phospholipids. The original diacyl-
glycerol is 16:0, but the replacement fatty acid is generally
unsaturated, leading to the observed abundance of un-
saturated fatty acids at position 2 of the glycerol and sat-
urated fatty acids at position 1 of the glycerol of many
phospholipids. Another type of remodelling occurs when
unsaturated lipids are converted to cyclopropane deriviti-
zed lipids when some organisms enter a dormant state and
must be resistant to oxidation.
Two pathways will illustrate the role of phospholipid as
substrate in cells. One is the synthesis of prostaglandins,
which use arachidonic acid as the starting material.
Arachidonic acid (20:4) is found acylated to phospholipids
in membranes in the 2 position of the glycerol. Phos-
pholipase A
2
will cleave the arachidonic acid from the
phospholipid, making it available for prostaglandin bio-
synthesis, ofteninresponse tothe activationof amembrane
receptor. The second example is the phosphorylation of
phosphatidylinositol. There is a kinase within many cells
that phosphorylates the sugar of phosphatidylinositol to
Lipids
ENCYCLOPEDIA OF LIFE SCIENCES & 2009, John Wiley & Sons, Ltd. www.els.net 7
produce a di- or tri-phosphorylated species. As seen later,
this phosphorylation can play an important role in signal
transduction.
Lipids may also act as chaparones. Phosphatidylethanola-
mine has been suggested to play a role in the folding and
insertion of bacterial membrane proteins into membranes
during their biosynthesis.
Introduction to lipids as signalling molecules
Membrane lipids can play roles as second messengers
within cells. In response to receptor activation at the
plasma membrane, phospholipases can be activated that
cleave phospholipids as described earlier for the produc-
tionof arachidonic acid. One suchenzyme is phospholipase
C (see Figure 6 for a schematic representation of the
enzymatic actionof the commonphospholipases). See also:
Phospholipases: Degradationof Membrane Phospholipids
Phospholipase C cleaves phosphatidylinositol to pro-
duce diacylglycerol and inositol phosphate. If the phos-
phatidylinositol has beenpreviously phosphorylated twice,
then one product of this cleavage will be inositol tripho-
sphate (commonly abbreviated IP
3
). Both of these cleavage
products can be second messengers. For example, IP
3
will
stimulate the release intracellular stores of calciuminto the
cytoplasm by interacting with a calcium channel in the
endoplasmic reticulum membrane. This process is gener-
ally a part of a cascade of events in which a receptor is
activated at the cell surface, which in turn leads to the ac-
tivation of a phospholipase C, which in turn releases IP
3
,
which opens a calcium channel in the endoplasmic re-
ticulum. See also: Calcium Channels
Summary
This necessarily provides only an introduction to the many
fascinating properties of biological lipids. Further reading
is recommended to explore lipids in the detail they deserve.
Further Reading
Vance DEandVance J (2008) Biochemistry of Lipids, Lipoproteins
and Membranes, 5th edn. Amsterdam: Elsevier.
Yeagle PL (1993) The Membranes of Cells, 2nd edn. San Diego,
CA: Academic Press.
Yeagle PL(2005) The Structure of Biological Membrane, 2nd edn.
Boca Raton, FL: CRC Press.
Web Links
http://goldbook.iupac.org/L03571.html.
http://www.cyberlipid.org/index.htm.
http://www.lipidlibrary.co.uk/
C
C
C
O
C O
C
C
C
C
C
O
C
C
C
C
C
C
O
P
O
O
C
O
O
A
2
D
N
C
C
C
C
C
Figure 6 A schematic representation of the enzymatic action of the
common phospholipases (A
2
, C and D).
Lipids
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