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Chapter 8

Biochemistry, 5th Edition


Reginald H. Garrett | Charles M. Grisham

Lipids

Candas

BIOLOGICAL MOLECULES

EXAMPLES OF LIPID STRUCTURES


Lipids are a chemically diverse group of compounds. Their structures
and functions are highly varied.

http://www.lipidmaps.org/data/classification/lipid_cns.html

THE STRUCTURE OF LIPIDS


Lipids can be broadly defined as hydrophobic or amphipathic small
molecules that originate entirely or in part by carbanion-based
condensations of thioesters and/or by carbocation-based condensations
of isoprene units.

condensation can be used to


produce fatty acyls, glycerolipids,
glycerophospholipids,
sphingolipids, saccharolipids and
polyketides

condensation can be used to


produce sterol lipids and prenol
lipids (derived from condensation
of isoprene subunits)

CLASSES OF LIPIDS

FUNCTIONS OF LIPIDS
Serve as structural components of biological membrane; mediate and
regulate boundary, transport, and signal functions.
Provide energy reserves, predominantly in the form of triglycerides.
Essential to the overall energy metabolism and energy economy of the
cell.
Lipophilic bile acids aid in lipid solubilization.
Certain lipids and lipid-derived derivatives serve as vitamins.
Lysogenic lipids act as second messengers and signaling molecules
and regulate inflammatory pathways.
Hormones have important roles in integration of metabolism.
Lipids and lipid-derived molecules that have important uses in
medicine, biotechnology and industrial applications.

CLINICAL RELAVANCE OF LIPIDS


Lipids and lipid-derived molecules have crucial roles in cell, tissue and
organ physiology.
They are critically related to health and many disease conditions.
Enzymes and pathways involved in lipid catabolism and biosynthesis
are now linked to pathogenesis and progression of many diseases
including cancer, diabetes, neurodegenerative and infectious diseases.
Dietary lipids are fundamental to normal growth and development.

LIPIDS

Hydrophobicity is the
common and defining feature
of all lipids.
insoluble in water, but
soluble in non-polar solvents
(typically, ether, hexane or
chloroform).
hydrophobic behavior is
based on molecular
structure.
consist mostly of
hydrocarbons, however may
have some polar bonds
associated with oxygen.
water-insolubility of lipids
contributes to much of the
complexity in their digestion,
transport, and metabolism.

hydrophobic

THE STRUCTURE OF LIPIDS


Lipids separate from water because the water molecules hydrogen bond to one
another and exclude the hydrophobic portion of the lipid.

FATTY ACIDS
Most lipids, like fatty acids, are amphipathic, having a
non-polar end and a polar end.

Fatty acids consist of a long hydrocarbon "tail, which is


hydrophobic due to nonpolar C-H bonds, attached to a
hydrophilic "head" consisting of a carboxyl group.

NOMENCLATURE OF FATTY ACIDS


Abbreviated notation for a 16-C fatty acid with one cis double bond
between carbons 9 &10 is 16:1 cis 9.
Polar head group

3
2

C
1

fatty acid with a cis-9 double bond

NOMENCLATURE OF FATTY ACIDS

Common names are historic and often reflect the source of fatty acid.
Systematic nomenclature indicates the length of the C-chain
Most naturally occurring fatty acids have an even number of carbon atoms.

NOMENCLATURE OF FATTY ACIDS

Saturated Fatty Acid


No double bonds

Octadecanoic acid; 18:0


(common:Stearic Acid)

Monounsaturated
Fatty Acid
1 double bond

Oleic Acid 18:1(9)

double bond starting at carbon 9

SATURATED VS UNSATURATED FATTY ACIDS


Each cis double bond causes a kink in the chain.

SATURATED VS UNSATURATED FATTY ACIDS

There is free rotation on C-C bonds in a fatty acid, except at a cis double bond.
Double bonds are rigid and cannot rotate.
Fatty acids with cis double bonds occupy more space. Presence of cis double
bonds introduce kinks/bends on the physical structure and reduce the
compaction/stacking of the fatty acids.
Takes less thermal energy to further disorder poorly ordered arrays of fatty
acids. Therefore, unsaturated FAs have a lower Tm (i.e., olive oil is more liquid
at room temperature than butter or beef fat).

cis VS trans UNSATURATED FATTY ACIDS


Fatty acid double bonds are usually cis.
Double bonds with trans configuration stack
up like saturated fatty acids, thus they
compact the lipid arrays like saturated fatty
acids.

Although trans fatty acids are


chemically "monounsaturated" or
"polyunsaturated," they are classified
in the same category as saturated fats.
Most trans configuration of the double bonds in dietary fatty acid chains are
not recognized in the human metabolism.

cis VS trans UNSATURATED FATTY ACIDS


Most of the trans fatty acids (although
chemically still unsaturated) are produced
as a byproduct of hydrogenation or when
heated to high temperatures or repeated reuse.
The major negative health effect of trans
fatty acids is that they tend to raise "bad"
LDL- cholesterol and lower "good" HDLcholesterol.

FATTY ACIDS IN FOOD


Each type of fat has a different profile
of lipids present which determines
the precise nature of its nutritional
and physiochemical properties.
Olive oil has more unsaturated fatty
acid than butter, which contains
triglycerides with a mixture of
saturated and unsaturated fatty acids.
Beef fat contains triglycerides with
mostly saturated fatty acids.

Modified from Mathews et al., Biochemistry, 3rd Edition

H
H
L

OXIDATION OF UNSATURATED FATTY ACIDS


Unsaturated (particularly polyunsaturated) fatty acids are prone to oxidation.
The methylene interrupter group (-CH=CH-CH2-CH=CH-) between two double
bonds of unsaturated fatty acid is particular prone to hydrogen atom (not ion)
abstraction.
The resultant lipid radical (R) rapidly reacts with oxygen to form a peroxy
radical via a free radical chain reaction.
The peroxy radical (ROO) can gain a hydrogen atom to form a lipid
hydroperoxide (ROOH) which is relatively stable and exists in significant
quantities in many natural fats.

In the presence of heat and a


metal catalyst, lipid
hydroperoxides rapidly break
down to form rancid-smelling
aldehydes.

OXIDATION OF UNSATURATED FATTY ACIDS


In the presence of heat and a metal catalyst, lipid hydroperoxides
rapidly break down to form rancid-smelling aldehydes.
Lipid oxidation can be inhibited by excluding oxygen, but this is not
practical for many foods. Even if it could be done, pre-existing lipid
hydroperoxides can breakdown to rancid flavors in the absence of
additional oxygen.

OXIDATION OF UNSATURATED FATTY ACIDS


Metal chelators (e.g. EDTA and citric acid) can bind the metal ions that
catalyze the breakdown of lipid hydroperoxides or the generation of
radicals.
Antioxidant additives (BHA and BHT) react with radical intermediates
and break the chain reaction before rancid flavors are generated.
However, once they react with a radical and oxidized, they are no
longer effective. So, they only serve to delay oxidation until they are all
consumed.

OXIDATION OF UNSATURATED FATTY ACIDS

Along with food, BHT and BHA are used in


cosmetics, many pharmaceuticals, jet fuels, rubber,
petroleum products, electrical transformer oil and
embalming fluid. However, there are growing
concerns since they have been linked to cancer,
allergic reactions, liver, thyroid, kidney problems,
impairment in lung function and blood coagulation.
Moreover, they are suggested to mimic estrogen and
can have an adverse impact on reproduction.

AUTOXIDATION OF UNSATURATED FATTY ACIDS

Am J Cardiol 2008;101(suppl):58D-68D.

Free radical-mediated lipid


oxidation have prominent roles
in cardiovascular disease.

Lipid soluble vitamins,


including A, E, lutein, and
carotenoids, can suppress the
oxidative damage of the
membranes by scavenging the
unpaired electron from the lipid
radical and break the chain
reaction.

ESSENTIAL FATTY ACIDS


Humans are unable to synthesize
certain fatty acids, so they are
labeled essential.
Their essentiality is linked to the
facts that in the body these fatty
acids form arachidonic acid, the
precursor to eicosanoids
(prostaglandins).
The two major essential fatty acids
are linoleic acid and alphalinolenic acid, more commonly
known as omega-6 and omega-3
fatty acids, respectively.

ESSENTIAL FATTY ACIDS

The human fatty acid desaturase systems can desaturate various chain
lengths at 4, 5, 6, and 9 positions.
However, humans cannot introduce double bonds beyond carbons 9 and 10.

Humans must have the polyunsaturated fatty acids linoleic (18:2 cis-9,12) and
linolenic (18:3 cis-9,12,15) provided in the diet.
These fatty acids are thus essential fatty acids in humans.

OMEGA-3 and OMEGA-6 FATTY ACIDS


18:29,12

18:39,12,15

Linoleic acid (LA)

-Linolenic acid (ALA)

OMEGA-3 FATTY ACIDS

Omega-6 fatty acids are very common in


our diet.

Most omega-3 fatty acids come as longchain polyunsaturated fatty acids


ranging from 18 to 22 carbon atoms in
chain length.

The presence of multiple double bonds


lowers the melting point of these fatty
acids such that all of them are highly
fluid and in liquid form at room
temperature and even more so at
internal human body temperatures of
37C .

There are three major types of omega-3


fatty acids that are ingested in foods
and used by the body:

-linolenic acid (ALA)


eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA)

Omega-6 and Omega-3 Fatty Acids


Upon ingestion, the body converts ALA to
EPA and DHA, the two types of omega-3 fatty
acids more readily used by the body and
which serve as important precursors for
eicosonoids, which are lipid-derived
modulators of cell signaling, gene
expression and inflammatory processes.
Omega-6 FAs are primarily responsible for
production of pro-inflammatory mediators.
Omega-3 fatty acids are essential for
production of anti-inflammatory mediators.

Omega-3 Fatty Acid Supplementation


Omega-6 FAs are in competition with omega-3
FAs for use of the same enzymes.
Therefore, when one type of essential FA is
found in the bloodstream at a higher
concentration than the other type of essential
FA, the metabolites of the more plentiful FA are
favored and exist in higher concentrations.
Furthermore, dietary trans fatty acids not only
are not processed in this pathway but also act
as inhibitor for delta 6 desaturase.
Increasing the amount of omega-3 fatty acids
in the diet brings improvement in
cardiovascular health not only by increasing
the anti-inflammatory mediators, but also by
decreasing pro-inflammatory mediators.
This translate into improved endothelial health
in the vessels and decreased in the incidence
and severity of atherosclerotic disease.

Clinical Importance of Omega-3 Fatty Acids

DHA has strong medical implications since its dietary presence has been positively
linked to better neurological function as well as to the prevention of cancer and heart
disease.

Aside to being the metabolic precursor for anti-inflammatory eicosanoids, beneficial


effects of DHA is believed to be related to the high degree of conformational flexibility
mediated by multiple double bonds.

DHAs interaction with other membrane lipids, particularly cholesterol, play a prominent
role in modulating the local structure and function of cell membranes.

Omega-3 Fatty Acid Supplementation

Omega-3 fats from plants, such as


those in flax seed oil, are enriched
in ALA. ALA must first be
converted to EPA (requiring three
independent reactions) and then
to DHA (requiring an additional
four reactions).

Omega-3 fats from fish are


enriched in EPA and DHA and thus
do not need to undergo the
complex conversion steps
required of ALA.

Due to low efficiency of


conversion of ALA to long chain
omega-3 PUFA, EPA and DHA
supplementation is recommended.

Production of omega-3 eicosapentaenoic acid


by metabolic engineering of Yarrowia lipolytica.
Nat Biotechnol. 2013 Aug;31(8):734-740
Industrial Biosciences, E.I. du Pont de Nemours and Company, Wilmington, Delaware, USA.

Natural pathway

Enginered pathway

TRIACYLGLYCEROLS (a.k.a.TRIGLYCERIDES)

Lipids are not polymers, but they are large molecules formed from smaller
molecules by dehydration reactions.

Typically, fatty acids are found as triacylglycerols, in which carboxyl groups of


fatty acids are joined to hydroxyl groups of glycerol - ester linkages.

TRIACYLGLYCEROLS (a.k.a.TRIGLYCERIDES)
They are the preferred molecule for
energy storage.
Stored in adipose cells (adipocytes, or
fat cells), which are part of connective
tissue forming cushioning and
insulation in animals along with
energy reserve.
Triglycerides form droplets in the
cytosol.
Contain highly reduced carbons and
yield large amounts of energy in the
oxidative reactions of metabolism.
Complete oxidation of 1 g triglyceride
gives 38 kJ.

leica-microsystems.com

imperial.ac.uk

TRIACYLGLYCEROLS (a.k.a.TRIGLYCERIDES)
Fats and oils are triglycerides.
Natural oils are mainly contain
triacylglycerols with unsaturated
fatty acids. They exist as liquids at
room temperature.
Solid fats contain primarily
saturated fatty acids. They are
more solid at room temperature.
Thereby raising the melting
temperature.

TRIACYLGLYCEROLS (a.k.a.TRIGLYCERIDES)
Most natural oils and fats are complex mixtures of simple triacyglycerols
(contain the same FA at all 3 positions) and mixed triacyglycerols (contain
2 or more different FA).
The length, number, and location of the double bonds in a fatty acid
define the physical and chemical characteristics of triglycerides.

TRIACYLGLYCEROLS (a.k.a.TRIGLYCERIDES)
SUNFLOWER OIL is composed of:
Palmitic acid (saturated): 5%
Stearic acid (saturated): 6%
Oleic acid (monounsaturated omega-9): 30%
Linoleic acid (polyunsaturated omega-6): 59%
It is low in saturated fats.
Unsaturated fatty acids profile varies and it is strongly influenced by
both genetics of the sunflower and climate that it grows.

TRIACYLGLYCERIDE/PHOSPHOLIPID STEREOCHEMISTRY
lipid chirality
Glycerol is not chiral, but it is a
prochiral molecule with the prochiral
carbon atom carrying two identical
CH2OH groups.
Even though the CH2OH groups on
prochiral glycerol are stereochemically
equivalent, they can be differentiated by
considering that glycerol has the
potential to become chiral by modifying
one of two identical substituents.
Triacylglycerides and phospholipids are
chiral and they exist in one
enantiomeric form.

TRIACYLGLYCERIDE/PHOSPHOLIPID STEREOCHEMISTRY
lipid chirality
A chiral object and its mirror image are called enantiomorphs (Greek opposite forms).
Achiral or non-chiral objects can be superposed on its mirror image.
If the mirror image of the compound is not superimposable on its mirror image, the
compound is chiral. If superimposable, the compound is achiral.

Achiral structure
The four identical ligands (white) are attached to the carbon (grey)

TRIACYLGLYCERIDE/PHOSPHOLIPID STEREOCHEMISTRY
lipid chirality

Achiral structure

Achiral structure

Achiral structure

Chiral structure

TRIACYLGLYCERIDE/PHOSPHOLIPID STEREOCHEMISTRY
lipid chirality
Notation of enantiomers is based on R/S convention.
1. Rank the four ligands according to the priority rules (suppose that the priority
of the ligands is Red -> Blue -> Yellow -> White)
2. Rotate the molecule so that the ligand with the lowest priority is far from you.
Look at the molecule from the opposite side of the lowest priority ligand.
3. Draw a round arrow from the highest priority ligand to the next highest to the
third highest.
If the arrow drawing direction is
in clockwise, the configuration
is R (R-form).

R-configuration

If the arrow is drawn


counter clockwise, the
molecule is S (S-form).

S-configuration

TRIACYLGLYCERIDE/PHOSPHOLIPID STEREOCHEMISTRY
lipid chirality
Isomers differing in configuration at all chiral centers are termed enantiomers.
Enantiomers have the same formula, molecular weight, boiling and melting
points and even matching nuclear magnetic resonance and mass spectra.
It is difficult to differentiate between them. They have equal but opposite
optical activities.
The equal mixture of both enantiomers is termed racemic.

TRIACYLGLYCERIDE/PHOSPHOLIPID STEREOCHEMISTRY
lipid chirality
The designation of the stereochemistry of acylated glycerol requires a
stereospecific numbering system for the carbon atoms of glycerol molecules.
Stereospecific numbering system has been developed to overcome the
ambiguity in naming glycerol phosphates using D and L system.
The molecules that are numbered in this manner have the prefix sn
(stereospecific numbering) preceding the term glycerol.

TRIACYLGLYCERIDE/PHOSPHOLIPID STEREOCHEMISTRY
lipid chirality
Identifying the pro-R and pro-S positions allows unambiguous naming.
The pro-S position is by convention made the 1-position.
C1 is carbon that would lead to S-configuration if its priority was
increased.

TRIACYLGLYCERIDE/PHOSPHOLIPID STEREOCHEMISTRY
lipid chirality
Chirality in glycerides is due to the fact that the central carbon in glycerol has
four different substitutions, thus it is a stereogenic center/chiral center.
All acylated glycerols are chiral when the fatty acid substituents at the sn-1 and
sn-3 positions are different.

TRIACYLGLYCERIDE/PHOSPHOLIPID STEREOCHEMISTRY
lipid chirality
Molecular stereospecificity generated by the fatty acid content on
triacylglycerol (TAG), or the distribution of saturated, polyunsaturated and
monounsaturated fatty acids on the TAG molecule have important implications
for dietary TAGs.
There is a wide spectrum of chiral mono-, di- and triacylglycerols, which are
processed by enzymes showing stereospecific preference in their action.
Atherogenic potential of dietary fats strongly influenced by the
stereospecificity of fatty acids on triglycerides. Metabolic processing and
effects of fasting lipids and postprandial lipemia (rise in triglyceride-rich
lipoproteins after eating) implicated in atherogenesis.
The positioning of unsaturated versus saturated fatty acids in the sn-2 position
of TAGs indicate differences in early metabolic processing and postprandial
clearance, which may explain modulatory effects on atherogenecity and
thrombogenecity.

TRIACYLGLYCERIDE/PHOSPHOLIPID STEREOCHEMISTRY
lipid chirality

Lipid chirality in cell membrane has been proposed to be the determining mechanistic
factors in a hypothesis for the origin of the three domains of life.

The origin of the Bacteria and Archaea is explained by divergence of first a population of
proto-bacteria and later a population of proto-archaea from the evolving precells, each by
the emergence of an enantio-selective lipid biosynthesis within the corresponding precell subtype.

The origin of the Eukarya is explained by symbiosis between a population of Bacteria and
a subpopulation of pre-cells with a predominance of the bacteria-type lipid enantiomers.

Molecular Microbiology (2003) 47(1), 1322. G. Wchterhuser..


MicroHypothesis: From pre-cells to Eukarya a tale of two lipids

TRIACYLGLYCERIDE/PHOSPHOLIPID STEREOCHEMISTRY
lipid chirality
Evolutionary difference in the
stereochemistry involving the
biosynthesis of phospholipids.

Why lipid chirality is important?


predicted
active site of
G1PDH

predicted
active site of
G3PDH

Comparison of the active sites between G1PDH and G3PDH. The nicotinamide
ring of NADH in the model structure of G1PDH is superimposed with that in the
crystal structure of G3PDH. The predicted active site of G1PDH is shown in a
green oval and that of G3PDH in a pink oval.
Analysis of membrane stereochemistry with homology modeling of sn-glycerol-1-phosphate dehydrogenase. Daiyasu et al. Protein Eng. (2002) 15 (12): 987-995.

SAPONIFICATION
Alkali hydrolysis of triacylglycerols yields to formation of glycerol and
free fatty acids (salt of free fatty acids - soap) as products.

WAXES
Waxes are esters of long-chain
alcohols with long-chain fatty
acids
Waxes are insoluble in water,
due to their mostly hydrocarbon
composition
They function as energy stores
and act as water-impermeable
coatings.

WAXES
Triacontanylpalmitate
major component of bees wax

Glands under the abdomen of


bees secrete a wax, which
they use to construct the
honeycomb.

Animal skin and fur are wax-coated and are water-repellant


Leaves of many plants and bird feathers are similarly water-repellant

BIOLOGICAL FUNCTION OF WAXES


Animal skin and fur are wax-coated and are water-repellant
The preen glands of birds secrete waxes to protect feathers.
Leaves of many plants are similarly water-repellant.

PROPERTIES OF WAXES

Thermal characteristics of waxes resemble


plastic polymers.

The wax molecules can slide by one


another. This is why waxes are soft and
have low melting temperatures.

Some waxes are harder/softer than others


depending upon the length of the carbon
chain (longer is harder) and branches in the
carbon chain (the more branching is harder
up to a point).

Depending on the fatty acid and fatty


alcohol content relative stiffness of the wax
will decrease as the temperature increases.

At very low temperatures, the material is


very stiff and brittle and if stressed enough
will fracture like "glass". As the temperature
increase, this brittle behavior transitions to
a more rubbery like behavior and the
material becomes more pliable.

APPLICATIONS / USES OF WAXES

GLYCEROPHOSPHOLIPIDS
Phospholipids constitute a broad class of
biological molecules.
They are similar to fats, but have only two
fatty acids rather than three. The third
hydroxyl group of glycerol is joined to a
phosphate group, which is negative in
electrical charge.
Phosphatidic acid is the backbone or parent
compound for glycerophospholipids.
The carbons 1 and 2 on the glycerol backbone
is esterified to two fatty acids, and carbon 3 is
esterified to a phosphate group.
They are amphipathic; their tails, which
consist of hydrocarbons, are hydrophobic and
are excluded from water. Their heads, which
consist of the phosphate group and its
attachments, are hydrophilic, and have an
affinity for water.

http://telstar.ote.cmu.edu/Hughes
http://www.bioteach.ubc.ca

GLYCEROPHOSPHOLIPIDS
Glycerophospholipids are
essential components of
cell membranes.
A 1,2-diacylglycerol that has
a phosphate group
esterified at carbon 3 of the
glycerol backbone is a
glycerophospholipid.
One of the fatty acids in
biological
glycerophospholipids is
usually unsaturated.
Unsaturated fatty acid is
typically on the carbon 2
position.

Glycerophospholipids are phospholipids but phospholipids are not necessarily


glycerophospholipids.

GLYCEROPHOSPHOLIPIDS
The phosphate is linked to a polar
(head group) alcohol.
The head groups are most
commonly either:
H
Serine
Inositol
Glycerol
Ethanolamine
choline
Ethanolamine and choline are
positively charged at neutral pH,
which balances the negative charge
of the phosphate, so that the net
charge on the polar head region of
the lipid is zero.
When the head group has no net
charge, the glycerophospholipid is
negatively charged due to the
phosphate.

ETHER GLYCEROPHOSPHOLIPID
An ether glycerophospholipid is
a variant on the phospholipid
theme in which one of the fatty
acids has been replaced by a
fatty alcohol so the connection
to the glycerol is via an ether
linkage, not an ester linkage.
They are synthesized in the
microsomal membrane fractions.

Fig. 8-08, p.255

ETHER GLYCEROPHOSPHOLIPID
PAF; platelet activating factor

1-O-alkyl-2-acetyl-sn-glycero-3phosphocholine; PAF; platelet


activating factor is an ether
glycophospholipid.
It is a lipid mediator that has
pleiotropic biological activities
besides platelet activation.
PAF is linked to
pathophysiology of asthma, and
anaphylaxis or endotoxin shock
(a.k.a. toxic shock syndrome).
Manifestations include
induction of asthma through
inflammation in air passages.
Fig. 8-09, p.255

ETHER GLYCEROPHOSPHOLIPID
PAF; platelet activating factor

Biochem J. 1993 June 15; 292(Pt 3): 617629.


Platelet-activating factor: receptors and signal transduction

ETHER GLYCEROPHOSPHOLIPID
plasmalogen
A plasmalogen is a variant of
an ether lipid in which the
fatty alcohol has a double
bond between carbons 1 and
2 (alkyl moiety is
unsaturated).
Plasmalogens can be
classified as antioxidants
since they
terminate lipid-oxidation
processes.
They are present in adequate
locations at sufficient
concentrations, and are
rapidly regenerated.

Fig. 8-10, p.256

ETHER GLYCEROPHOSPHOLIPID
plasmalogen
Lipid membrane and plasma
lipoproteins are less efficiently
protected against oxidative
stress than the various
aqueous compartments of
mammalian organisms.
Free radicals and oxidants,
including peroxyl radicals,
metal ions, singlet oxygen and
halogenating species attack on
lipids easily.
If not terminated, oxidative
attacks leads to propagating
damage to the lipid membrane.
In addition, end products of
lipid peroxidation may be
mutagenic and carcinogenic.
Mechanisms of lipid peroxidation

ETHER GLYCEROPHOSPHOLIPID
plasmalogen
The plasmalogens are easily react with a variety of free radicals in and
around the lipid membrane, preventing the oxidation of highly
polyunsaturated fatty acids.
Products of plasmalogen degradation do not propagate lipid oxidation.
Although cells rapidly incorporate and synthesize plasmalogens de novo,
their plasmalogen contents can be deliberately increased by
supplementation with precursors.

Biochem Soc Trans. 2004 Feb;32(Pt 1):147-50.


Plasmalogens: targets for oxidants and major lipophilic antioxidants.
Engelmann B.
Institut fr Klinische Chemie, Ludwig-Maximilians-Universitt, Mnchen, Germany.

SPHINGOLIPIDS
Sphingolipids are another class of lipids
found in biological membranes.
Sphingosine is the backbone instead of
glycerol.
Sphingosine is an 18-C amino alchohol (a
fatty acid and a polar head group (like
phosphocholine or one or more sugar
moieties).
A fatty acid is joined to sphingosine via
amide linkage to form ceramide.
Sphingolipids come in two major varieties,
phosphosphingolipids and
glycosphingolipids, both based on
ceramide.

SPHINGOLIPIDS
Sphingolipids are highly enriched in nervous cells, where they participate
to several signaling pathways controlling neuronal survival, migration,
and differentiation, responsiveness to trophic factors, synaptic stability
and synaptic transmission, and neuronglia interactions.
Their molecular function is associated with structural and geometrical
properties and the lateral order of cellular membranes, as well as
modulation of the function of several membrane-associated proteins, and
giving rise to important intra- and extracellular lipid mediators.

SPHINGOLIPIDS
Sphingolipid metabolism and spatial and temporal expression patterns
are regulated during differentiation and functional development of the
nervous system.
In several neurodegenerative diseases, sphingolipid metabolism is
deregulated, leading to the expression of abnormal sphingolipid patterns
and altered membrane organization that participate to several events
related to the pathogenesis of these diseases.
Anomalous sphingolipidprotein interactions are in part responsible for
the misfolding events that cause the fibrillogenic and amyloidogenic
processing of disease-specific protein isoforms, such as amyloid
peptide in Alzheimers disease, huntingtin in Huntingtons disease, synuclein in Parkinsons disease, and prions in transmissible
encephalopathies.

GLYCOSPHINGOLIPIDS
Glycosphingolipids with one sugar are cerebrosides.
Ceramides with 3 or more sugars, one of which is a sialic acid, are
gangliosides.

SPHINGOMYELINS
Sphingomyelins represent a
phosphorus-containing subclass
of sphingolipids.

MULTIPLE SCLEROSIS

Demyelination occurs due to attack


of activated lymphocytes, which are
induced and released from lymph
nodes upon binding to sphingosine1-phosphate in CNS.
Antibody-based drug natalizumab is an
effective therapy, however, MS activity
returns after discontinuation since the drug
sequesters antigen-reactive leukocytes
away from the CNS and into the peripheral
blood (1), where leukocytes assume a more
inflammatory phenotype (2).

Fingolimod antagonizes the sphingosine-1phosphate receptors on leukocytes (3),


which specifically prevents CD4+ T-helper
cellsfrom lymphatic tissues.

ISOPRENE AND ISOPRENOIDS

Isoprenes (a.k.a. terpenes) are the largest


class of chemicals made by living
organisms.

Commonly occur in plants as constituents


of oils, and give plants their fragrance.

Their biosynthesis involve some of the


most complex reactions found in biology.

Many isoprenes are small molecules that


evaporate at relatively low temperatures.
These often serve as important chemical
signals for plants.

Terpene name comes from one of their


best-known representatives, the paint
thinner turpentine (used as paint thinner) - a
derivative of pine sap.

Isoprenes are also used in cosmetics and


flavorings.

ISOPRENE AND ISOPRENOIDS

Plants evolved to emit isoprenes as a


mechanism for coping with heat and damaging
sun radiation.

Isoprenes enhance plants membrane function


and confers tolerance of reactive oxygen
species.

Isoprenes reacts very rapidly with hydroxyl


radicals in the atmosphere making
hydroperoxides that can enhance ozone
formation.

The emission capacity varies through the


seasons and is controlled by expression of the
isoprene synthase gene as well as at several
different points in isoprene metabolism.

Emission rates are positively correlated with temperature and light, supporting a role for isoprene in
maintaining photosynthesis under transient heat and light stress from sunflecks (brief increases in
solar irradiance).

ISOPRENE AND ISOPRENOIDS

Their fundamental building block is the hydrocarbon isoprene:

CH2=C(CH3)-CH=CH2
(2-methyl-1,3-butadiene)

When isoprenes are modified chemically, such as by oxidation or


rearrangement of the carbon skeleton, the resulting compounds are generally
referred to as isoprenoids (also known as terpenoids ).

ISOPRENE AND ISOPRENOIDS

The larger structures are "assembled" from several isoprene units,


usually by "head-to-tail" linked isoprene units.

ISOPRENE AND ISOPRENOIDS


Isoprene compounds are
very diverse and they have
little functional and
structural similarity as can
be examplified by steroids,
carotenoids, gibberelic
acid.

Several thousand different types of


molecules from very different plant groups
have been isolated and characterized.
Despite their varied structures, all of them
are synthesized by only a few pathways.

ISOPRENE AND ISOPRENOIDS

ISOPRENE AND ISOPRENOIDS

Dolichol phosphate is an
initiation point for the synthesis
of carbohydrate polymers in
animals.

The analogous alcohol in


bacterial systems, undecaprenol,
also known as bactoprenol,
consists of 11 isoprene units.

Undecaprenyl phosphate delivers


sugars from the cytoplasm for
the synthesis of cell wall
components such as
peptidoglycans,
lipopolysaccharides, and
glycoproteins.

Polyprenyl compounds also


serve as the side chains of
vitamin K, the ubiquinones,
plastoquinones, and tocopherols
(such as vitamin E).

ISOPRENE AND ISOPRENOIDS


Examples of applications involving terpenes and terpenoids:

Warfarin (coumadin ) - anti-coagulation drug / antagonist of vitamin K


Forskolin metabolic modulator / activates adenylate cyclase
Artemisinin anti malarial drug
Steviol sugar substitute / natural sweetener
Cafestol cholesterol increasing diterpene in unfiltered coffee
Paclitacel anti-cancer drug / stabilizes mitotic spindle

ARCHAEAL MEMBRANE LIPIDS

Lipid membranes of archaea is


fundamentally different than eukaryotic
and bacterial cell membranes.

The unique membrane composition in


archaea provides exceptional stability
and it is the primary biochemical basis
of their adaptation to chronic energy
stress in harsh environments, with
numerous secondary adaptations
among the metabolic pathways.

The headgroups of phospholipids can


be a range of polar compounds for
example, glycerol, serine, inosine,
ethanolamine, myo-inositol or
aminopentanetetrols. Glycolipids also
exhibit a range of sugar residues for
example, glucose, mannose, galactose,
gulose, N-acetylglucosamine or
combinations thereof.

ARCHAEAL MEMBRANE LIPIDS

In eukaryotes and bacteria, the


glycerol moiety is ester-linked to an
sn-glycerol-3-phosphate backbone,
whereas in archaea the isoprenoid side
chains are ether-linked to an snglycerol-1-phosphate moiety.

Typical chemical differences in the


lipids used by archaea and bacteria
include the monolayers produced by
some archaea and the highly
unsaturated molecules produced by
some bacteria resulting in a general
trend of increasing permeability to
ions such as protons and sodium.

doi:10.1038/nrmicro1619

CHOLESTEROL AND STEROLS (STEROIDS)


Triterpenes including squalene and lanosterol, are two of the
precursors for cholesterol, which is the most common steroid in
animals and the precursor for all other animal steroids.
Gonane is the underlying tetracyclic hydrocarbon of steroids without
any alkyl sidechains.

CHOLESTEROL AND STEROLS (STEROIDS)

Cholesterol is converted to cholesteryl esters for storage in cell.


The ester bond is formed between the carboxylate group of a fatty acid
and the hydroxyl group of cholesterol.
Cholesteryl esters have a lower solubility in water due to their
increased hydrophobicity.

CHOLESTEROL AND STEROLS (STEROIDS)

Cholesterol has a rigid ring system and a short branched hydrocarbon tail. It is
largely hydrophobic, but has one polar group, a hydroxyl, making it
amphipathic.
It is found in animal cell membrane and functions to help stabilize the
membrane.
It is the precursor for synthesis of steroid hormones, vitamin D, and bile acids.
High levels of it in the blood may contribute to atherosclerosis.

CHOLESTEROL AND STEROLS (STEROIDS)

The hydroxyl group at position C-3


is modified in various common
steroid hormones.

STEROID HORMONES
Cortisol - provides control of carbohydrate, protein, and lipid metabolism
Testosterone - primary male sex steroid hormone
Estradiol - primary female sex steroid hormone
Progesterone a precursor of testosterone and estradiol

STEROID HORMONES
Desmolase is the cholesterol side-chain cleavage enzyme. It is also commonly referred to
as P450scc, where "scc" is an acronym for side-chain cleavage. It is a mitochondrial enzyme
that catalyzes the first reaction in the process of steroidogenesis in all mammalian tissues
that specialize in the production of various steroid hormones.

p.264

BILE ACIDS
Bile acids, such as cholic acid and deoxycholic acid, are derivatives of
cholesterol.
Produced in the liver and stored and secreted from the gallbladder.
Act as detergent molecules assisting in the solubilization/emulsification and
absorption of dietary lipids in the intestine.
Bile acids also are important signaling molecules in regulation of lipid and
cholesterol metabolism.

VITAMIN D

Vitamin D is a fat-soluble vitamin that is naturally present in very few foods.


It is also produced endogenously when skin is exposed to ultraviolet rays from
sunlight.
Vitamin D promotes calcium absorption in the gut and maintains adequate
serum calcium and phosphate concentrations to enable normal mineralization
of bone and to prevent hypocalcemic tetany. It is also needed for bone growth
and bone remodeling by osteoblasts and osteoclasts.
Vitamin D obtained from sun exposure, food, and supplements is biologically
inert and must undergo two hydroxylations in the body for activation. The first
reaction occurs in the liver, and the second occurs primarily in the kidney and
forms the physiologically active 1,25-dihydroxyvitamin D [1,25(OH)2D], also
known as calcitriol.

PLANT STENOLS
Dietary guidelines for optimal health call for reducing cholesterol
intake.
Eating plant sterols and stanols can play a role.
These cholesterol mimics bind to cholesterol receptors on intestinal
cells and block absorption of cholesterol itself.
Plant sterols and stanols are not themselves absorbed.

Stanols are fully reduced sterols

PLANT STENOLS

Serum cholesterol before and after consumption of Benecol.

Green circles: 0g/day


Red squares: 2.6g/day
Blue triangles: 1.8g/day

LIPIDS AND CELL SIGNALING


Modification and breakdown of glycerophospholipids produce a
variety of lipid signals.
Lipids signals act locally, either within the cell where they are made or
on nearby cells.
These signals typically initiate a cascade of reactions with multiple
regulatory effects.
The lifetimes of these signals are usually very short.
The creation and breakdown of lipid signals is carefully regulated and
timed.

PHOSPHOLIPASES

Phospholipases are enzymes that hydrolyze specific ester bonds in phosphoglycerides


or glycerophosphatidates, converting the phospholipids into fatty acids and other
lipophilic substances.
Phospholipase A1 hydrolyzes the acyl group attached to the 1-position.
Phospholipase A2 hydrolyzes the acyl group attached to the 2-position to form fatty acid
and lysophospholipid products.

PHOSPHOLIPASES
Phospholipase A1
hydrolyzes the acyl
group attached to the
1-position.

Phospholipase A2
hydrolyzes the acyl
group attached to the
2-position to form fatty
acid and
lysophospholipid
products.

PHOSPHOLIPASES

PLA2 is commonly found insect and snake venom.

Venom from both snakes and insects also contain


melittin, which is a stimulant of PLA2.

Excessive PLA2 activity leads to disproportionate


release of proinflammatory mediators from the cell
membrane, resulting in inflammation and pain at
the site.

There are also prokaryotic A2 phospholipases.

THE SPECTRUM OF PHOSPHOLIPASE A2


Phospholipases are involved in processing nutrients for transport and
modification of the plasma membrane.
Phospholipases are also involved in signaling cascades and they play many
roles in cell growth, inflammation, and diseases.

www.caymanchem.com

LIPID SIGNALING

Glycerophospholipid breakdown phospholipases produces a variety of signal


products
Arachidonic acid
Lysophosphatidic acid
Diacylglycerol
Inositol phosphates, including inositol-1,4,5-trisP

LIPIDS AND CELL SIGNALING


Phospholipases and phospholipids participate in transmission of ligand-receptor induced
signals from the plasma membrane to intracellular proteins, primarily PKC. PKC activity is
mediated by receptors that are coupled to activation of phospholipase C.
formation DAG and IP3 and pathway leading to elevation of cytosolic Ca2+

ENDOCANNABINOID SIGNALING

After the binding of neurotransmitters to their receptors, activated postsynaptic neurons


synthesize membrane-bound endocannabinoid precursors and cleave them to release
endocannabinoids.
This is generally induced by an increase in the cytosolic concentration of free Ca2+.
Endocannabinoids subsequently act as retrograde messengers by binding to presynaptic
CB1 cannabinoid receptors, which are coupled to the inhibition of Ca2+ influx into the
cell and, in turn, to the blockade of neurotransmitter release.
This allows the tuning of key biological processes such as memory, movement, appetite
and pain.

9-tetrahydrocannabinol

N-arachidonoylethanolamine

2-Arachidonoylglycerol

ENDOCANNABINOID SIGNALING
The activities of Phospholipase C (PLC) and
diacylglycerol lipase (DGL) mediate the
formation of 2-Arachidonoylglycerol (2-AG)
from the omega-6 fatty acid arachidonic acidcontaining diacylglycerol (DAG).

Activation of phospholipase D (PLD)


on postsynaptic cell forms the
anandamide from N-arachydonoyl
phosphatidylethanolamine (NAPE).

LIPIDS AND CELL SIGNALING

Endocannabinoids are released into the


synaptic cleft and act via presynaptic
cannabinoid 1 (CB1) receptors.

These receptors are guanine nucleotide


binding (G) protein-coupled receptors
coupled to Gi/o transduction pathways, and
their activation leads to inhibition of
adenylate cyclase (AC), opening of
presynaptic potassium (K+) channels, and
inhibition of presynaptic Ca2+ channels.

These effects result in inhibition of releases


of glutamate or -aminobutyric acid (GABA)
from presynaptic terminals.

LIPIDOMICS
Many human diseases involve the
disruption of lipid metabolic enzymes
and pathways.
New techniques have made possible
the global analysis of lipids and their
interacting protein partners in organs,
cells, and organelles an approach
termed lipidomics.
Typical cells contain over a thousand
different lipids.
Complete understanding of lipid
function will require the determination
of which lipids are present and in what
concentrations.
Cellular lipidomics provides a
framework for understanding the roles
of lipids.

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