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Lipids
Candas
BIOLOGICAL MOLECULES
http://www.lipidmaps.org/data/classification/lipid_cns.html
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.
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
FATTY ACIDS
Most lipids, like fatty acids, are amphipathic, having a
non-polar end and a polar end.
3
2
C
1
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.
Monounsaturated
Fatty Acid
1 double bond
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).
H
H
L
Am J Cardiol 2008;101(suppl):58D-68D.
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.
18:39,12,15
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.
DHAs interaction with other membrane lipids, particularly cholesterol, play a prominent
role in modulating the local structure and function of cell membranes.
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.
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
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.
TRIACYLGLYCERIDE/PHOSPHOLIPID STEREOCHEMISTRY
lipid chirality
Evolutionary difference in the
stereochemistry involving the
biosynthesis of phospholipids.
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
PROPERTIES 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
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.
ETHER GLYCEROPHOSPHOLIPID
PAF; platelet activating factor
ETHER GLYCEROPHOSPHOLIPID
PAF; platelet activating factor
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.
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.
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
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).
CH2=C(CH3)-CH=CH2
(2-methyl-1,3-butadiene)
Dolichol phosphate is an
initiation point for the synthesis
of carbohydrate polymers in
animals.
doi:10.1038/nrmicro1619
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.
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
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.
PLANT STENOLS
PHOSPHOLIPASES
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
www.caymanchem.com
LIPID SIGNALING
ENDOCANNABINOID SIGNALING
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).
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.