Download FATTY ACIDS (FAs) SIMPLE AND COMPLEX LIPIDS

2016-11-15
FATTY ACIDS (FAs)
SIMPLE AND COMPLEX
LIPIDS
Dicarboxylic acids, ketone bodies.
Department of General Chemistry
Structure and classification of lipids
Lipids can be divided into five categories, on the
basis of lipid function
Energy-storage lipids (triacylglycerols)
Membrane lipids (e.g. phospholipids)
Emulsification lipids (bile acids)
Messenger lipids (e.g. steroid hormones)
Protective-coating lipids (biological waxes)
1.
2.
3.
4.
5.
Chemically, lipids are an extremely diverse group of
molecules.
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Chemically, lipids are an extremely diverse group of
molecules.
The simplest lipids are the fatty acids.
These
are
long
chain
hydrocarbons with carboxyl
groups (COOH groups).
At physiological pH, the
carboxyl group is readily
ionized.
FA are monocarboxylic acids
with a short (≤6 carbon
atoms), medium (8-14 carbon
atoms), or long (≥14 carbon
atoms) aliphatic chain
Fatty acids
Fatty acids that occur in living systems normally contain an
even number of carbon atoms, the hydrocarbon chain is
usually unbranched and the length of the chain usually ranges
from 12 to 24 carbons.
Fatty acids that contain no carbon-carbon double bonds are
termed saturated fatty acids; those that contain double
bonds are unsaturated fatty acids.
Unsaturated fatty acids have one or more double bonds
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Fatty acids
Biological important ones are usually linear molecules with an
even number of carbon atoms
Fatty acids are numbered using either arabic numbers (COOH
is 1) or the Greek alphabet (COOH is not given a symbol;
adjacent carbon atom are α, β , γ, etc)
A few fatty acids with an α-OH group are produced and used
structurally by humans
FATTY ACIDS
CHAIN LENGTH
• Short chain = less than 6 carbons
• Medium chain = 6-10 carbons
• Long chain = 12 or more carbons
• The shorter the carbon chain, the more liquid the
fatty acid is
Fatty acids
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Fatty acids
common saturated FA’s:
n = 12: lauric acid (n-dodecanoic acid; C12:0)
n = 14: myristic acid (n-tetradecanoic acid; C14:0)
n = 16: palmitic acid (n-hexadecanoic acid; C16:0)
n = 18; stearic acid (n-octadecanoic acid; C18:0)
n = 20; arachidic (eicosanoic acid; C20:0)
n= 22; behenic acid
n = 24; lignoceric acid
Unsaturated fatty acids
Monoenoic acids (one double bond):
C 16:1 ∆9 ω 7: palmitoleic acid
C 18:1 ∆9 ω 9: oleic acid
C 24:1 ∆15 : ω 9 nervonic acid
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Unsaturated Fatty Acids
Most naturally occurring fatty
acids have cis double bonds and
are usually liquid at room
temperature
Omega families of fatty acids
A double bond is indicated by ∆n , where n is a number of the
first carbon of the bond
Since fatty acids are elongated in vivo from the carboxyl end,
biochemists use alternate terminology to assign these fatty
acids to families
Omega (ω) minus x (or n-x), where x is the number of carbon
atoms from the methyl end where the double bond is first
encountered.
Fatty acids and types of fatty acids
Unsaturated fatty acids and double-bond position
Several families of unsaturated fats may be recognized by the
number of saturated carbon atoms that follow the last double
bond (the placement of the methyl end of the chain with
respect to the double bond).
1
3
ω-3 (omega-3 fatty acid)
2
2
1
4
3
6
ω-6 (omega-6 fatty acid)
5
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Omega-6 and Omega-3
Fatty Acids
The first double bond:
In vegetable oils is at carbon 6 (omega-6).
In fish oils is at carbon 3 (omega-3).
Essential Fatty Acids
The Essential Fats are a group of fatty acids that are
essential to human health.
Omega-6 (ω6) – Linoleic acid, C 18:2 ∆9,12
Omega-3 (ω3) – α Linolenic acid, C 18:3 ∆9,12,15
Omega-6 (ω6) – γ Linolenic acid, C 18:3 ∆6,9,12
Omega-6 (ω6) – Arachidonic acid, C 20:4 ∆ 5,8,11,14
Omega 3 and omega 6 fatty acids
DHA
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Omega – 3 fatty acids
Docosahexaenoic acid or
DHA is an omega-3 fatty
acid with six cis double
bonds and 22 carbons
(22:6n-3).
Eicosapentaenoic acid or
EPA is an omega-3 fatty
acid with five cis double
bonds and 20 carbons
(20:5n-3).
There is evidence that essential fatty acids (EFAs), and
especially polyunsaturated fatty acids (PUFAs), such as
docosahexaenoic acid (DHA) and eicosapentaenoic acid
(EPA), play fundamental role in development and proper
functioning of the nervous system;
Consequently, the EFA composition of membrane
phospholipids likely plays a direct role in a variety of cellular
and multicellular processes, including inflammation and
immunity, with implications for neurodegenerative diseases
such as multiple sclerosis (MS) and Parkinson's disease (PD).
Function of EFAs
Formation of healthy cell membranes
Proper development and functioning of the brain and nervous
system
Production of hormone-like substances called Eicosanoids
Thromboxanes
Leukotrienes
Prostaglandins
Responsible for regulating blood pressure, blood viscosity,
vasoconstriction, immune and inflammatory responses.
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Lipids
Two of the major functions of lipids are to serve as
The major form of energy storage in the body
The basic structural unit of cellular membranes.
Classification of lipids
MOST FATTY ACIDS IN HUMANS OCCUR AS
TRIACYLGLYCEROLS (TAG)
Fatty acids occur primarily
as esters of glycerol, when
they are stored for future
utilization
In TAG all three hydroxyl
groups on the glycerol are
esterified with a fatty acid
Glycerol
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The fatty acids present in triacylglycerols are
predominantly saturated or monounsaturated.
Stereospecific numbering
Carbon 2 of triglycerides is frequently asymmetric
since C-1 and C-3 may be substituted with different
acyl groups
By convention we normally draw the hydroxyl group
at C-2 to the left and use the designation of sn2 for
that particular substituent
C-1 and C-3 of the glycerol molecule become sn1 and
sn3 respectively
MAG and DAG
Compounds with one (monoacylglycerols = MAG) or two
(diacylglycerols =DAG) acids are present only in relatively
minor amounts and occur largely as metabolic intermediates
in the biosynthesis and degradation of glycerol-compounds.
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Digestion of triacylglycerols
Pancreatic Lipase, which is secreted into the intestine, catalyzes
hydrolysis of triacylglycerols at their 1 and 3 positions, forming
1,2-diacylglycerols and then 2-monoacylglycerols
(monoglycerides).
A protein colipase is required to aid binding of the pancreatic
lipase at the lipid-water interface.
Monoacylglycerols, fatty acids, and cholesterol are absorbed by
intestinal epithelial cells.
Within intestinal epithelial cells, triacylglycerols are
resynthesized from fatty acids and monoacylglycerols
Digestion of Triacylglycerols
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Digestion of triacylglycerols
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Hydrolysis of TAGs by lipases
In hydrolysis, triacylglycerols are split into glycerol and three fatty
acids.
Saponification and Soap
Soaps are:
Salts of fatty acids.
Formed by saponification, a reaction in which a triacylglycerol
reacts with a strong base.
O
CH2
O
C
(CH2)16CH3
O
CH
CH2
O
O
C
O
C
(CH2)16CH3
+ 3 NaOH
(CH2)16CH3
CH2 OH
CH
OH
CH2
OH
O
+-
+ 3 Na O C (CH2)16CH3
salts of fatty acids (soaps)
Saponification reaction
Mixtures of soaps
Long-chain fatty acids are insoluble in
water, but soaps form micelles
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Waxes
Waxes are:
Esters of saturated fatty acids and long-chain alcohols.
Coatings that prevent loss of water by leaves of plants.
Waxes
Triacontanylpalmitate is the
main component of beewax.
Palmitic acid (C16:0) is
esterified by a C30 chain,
triacontanol (or melissyl
alcohol).
LIPIDS
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General structure of glycerophospholipids
C-2 of phospholipids
asymmetric center
represents
an
The stereospecific numbering (sn) system is the best way to designate the different
hydroxyl groups in glycerol molecule
Saturated C16 or C18 FA
Phosphodiester
linkage
Unsaturated C16 – C20 FA
Derived from polar alcohol
• smallest = H (from H-OH)
• least common in membranes
• phosphatidic acid
Phosphatidic acid
Most phospholipids have a
saturated fatty acid on C-1
and an unsaturated fatty acid
on C-2 of the glycerol
backbone
1,2-diacylglycerol 3-phosphate
= Phosphatidic acid
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Phospholipids
Phospholipids contain
1,2-Diacylglycerol (DAG)
and a base (X) connected
by a phosphodiester bridge
that links the glycerol
backbone to some base,
usually a nitrogenous one,
such as choline, serine, or
ethanolamine
↓
DAG
Phosphatidylglycerols (PG)
These molecules are
found in high concentration in mitochondrial
membranes
and
as
components of pulmonary surfactant.
Phosphatidylglycerol is
also a precursor for the
synthesis of cardiolipin
(diphosphatidylglycerols =DPGs).
Phosphatidylglycerols exhibit a net
charge of -1 at physiological pH.
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Cardiolipin (diposphatidylglycerol=DPG)
Cardiolipin is composed of
two
molecules
of
phosphatidic acid linked
together covalently through
a molecule of glycerol, thus
is a very acidic (charge, -2)
Cardiolipin
is
found
primarily in the inner
membrane of mitochondria
and also as components of
pulmonary surfactant.
These molecules are very acidic, exhibiting
a net charge of -2 at physiological pH
Lecithin and Cephalin
Lecithin and cephalin are glycerophospholipids:
Abundant in brain and nerve tissues.
Found in egg yolk, wheat germ, and yeast.
Phosphatidylcholine (PC)
This
class
of
phospholipids is also
called the lecithins.
Phosphatidylcholine
(PC) contains mostly
palmitic acid (16:0) or
stearic acid (18:0) in the
sn-1
position
and
primarily the unsaturated
C18 fatty acids oleic,
linoleic or linolenic in
the sn-2 position
At physiological pH, phosphatidylcholines
are neutral zwitterions.
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Phosphatidylcholine and Phosphatidylethanolamine
Phosphatidylethanolamine
(PE) has the same saturated
fatty acid at the sn-1
position but contains more
of
the
long-chain
polyunsaturated fatty acids –
namely 18:2, 20:4 and 22:6
at the sn-2 position
PE
PC
PULMONARY SURFACTANT
(COMPOSITION OF SURFACTANT)
It is about 90% lipid, of which 90% is phospholipid,
of which about 2/3 is
1,2-Dipalmitoylphosphatidylcholine (DPPC).
DPPC has important mechanical properties that
allows it to act as pulmonary surfactant.
The lecithin - dipalmitoyllecithin (DPPC)
The dipalmitoyllecithin is a
component of lung or
pulmonary surfactant.
It contains palmitate at both
carbon 1(R1) and 2 (R2) of
glycerol and is the major
(80%) phospholipid found
in the extracellular lipid
layer lining the pulmonary
alveoli.
Polar head
(choline)
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Dipalmitoylphosphatidylcholine is necessary for normal lung
function
This lipid decreases the
surface tension of the
aqueous surface layer of the
lung
Premature babies develop
RDS (respiratory distress
syndrome)
because
of
immaturity of their lungs,
resulting from a deficiency
of pulmonary surfactant
Phosphatidylserine (PS)
Phosphatidylserine (PS) has a net charge -1, causing it to be an acidic
phospholipids
Phosphatidylinositol (PI)
These molecules contain almost
exclusively stearic acid at
carbon 1 and arachidonic acid at
carbon 2.
Phosphatidylinositols composed
exclusively of non-phosphorylated inositol exhibit a net
charge of -1 at physiological pH.
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Phosphatidylinositol (PI)
These molecules exist in
membranes with various levels
of phosphate esterified to the
hydroxyl of the inositol.
Molecules with phosphorylated
inositol are termed polyphosphoinositides.
The polyphosphoinositides are
important intracellular transducers of signals emanating
from the plasma membrane
Plasmalogens
Plasmalogens
Plasmalogens are compounds in
which O-(1-Alkenyl) substituents
occur at C-1 of the sn-glyceryl
moiety of phosphoglycerides in
combination with an O-acyl
residue esterified to the C-2
position
Relatively large amounts of
ethanolamine plasmalogen occur
in myelin with lesser amounts in
heart muscle, where choline
plasmalogen is abundant
Plasmalogen has one etherlinked alkenyl chain
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Structure of plasmalogen platelet activating
factor (PAF)
Platelet-activating factor (PAF)
or 1-alkyl-2-acetyl-sn-glycero-3phosphocholine is an ether
analogue of phosphatidylcholine.
PAF contains an O-alkyl moiety
at sn-1 and an acetyl residue
instead of a long-chain fatty acid
in position 2 of the glycerol
moiety
PAF is a major mediator of
hypersensitivity, acute inflammatory reactions and anaphylactic
shock
DEGRADATION OF PHOSPHOLIPIDS
The degradation of phosphoglycerides is performed by
phospholipases found in all tissues and pancreatic juice.
A number of toxins and venoms have phospholipase activity, and
several pathogenic bacteria (Baccili) produce phospholipases that
dissolve cell membranes and allow the spread of infection.
Sphingomyelin is degraded by the lysosomal phospholipase,
sphingomyelinase.
Action of phospholipases
Phospholipases A1 and A2 hydrolyze
the ester bonds at C-1 and C-2
Phospholipases C and D each split
one of phosphodiester bonds in the
head group
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Phospholipase A2
Phospholipase A2 is also an
important enzyme, whose
activity is responsible for
the release of arachidonic
acid from the C-2 position
of membrane phospholipids.
The released arachidonate
is then a substrate for the
synthesis
of
the
prostaglandins
and
leukotrienes.
Lysophospholipid
Eastern diamondback rattlesnake
Cobra and bee venoms contain
Phospholipase A2.
These venoms, when injected into the blood,
produce lysophospholipids that disrupt cellular
membranes and lyse blood cells.
Indian cobras kill several
thousand people each year.
Sphingolipids
The sphingolipids include the sphingomyelins and
glycosphingolipids (the cerebrosides, sulfatides, globosides
and gangliosides).
Sphingomyelins are the only sphingolipid that are
phospholipids.
Sphingolipids are a component of all membranes but are
particularly abundant in the myelin sheath.
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Sphingolipids
Also major component of membranes
Phospholipid or glycolipid (depends on polar group)
Derivatives of sphingosine (instead of glycerol)
C18 amino alcohol
Ceramide
Acylated amine
Parent compound of most abundant sphingolipids
• Polar head group derivatives
• Phosphodiester or glycosididic
or linkage
Sphingosine
trans-1,3-dihydroxy-2-amino-4-octadecene
Sphingosine possesses two asymmetric carbon atoms (position C-2 and C-3)
CERAMIDES
are fatty acid amide derivatives
of sphingosine =
N-acylsphingosine
CERAMIDE = N-acylsphingosine
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Sphingolipids
Also major component of membranes
Phospholipid or glycolipid (depends on polar group)
Derivatives of sphingosine (instead of glycerol)
C18 amino alcohol
Ceramide
Acylated amine
Parent compound of most abundant sphingolipids
• Polar head group derivatives
• Phosphodiester or glycosididic
or linkage
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Structure of sphingomyelin
Sphingomyelins are
sphingolipids that are also
phospholipids.
Sphingomyelins are
important structural lipid
components of nerve cell
membranes.
The predominant
sphingomyelins contain
palmitic or stearic acid
N-acylated at carbon 2 of
sphingosine.
Glycosphingolipids
Glycosphingolipids
contain monosaccharides bonded to the
–OH of sphingosine by a
glycosidic bond.
Cerebrosides contain
only one monosaccharide.
GLYCOLIPIDS
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GLYCOLIPIDS
Cerebrosides
One sugar molecule
Galactocerebroside – in neuronal membranes
Glucocerebrosides – elsewhere in the body
Sulfatides or sulfogalactocerebrosides
A sulfuric acid ester of galactocerebroside
Globosides: ceramide oligosaccharides
Lactosylceramide
2 sugars ( eg. lactose)
Gangliosides
Have a more complex oligosaccharide attached
Biological functions: cell-cell recognition; receptors
for hormones
Structure of cerebroside
Cerebrosides have a single sugar group linked to ceramide. The most common of these is
galactose (galactocerebrosides), with a minor level of glucose (glucocerebrosides).
Galactocerebroside
Galactocerebrosides are found predominantly in neuronal cell membranes.
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Major fatty acids in cerebrosides contain 24
carbons
Lignoceric acid CH3 (CH2)22 COOH
cerebronic acid, hydroxynervonic acid and
nervonic acid are constituents of the ceramide part of
cerebrosides (glycosphingolipids found mainly in
nervous tissue)
Major fatty acids in cerebrosides
2-hydroxytetracosanoic acid
(cerebronic acid) and
2-hydroxy-15-tetracosenoic
acid (hydroxynervonic
acid) are constituents of the
ceramide part of
cerebrosides (glycosphingolipids found mainly in
nervous tissue)
SULFATIDES
This group (known also as cerebroside
3-sulfate) is mainly formed of 3-sulfate
esters of galactosyl-cerebrosides
(galactosyl-3-sulfate esters) and is
found in mammalian tissues as the
corresponding cerebroside group.
Excess accumulation of sulfatides is
observed in sulfatide lipidosis
(metachromatic leukodystrophy).
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Gangliosides
Gangliosides are very similar to globosides except that they
also contain NANA in varying amounts.
The specific names for gangliosides are a key to their
structure.
The letter G refers to ganglioside, and the subscripts M, D, T
and Q indicate that the molecule contains mono-, di-, tri and
quatra(tetra)-sialic acid.
The numerical subscripts 1, 2 and 3 refer to the carbohydrate
sequence that is attached to ceramide; 1 stands for
GalGalNAcGalGlc-ceramide, 2 for GalNAcGalGlc-ceramide
and 3 for GalGlc-ceramide.
Gangliosides
Nomenclature of dicarboxylic acids
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Major dicarboxylic acids of Krebs cycle
Oxaloacetic Acid
Malic Acid
Succinic Acid
Fumaric acid
Citric acid
The three ketone bodies
Acetoacetate
Acetone
β-Hydroxybutyrate
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Reactions of Ketogenesis
Ketone bodies
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oxidation to
CO2
Thiolase
CoA
Acetoacetyl CoA
Fatty acid
β-oxidation
2 Acetyl
(excess CoA
acetyl CoA)
MITOCHONDRIUM
Citric
acid
cycle
Ketone body formation acetyl CoA
HMG-CoA synthase
(ketogenesis) in liver
mitochondria from excess
CoA
acetyl CoA derived from the
Hydroxymethylglutaryl CoA (HMGCoA)
β-oxidation of fatty acids
HMG-CoA-lyase
acetyl
CoA
(non-enzymatic)
Acetone
Acetoacetate
NADH
β-Hydroxybutyrate
dehydrogenase
NAD+
β-Hydroxybutyrate
Ketone bodies are a water-soluble,
transportable form of acetyl units
Acetoacetate is activated by
the transfer of CoA from
succinyl CoA in a reaction
catalyzed by a specific CoA
transferase.
Acetoacetyl CoA is cleaved
by thiolase to yield two
molecules of acetyl CoA
(enter the citric acid cycle).
CoA transferase is present
in all tissues except liver
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Ketogenesis
Ketone bodies can be transported through the
circulatory system.
During times of starvation ketone bodies act as the
major source of energy for many tissues, including
the brain.
In these tissues reconversion of ketone bodies to
acetyl-CoA inside the mitochondria provides
metabolic energy
Clinical Significance of Ketogenesis
The production of ketone bodies occurs at a relatively low rate
during normal feeding and under conditions of normal
physiological status.
Normal physiological responses to carbohydrate shortages
cause the liver to increase the production of ketone bodies
from the acetyl-CoA generated from fatty acid oxidation.
This allows the heart and skeletal muscles primarily to use
ketone bodies for energy, thereby preserving the limited
glucose for use by the brain.
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Utilization of Ketone Bodies
Liver produces Ketone bodies
Liver cannot use acetoacetate
as fuel ( lacks enzyme for the
conversion of acetoacetate to
acetoacetylCoA
AcetoacetylCoA is converted
to 2 acetylCoA which are
oxidized by the TCA
Increased Ketogenesis
Conditions
Starvation
Severe DM
Rapid
mobilization of fat
Result to
ketonemia
ketoacidosis
LIPIDS
DENTINE: 0.04-0.36 %
Cholesterol and cholesterol esters
Glycerolipids (tri-,di- and monoglycerides)
Phospholipids
DENTAL PULP: 57.4% phospholipids and 42.6
simple lipid
CARBOXYLIC ACIDS:
Dentine: citric and lactic acid
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Structure of the following compounds are obligatory
for the control test of fatty acids and simple and
complex lipids
Fatty acid structures: palmitic, stearic, palmitoleic, oleic, linoleic,
α and γ linolenic, arachidonic (omega family of FAs)
Monoacylglycerols, diacylglycerols and triacylglycerols with different
type of fatty acids
Saponification reaction
Phosphatidic acid, phosphatidylcholine (lecithin),
lysophosphatidylcholine, phosphatidylethanolamine (cephalin),
phosphatidylserine, plasmalogen, platelet activating factor (PAF)
Sphingosine and ceramide, sphingomyelin, cerebroside
Dicarboxylic acids: Oxaloacetate, Malate, Succinate, Fumarate, and
Citric acid
Ketone bodies: Acetoacetate , Acetone, β-Hydroxybutyrate
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