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it explain all you need to know about lipids...their structure functions and naming.
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Introduction
Definition: water insoluble compounds Most lipids are fatty acids or ester of fatty acid They are soluble in non-polar solvents such as
petroleum ether, benzene, chloroform Functions
Energy storage Structure of cell membranes Thermal blanket and cushion Precursors of hormones (steroids and
prostaglandins) Types:
Fatty acids Neutral lipids Phospholipids and other lipids
Classification:
Saponifiable—can be hydrolyzed by NaOH to make soap
Non-saponifiable—cannot be hydrolyzed, includes sterols such as cholesterol
Saponifiable lipids are further subdivided:
Simple- made of fatty acids plus alcohol
Compound- either phospho- or glyco- lipids, which contain phosphate or sugar groups as well as fatty acids
Lipids are non-polar (hydrophobic) compounds, soluble in organic solvents.
Most membrane lipids are amphipathic, having a non-polar end and a polar end.
Fatty acids consist of a hydrocarbon chain with a carboxylic acid at one end.
A 16-C fatty acid: CH3(CH2)14-COO-
Non-polar polar
A 16-C fatty acid with one cis double bond between C atoms 9-10 may be represented as 16:1 cis 9.
Some fatty acids and their common names:14:0 myristic acid; 16:0 palmitic acid; 18:0 stearic acid; 18:1 cis9 oleic acid18:2 cis9,12 linoleic acid18:3 cis9,12,15 -linonenic acid 20:4 cis5,8,11,14 arachidonic acid20:5 cis5,8,11,14,17 eicosapentaenoic acid (an omega-3)
Double bonds in fatty acids usually have the cis configuration. Most naturally occurring fatty acids have an even number of carbon atoms.
C
O
O 1
23
4
fatty acid with a cis-9 double bond
There is free rotation about C-C bonds in the fatty acid hydrocarbon, except where there is a double bond.
Each cis double bond causes a kink in the chain.
Rotation about other C-C bonds would permit a more linear structure than shown, but there would be a kink.
C
O
O 1
23
4
fatty acid with a cis-9 double bond
Fats & OilsSimplest lipids, called triacylglycerols
or simply triglycerides. Main form of fat storage in plants, animals, and man. Males store 21% fat on average, females 26%.
Essential Fatty Acids
Fatty acids which cannot be made by the body, but are important for health and growth are called essential.
Linolenic acid, found mostly in vegetable oils, is an important reducer of LDL (low density lipoproteins), which help to take cholesterol into the blood and cause atherosclerosis (buildup of plaque in the blood vessels) a prime cause of heart attacks
Arachidonic acid is important in making eicosanoids, molecules which regulate and protect the body from invasion by microorganisms.
Simple Lipids—Fatty Acids
Simple triglycerides contain the same fatty acid in all three positions; mixed triglycerides contain two or three different fatty acids
Fatty acids are carboxylic acids with from 4 to 20 carbons in the chain. The chain can be saturated (only single bonds) or unsaturated (one or more double bonds in the chain), Saturated are usually solid at room temperature, unsaturated are usually liquid
Less common fatty acids
iso – isobutyric acid anteiso odd carbon fatty acid – propionic acid hydroxy fatty acids – ricinoleic acid,
dihydroxystearic acid, cerebronic acid cyclic fatty acids – hydnocarpic,
chaulmoogric acid
R
H3C
H3C H3CR
CH3
(CH2)12-CO2H (CH2)10-CO2H
chaulmoogric acid hydnocarpic acid
H3C
CH3 CH3 CH3 CH3
COOH
PHYTANIC ACID
A plant derived fatty acid with 16 carbons and branches at C 3, C7, C11 andC15. Present in dairy products and ruminant fats.A peroxisome responsible for the metabolism of phytanic acid is defectivein some individuals. This leads to a disease called Refsum’s disease
Refsum’s disease is characterized by peripheral polyneuropathy, cerebellarataxia and retinitis pigmentosa
(CH2)10H3C C C (CH2)4 COOH
TARIRIC ACID
CHH2C (CH2)4 C C C C (CH2)7 COOH
ERYTHROGENIC ACID
Less common fatty acids
These are alkyne fatty acids
Unsaturated fatty acids number and position of the double
bond(s)Various conventions are in use for indicating the
HC CH(CH2)7COOH(CH2)7H3C
1918
10
18:1,9 or 9 18:1
H3C CH2CH2CH2CH2CH2CH2CH2CH CH(CH2)7COOH
191017n
2 3 4 5 6 7 8 9 10 18
9, C18:1 or n-9, 18:1
Unsaturated fatty acids
Monoenoic acids (one double bond): 16:1, 9 7: palmitoleic acid (cis-9-
hexadecenoic acid 18:1, 9 9: oleic acid (cis-9-octadecenoic
acid) 18:1, 9 9: elaidic acid (trans-9-
octadecenoic acid) 22:1, 13 9: erucic acid (cis-13-docosenoic
acid) 24:1, 15 9: nervonic acid (cis-15-
tetracosenoic acid)
Unsaturated fatty acids
Trienoic acids (3 double bonds) 18:3;6,9,12 6 : -linolenic acid (all cis-
6,9,12-octadecatrienoic acid) 18:3; 9,12,15 3 : -linolenic acid (all-cis-
9,12,15-octadecatrienoic acid)
Tetraenoic acids (4 double bonds) 20:4; 5,8,11,14 6: arachidonic acid (all-
cis-5,8,11,14-eicosatetraenoic acid)
Unsaturated fatty acids Pentaenoic acid (5 double bonds)
20:5; 5,8,11,14,17 3: timnodonic acid or EPA (all-cis-5,8,11,14,17-eicosapentaenoic acid)*
Hexaenoic acid (6 double bonds) 22:6; 4,7,10,13,16,19 3: cervonic acid
or DHA (all-cis-4,7,10,13,16,19-docosahexaenoic acid)*
Both FAs are found in cold water fish oils
Waxes
Waxes are simple lipids which are esters of long chain alcohols and fatty acids. Beeswax is a 30 C alcohol connected to a 16 C fatty acid
Waxes are completely water resistant and make the coatings on leaves, skin, feathers, fur, and fruit. They can be used on floors and furniture for the same protecting quality.
4. Membrane lipids1) phospholipids- phosphoglyceride: phosphatidyl serine (ethanolamine,
choline, inositol)- sphingolipid: spingosine → sphingomyelin 2) glycolipids- sugar-containing lipids- cerebrosides- gangliosides3) cholesterol
CH2
CH
CH2
OH
OH
OH
C
R3
CH2
CH
H2C
OH
O
O
C
R1
C
R2
O
O
O
CH2 OC
CH O
C
O
R2
CH2 O
C
O
R3
R1
O
GLYCEROL
TRI ACYL GLYCEROL ( TRIGLYCERIDE)
Triacyl glycerol
BIOLOGICAL MEMBRANES
O
R
CH2
CH
CH2
O
O
O
O
R
P
O
OHOH
Glycerol phospholipids
O
R
CH2
CH
CH2
O
O
O
O
R
P
O
OOH
CH2
CH2
NH2
O
R
CH2
CH
CH2
O
O
O
O
R
P
O
OOH
CH2
CH2
N+
CH3
CH3CH3
O
R
CH2
CH
CH2
O
O
O
O
R
P
O
OOH
CH2
CH
NH2
COOH
O
R
CH2
CH
CH2
O
O
O
O
R
P
O
OH CH
CH
CH
CH
CH
CH
O
OH
OH
OH
OH
OH
O
R
CH2
CH
CH2
O
O
O
O
R
P
O
OOH
CH
CH
CH2
OH
HOOH
O
R
CH2
CH
CH2
O
O
O
O
R
P
O
OOH
CH
CH
CH2
OH
OHO
R
CH2
CH
CH2
O
O
O
O
R
P
O
OOH
Phosphotidyl serine
Phosphotidyl Inositol
Phosphatidyl glycerol
Diphosphatidylglycerol (cardiolipin)
H2C CH
H2C
O
O
O
O
O
P
O
OH
OH2C
H2C NH2
H2C CH
H2C
O
O
O
O
O
P
O
OH
OH2C
H2C N CH3
CH3
CH3
H2C CH
H2C
O
O
O
O
O
P
O
OH
O
HO OH
OH
OHHO
H2C CH
H2C
O
O
O
O
P
O
OH
NH2
CH CH2C
OH
OO
Phosphotidyl Ethanolamine
Phosphotidyl Choline
Phosphotidyl Inositol
Phosphotidyl Serine
H2C CH
H2C
OO
R
R
O
O
O
P
O
OH
O
CH2CHH2C
OO
R
R
O
O
O
P
O
OH
HC C
H
H2C OH
OH
OH
H2C CH
H2C
OO
R
R
O
O
O
P
O
OH
OHC C
H
H2C O
OH
OH
Phosphotidyl Glycerol
Diphosphotidyl Glycerol
Ether glycerophospholipids Possess an ether linkage instead of an
acyl group at the C-1 position of glycerol PAF ( platelet activating factor)
A potent mediator in inflammation, allergic response and in shock (also responsible for asthma-like symptom
The ether linkage is stable in either acid or base
Plasmalogens: cis ,-unsaturated ethers
The alpha/beta unsaturated ether can be hydrolyzed more easily
Ether glycerophospholipids
H2C CH
O
CH2
O
O
P
O
-O O
C O
CH3
CH2 CH2 N
CH3
CH3
CH3
platelet activating factor or PAF
H2C CH
O
CH2
O
O
P
O
-O O
C O
CH2 CH2 N
CH3
CH3
CH3
A choline plasmalogen
H
H
O
R
CH2
CH
CH2
O
O
O
O
R
P
O
OOH
X
Phospholipase A1Phospholipase A2
Phospholipase C
Phospholipase D
O
PALMITIC
CH2
CH
CH2
O
O
O
O
PALMITIC
P
O
OOH
CH2
CH2
N+
CH3
CH3CH3
SURFACTANT ( DIPALMITOYL PHOSPHATIDYL CHOLINE
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH
CHCH
CHCH2
OH
NH2
OH
CH2
CH3
CH3CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2C
O
OH
CH3CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2C
O
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH
CHCH
CHCH2
OHNH
OH
CH2
CH3
Sphingosine
Palmitic acid
+
Ceramide
R1 CH2
CH2
CH2C
NHR
CHCH
CHCH
CH2
O
OH
OH
Ceramide
Acylated Sphingosine
SPHINGOLIPIDS
R1
CH2
CH2
CH2
C
NH
R
CH
CH
CH
CH
CH2
O
OH
O
P
O
OHO
CH2
CH2
N+
CH3
CH3
CH3
Hydrophilic end
Hydrophobic end
CERAMIDE
SPHINGOMYELIN
OH
NH2
OH
O
OH
O
OHNH
OH
Sphingosine
Palmitic acid
+
Ceramide
R1
NHR
O
OH
OH
Ceramide
Acylated Sphingosine
SPHINGOLIPIDS
OH
NH2
OH
O
OH
O
OHNH
OH
Sphingosine
Palmitic acid
+
Ceramide
R1
R
O
OH
OH
Ceramide
Acylated Sphingosine
SPHINGOLIPIDS
SPHINGOLIPIDS
OH
CH2HC
CHCH
CH
(CH2)12
NH
CH3
O
C
RCH3
O
CH2
OH
O
OH OH
OH
OH
CH2CH
CHCH
CH
(CH2)12
NH
CH3
O
C
RCH3
O
CH2
OH
O
OH OH
OH
Galactocerebroside
Glucocerebroside
OH
CH2CH
CHCH
CH
(CH2)12
NH
CH3
O
C
RCH3
O
CH2
OH
O
OH OHO
CH2
OH
O
OH OH
OH
Lactosyl ceramide
O
CH2
OH
O
OH OH
OH
OH
CH2CH
CHCH
CH
(CH2)12
NH
CH3
CH2
C
RCH3
O
CH2
OH
O
OH OHO
CH2
OH
O
OH OH
Trihexosyl ceramide
CEREBROSIDES
R OH
NH
OH
R1
O
R1
CH2
CH2
CH2
C
NH
R
CH
CH
CH
CH
CH2
O
OH
O
O
H OH
HH
OH
H
OSO3H
H
OH
Some Galactocerebrosides are sulfated at position 3 of the galactose
(CH2)12
R NHO H2
CO
OH
O
O
OO
O
OH
CH2
HO
OH
OCH2
HOCH2
HO OH
O
OHNH
HO HO
OH
H2C
HO
Cer
GlcGal GalNAc
CO
CH3 Gal
O
NANA
Cer Glc Gal GalNAc Gal
GM1
GM2
GM3
NANA
GANGLIOSIDES
O
O
OH
OH
OH
O
OO
OH
OH
OH
OHO
OH
OH
OH OH
NH
O
OHO
OH
OH
NH
O
O
OH
OH
OH
O
OO
OH
OH
OH
OHO
O
OH
OH OH
NH
O
O
Globoside Gb3
Globoside Gb4
Blood Group A
Blood Group B
Blood Group O
Fuc(a1-2)
Gal(B1-4)
GalNAc(a1-3)
GalNAc(B) O Cer
Fuc(a1-2)
Gal(B1-4)
Gal(a1-3)
GalNAc(B) O Cer
Fuc(a1-2)
Gal(B1-4)GalNAc(B) O Cer
THE UNIVERSAL BLOOD GROUP ANTIGENS ARE SPHINGOLIPIDS WHICH ARE EXPRESSED ON THE SURFACE OF ERYTHROCYTES
13
149
810
1712
11
15
16
75
6
18
191
4
2
3H
H
HHO
CH CH2 CH2 CH2
CH3
HC
CH3
CH3
21
20 22 23 24 25
26
27
Polar Head Non polar Head
CHOLESTEROL
Steroids
Cholesterol is largely hydrophobic.
But it has one polar group, a hydroxyl, making it amphipathic.
C holestero lH O
Cholesterol, an important constituent of cell membranes, has a rigid ring system and a short branched hydrocarbon tail.
cholesterol PDB 1N83
Cholesterolin membrane
Cholesterol inserts into bilayer membranes with its hydroxyl group oriented toward the aqueous phase & its hydrophobic ring system adjacent to fatty acid chains of phospholipids.
The OH group of cholesterol forms hydrogen bonds with polar phospholipid head groups.
C holestero lH O
But the presence of cholesterol in a phospholipid membrane interferes with close packing of fatty acid tails in the crystalline state, and thus inhibits transition to the crystal state.
Phospholipid membranes with a high concentration of cholesterol have a fluidity intermediate between the liquid crystal and crystal states.
Cholesterolin membrane
Interaction with the relatively rigid cholesterol decreases the mobility of hydrocarbon tails of phospholipids.
OUT
IN
Peripheral proteins are on the membrane surface. They are water-soluble, with mostly hydrophilic surfaces. Often peripheral proteins can be dislodged by conditions that disrupt ionic & H-bond interactions, e.g., extraction with solutions containing high concentrations of salts, change of pH, and/or chelators that bind divalent cations.
Membrane proteins may be classified as: peripheral integral having a lipid
anchor
integral
lipid anchor
peripheral
lipid bilayer
Membrane Proteins
Integral proteins have domains that extend into the hydrocarbon core of the membrane.
Often they span the bilayer.
Intramembrane domains have largely hydrophobic surfaces, that interact with membrane lipids.
integral
lipid anchor
peripheral
lipid bilayer
Membrane Proteins
Some proteins bind to membranes via a covalently attached lipid anchor, that inserts into the bilayer.
A protein may link to the cytosolic surface of the plasma membrane via a covalently attached fatty acid (e.g., palmitate or myristate) or an isoprenoid group.
Palmitate is usually attached via an ester linkage to the thiol of a cysteine residue. A protein may be released from plasma membrane to cytosol via depalmitoylation, hydrolysis of the ester link.
lipid anchor
membrane
H3C (CH2)14 C
O
S CH2 CH
C
NH
O
palmitate
cysteine residue
An isoprenoid such as a farnesyl residue, is attached to some proteins via a thioether linkage to a cysteine thiol.
C H C H 2CH 3 C
C H 3
C H C H 2CC H 2
C H 3
C H C H 2 S P r o t e i nCC H 2
C H 3
f a r n e s y l r e s i d u e l i n k e d t o p r o t e i n v i a c y s t e i n e S
lipid anchor
membrane
Glycosylphosphatidylinositols (GPI) are complex glycolipids that attach some proteins to the outer surface of the plasma membrane.
The linkage is similar to the following, although the oligosaccharide composition may vary:
protein (C-term.) - phosphoethanolamine – mannose - mannose - mannose - N-
acetylglucosamine – inositol (of PI in membrane)
The protein is tethered some distance out from the membrane surface by the long oligosaccharide chain.
GPI-linked proteins may be released from the outer cell surface by phospholipases.
Lipid storage diseases
also known as sphingolipidoses genetically acquired due to the deficiency or absence of a catabolic
enzyme examples:
Tay Sachs disease Gaucher’s disease Niemann-Pick disease Fabry’s disease
http://www.ninds.nih.gov/disorders/lipid_storage_diseases/lipid_storage_diseases.htm
What are Lipid Storage Diseases?
Lipid storage diseases are a group of inherited metabolic disorders in which harmful amounts of fatty materials (called lipids) accumulate in some of the body’s cells and tissues. Over time, this excessive storage of fats can cause permanent cellular and tissue damage, particularly in the brain, peripheral nervous system, liver, spleen, and bone marrow. Lipid storage diseases are inherited from one or both parents who carry a defective gene. Symptoms may appear early in life or develop in the teen or even adult years. Neurological complications of the lipid storage diseases may include ataxia, eye paralysis, brain degeneration, seizures, learning problems, spasticity, feeding and swallowing difficulties, slurred speech, loss of muscle tone, hypersensitivity to touch, burning pain in the arms and legs, and clouding of the cornea
Genetic defects in ganglioside metabolism leads to a buildup of gangliosides
(ganglioside GM2) in nerve cells, killing them
NAcGal Gal Gal Glu
NAcNeu
enzyme that hydrolyzes here (beta hexosaminodase)is absent in Tay-Sachs disease
CER
Tay-Sachs disease
a fatal disease which is due to the deficiency of hexosaminidase A activity
accumulation of ganglioside GM2 in the brain of infants
mental retardation, blindness, inability to swallow
a “cherry red “ spot develops on the macula (back of the the eyes)
Tay-Sachs children usually die by age 5 and often sooner
Genetic defects in globoside metabolism Fabry’s disease:
Accumulation of ceramide trihexoside in kidneys of patients who are deficient in lysosomal -galactosidase A sometimes referred to as ceramide trihexosidase
Skin rash, kidney failure, pains in the lower extremities
Now treated with enzyme replacement therapy: agalsidase beta (Fabrazyme)
Genetic defects in cerebroside metabolism Krabbe’s disease:
Also known as globoid leukodystrophy Increased amount of galactocerebroside in the white
matter of the brain Caused by a deficiency in the lysosomal enzyme
galactocerebrosidase Gaucher’s disease:
Caused by a deficiency of lysosomal glucocerebrosidase Increase content of glucocerebroside in the spleen and
liver Erosion of long bones and pelvis Enzyme replacement therapy is available for the Type I
disease (Imiglucerase or Cerezyme) Also miglustat (Zavesca) – an oral drug which inhibits
the enzyme glucosylceramide synthase, an essential enzyme for the synthesis of most glycosphingolipids
Miglustat (Zavesca)
Genetic defects in ganglioside metabolism Metachromatic leukodystrophy
accumulation of sulfogalactocerebroside (sulfatide) in the central nervous system of patient having a deficiency of a specific sulfatase
mental retardation, nerves stain yellowish-brown with cresyl violet dye (metachromasia)
Generalized gangliosidosis accumulation of ganglioside GM1 deficiency of GM1 ganglioside: -galactosidase mental retardation, liver enlargement, skeletal
involvement
Niemann-Pick disease
principal storage substance: sphingomyelin which accumulates in reticuloendothelial cells
enzyme deficiency: sphingomyelinase
liver and spleen enlargement, mental retardation
Prostaglandins and other eicosanoids (prostanoids) local hormones, unstable, key
mediators of inflammation derivatives of prostanoic acid
COOH
20
8
12
prostanoic acid
9
1115
Prostaglandins
O R
O
O
OP
O
O
O-
X
O
COOH
CH3
phospholipase A 2 (enzyme that hydrolyzesat the sn-2 position - inhibitedindirectly by corticosteroids)
H20
prostaglandin synthase(also known as cyclooxygenase)
O
O
COOH
OH
very unstablebond
PGH2
COX is inhibibited byaspirin and other NSAIDs
O
O
COOH
OH
PGH2
COOH
OH
O
HO
COOH
OHHO
HO
PGE2 PGF2
key mediator of inflammation
O
R1
R2
O
R1
R2
PGA PGB
O
R1
R2
PGC
R1
R2
HO
OPGD
R1
R2
O
HO
R1
R2
HO
HO
R1
R2
O
O
PGE PGFa PGG and PGHR2
HO
O
R1
R1
R2
O
PGJ
R1
R2
O
O
PGK
PGI
O
O
R1
R2 O
R1
R2HO
OH
TXA TXB
SUBSTITUTION PATTERN OF PROSTANOIDS
Prostacyclins, thromboxanes and leukotrienes PGH2 in platelets is converted to
thromboxane A2 (TXA2) a vasoconstrictor which also promotes platelet aggregation
PGH2 in vascular endothelial cells is converted to PGI2, a vasodilator which inhibits platelet aggregation
Aspirin’s irreversible inhibition of platelet COX leads to its anticoagulant effect
Functions of eicosanoids
Prostaglandins – particularly PGE1 – block gastric production and thus are gastric protection agents
Misoprostol (Cytotec) is a stable PGE1
analog that is used to prevent ulceration by long term NSAID treatment
PGE1 also has vasodilator effects Alprostadil (PGE1) – used to treat infants
with congenital heart defects Also used in impotance (Muse)
Functions of eicosanoids
PGF2 – causes constriction of the uterus Carboprost; “Hebamate” (15-Me-PGF2) –
induces abortions
PGE2 is applied locally to help induce labor at term
C5H11
COOHO
LEUKOTRIENE A 4 (LTA 4)
C5H11
HO
COOH
OH
LEKOTRIENE B 4 (LTB4)
Non-peptidoleuktrienes: LTA4 is formed by dehydration of5-HPETE, and LTB4 by hydrolysis of the epoxide of LTA4
Leukotrienes
Biological activities of leukotrienes
1. LTB4- potent chemoattractent- mediator of hyperalgesia- growth factor for keratinocytes
2. LTC4- constricts lung smooth muscle- promotes capillary leakage
1000 X histamine3. LTD4 - constricts smooth muscle;
lung- airway hyperactivity- vasoconstriction
4. LTE4- 1000 x less potent than LTD4(except in asthmatics)
C5H11
H S
Cys
gGlu
OH
COOH
LEUKOTRIENE F4 (LTF4)
C5H11
H S
Cys
OH
COOH
Gly
gGlu
LEUKOTRIENE C4 (LTC4)
Leukotrienes are derived from arachidonic acid via the enzyme 5-lipoxygenase which converts arachidonic acid to 5-HPETE (5-hydroperoxyeicosatetranoic acid) and subsequently bydehydration to LTA4
peptidoleukotrienes
Leukotrienes
C5H11
H S
Cys
OH
COOH
LEUKOTRIENE E 4 (LTE4)
C5H11
H S
Cys
OH
COOH
Gly
LEUKOTRIENE D 4 (LTD4)
Leukotrienes are synthesized in neutrophils, monocytes, macrophages,mast cells and keratinocytes. Also in lung, spleen, brain and heart.A mixture of LTC4, LTD4 and LTE4 was previously known as theslow-reacting substance of anaphylaxis
peptidoleukotrienes
Leukotrienes
