lipid chemistry - bio synthesis of fatty acid
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LIPIDCHEMISTRY
Maria Theresa Llamas- Carin MDDepartment of BIOCHEMISTRY
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Lipids Heterogenous group of
compounds
( fats, oils, steroids, waxes)
COMMON PROPERTIES:
1. Insoluble in water
2. Soluble in Non-polar solvents
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LIPIDS1. The ELEMENTS found in Lipids areCARBON, HYDROGEN and OXYGEN.
2. The SMALLEST MOLECULES used to make Lipids
are: GLYCEROL plus 3 FATTY ACIDS.
3. GLYCEROL - simple molecule with just
three carbons and three OH-groups.
- colourless, gunky liquid sometimescalled 'glycerine'
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ACIDS in biological chemistry are anymolecule with the -COOH (Carboxyl)group
FATTY ACIDS are acids with VERY LONGHYDROCARBON CHAINS ATTACHED(more than 16 carbons in the chain for the
molecule to considered a FATTY acid).
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Three fatty acids bond to the glycerol in aTRIPLE CONDENSATION REACTION toform a standard TRIGLYCERIDE LIPID heldtogether by three ESTER BONDS
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BIOMEDICAL IMPORTANCE
1.Dietary constituents
2.Thermal insulator
3. Electrical insulators 4. Cellular constituents( lipoprotein)
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CLASSIFICATION
1. SIMPLE
2. COMPLEX
3. PRECURSOR and DERIVED lipids
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CLASSIFICATION
1.SIMPLE esters of FA with various
alcohols
a. Fats EFA with glycerol
b. Waxes EFA with higher
molecular weight monohydric
alcohols
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Classification
2. COMPLEX EFA containing groups
in addition to an alcohol and a FA
a. Phospholipids + phosphoric acid
residue/ nitrogen-containing bases
(ex.glycerophospholipids/sphingophospholipids)
b. GlycolipidsFA +sphingosine + CHO
c. Other complex lipids lipoproteins/
sulfolipids/ aminolipids
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COMPLEX LIPIDS
PHOSPHOLIPIDS
- lipids + FA + alcohol +
phosphoric acid residue
- have nitrogen-containing
bases + other substances
eg. Glycerophospholipids
Sphingophospholipids
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PHOSPHOLIPID
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PHOSPHOLIPIDS
Main lipid constituents of membranes
Derivatives of phosphatidic acid phosphateesterified with theOH of a suitable alcohol
A. PHOSPHATIDYLCHOLINES(lecithin)
B. PHOSPHATIDYLETHANOLAMINE (cephalins)
C. PHOSPHATIDYLINOSITOL
D. DIPHOSPHATIDYLGLYCEROL ( cardiolipin)
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PHOSPHATIDYLCHOLINES
Most abundant phospholipids of cellmembrane
Large proportion of the bodys store of
choline
*Choline= nervous transmission
*Dipalmitoyl lecithin= surface active
agent/ major constituent of surfactant
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PHOSPHATIDYLINOSITOL
Precursor of second messengers
Phosphatidylinositol 4,5-biphosphate
diacylglycerol inositol triphosphate
(internal signals or second messengers)
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DIPHOSPHATIDYLGLYCEROL
Major lipid of mitochondrial membranes
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GLYCOLIPIDS
Glycosphingolipids
Nervous tissues
Outer leaflet of plasma membranes (contribute tocell surface carbohydrates)
A. Galactoceramides
B. Glucosylceramides
C. Gangliosides
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GLYCOLIPIDS
GALACTOSYLCERAMIDES
-major glycolipid of brain/ nervous tissue
GLUCOSYLCERAMIDES
-extraneural tissues
GANGLIOSIDES
- nervous tissues
- complex glycosphingolipids derived from
glucosylceramide plus sialic acid
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Classification
3. Precursor and derived lipids
- FA, glycerol, steroids, other alcohols,
fatty aldehydes, ketone bodies,hydrocarbons, lipid-soluble vitamins,
hormones
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FA subdivided:
1.UNSATURATED
a. Monounsaturated = one double bond
b. Polyunsaturated= 2 or more (=)
2.SATURATED = none
3. EICOSANOIDS= 20-carbon polyenoic
FA ( prostanoidsprostaglandins,
prostacyclins,thromboxanes;
leukotrienes; lipoxins)
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POLYUNSATURATED FATTYACIDS
ESSENTIAL PUFAS
1. LINOLEIC ACID
2. -LINOLENIC ACID
3. ARACHIDONIC ACID ( can be
formed from Linoleic acid)
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SATURATED FATTY ACIDS
Symbol common name systematic
name
structure mp(C)
12:0 Lauric acid dodecanoicacid
CH3(CH2)10COOH
44.2
14:0 Myristic acid tetradecanoic
acid
CH3(CH2)12CO
OH
52
16:0 Palmitic acid Hexadecanoicacid
CH3(CH2)14COOH
63.1
18:0 Stearic acid Octadecanoicacid
CH3(CH2)16COOH
69.6
20:0 Arachidic aicd Eicosanoic acid CH3(CH2)18COOH
75.4
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UNSATURATED FATTY ACIDS
Symbol common name systematic name structure mp(C
)
16:1D9 Palmitoleic acid Hexadecenoic acid CH3(CH2)5CH=CH-(CH2)7COOH-0.5
18:1D9 Oleic acid 9-Octadecenoic acid CH3(CH2)7CH=CH-(CH2)7COOH13.4
18:2D9,12
Linoleic acid 9,12 -Octadecadienoic acid CH3(CH2)4(CH=CHCH2)2(CH2)6COOH
-9
18:3D9,12,15 a-Linolenic acid 9,12,15 -Octadecatrienoic acid
CH3CH2(CH=CHCH2)3(CH2)6COOH
-17
20:4D5,8,11,14 arachidonic acid 5,8,11,14-Eicosatetraenoic acid
CH3(CH2)4(CH=CHCH2)4(CH2)2COOH
-49
20:5D5,8,11,14,17
EPA 5,8,11,14,17-Eicosapentaenoic-acid
CH3CH2(CH=CHCH2)5(CH2)2COOH
-54
22:6D4,7,10,13,16,19
DHA Docosohexaenoicacid
22:6w3
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Triglycerides Triacylglycerol
Main storage forms of
FA
Esters of the trihydricalcohol glycerol and FA
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CHOLESTEROL
-Best known steroid
Major constituent of the plasma membraneand of plasma lipoproteins
Precursor of large number of steroids bileacids, adrenocortical hormones, sexhormones, D vitamins, cardiac glycosides
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Sources of dietarycholesterol
Richest egg yolk, mayonnaise and shell fish.
Moderate Fat on meat, duck, goose, cold cuts,
whole milks, cream, ice cream, cheese,butter and most commercially madecakes, biscuits and pastries.
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Cholesterol sources
Poor
All fish and fish canned in vegetable oil, verylean meats, poultry without skin, skimmedmilk, low fat yoghurt and cottage cheese.
Cholesterol free
All vegetables, and vegetable oils, fruit(including avocados and olives), nuts, rice,
egg white and sugar.
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LIPID METABOLISM
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LIPID METABOLISM
1.fatty acid activation and oxidation
2. fatty acid synthesis
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LIPID METABOLISM
1.fatty acid synthesis
2.fatty acid activation and oxidation
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BIOSYNTHESIS OF FATTY ACIDS
Synthesized by an extramitochondrial system
Complete synthesis of PALMITATE fromACETYL CoA
CYTOSOL
Liver, kidney, brain, lung, mammary gland,adipose tissue
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BIOSYNTHESIS OF FATTY ACIDS
Co-factor requirements:
- NADPH, ATP, Mn++, Biotin, HCO2
ACETYL CoA = immediate substrate
FREE PALMITATE = end product
Production of MALONYL CoA = initial andcontrolling step
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FA biosynthesis
Formation of long chain FA stored in adipose
ACETYL CoA
- provides all the carbon atoms
- made from pyruvate in mitochondria
- needs to get enter into the cytoplasm
( as CITRATE ; enz: ATP CITRATE
LYASE)
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ORIGIN OF CYTOPLASMIC
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ORIGIN OF CYTOPLASMICACETYL CoA
Pyruvate oxaloacetate malate
pyruvate ( enters the mitochondria)
oxaloacetate ACETYL CoA
M i f NADPH f
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Main sources of NADPH forlipogenesis
1. Pentose phosphate pathway
2. Malic enzyme
3. Isocitrate dehydrogenase
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Biosynthesis of FA
2 enzyme systems
a.Acetyl CoA carboxylase (ACC)
b. Fatty acid synthase (FAS)
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1. Transport
Mitochondrial acetylCoA out ofmitochondria and intocytosol via citratetransport system (alsoproduces one NADPHin the cytosol as aresult)
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2. Carboxylation ofAcetyl CoA
acetyl CoA +
HCO3- malonyl CoA viaacetyl CoA
carboxylase biotin co-factor
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3.Assembly of fatty acid chain by fatty acidsynthase
a. loading of acetyl CoA and malonyl CoA onto Acyl
Carrier Proteins (ACP)b. condensation of acetyl ACP and malonyl ACP
c. reduction
d. dehydratione. reduction
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Fatty acid synthase
Multienzyme complex of one polypeptidechain with 7 separate enzyme activities andan acyl protein carrier (ACP)
ACP contains phosphopantotheinemoietycarrying the intermediates of FA synthesis
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Fatty acid elongation: steps
1. a. Acetyl CoA combines withSH
group (nz. Acetyl transcyclase)
b. Malonyl combines withSH onphosphopantotheine of ACP
( nz. Malonyl transcyclase)
ACETYL (ACYL)-MALONYL ENZ.
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Fatty acid elongation: steps
2. Acetyl group attacks the methylene groupof the malonyl residue
CO2
3- ketoacyl enzyme
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Fatty acid elongation: steps
3. 3-Ketoacyl group= reduced,dehydrated,reduced again
corresponding acylS- enzymes
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Fatty acid elongation: steps
4. sequence repeated 6X
16-carbon acyl radical assembled
Thioesterase
FREE PALMITATE
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Fatty acid elongation: steps
Fates of free palmitate
1. esterification into acylglycerol
2. chain elongation / desaturation
3. esterification to cholesteryl esters
BIOSYNTHESIS OF FATTY
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OS S S OACIDS
CO2
Acetyl CoA Malonyl CoA
PALMITATE
Overall synthesis of palmitate
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Overall synthesis of palmitatefrom acetyl and malonyl CoA
AcetylCoA + 7 malonylCoA + 14 NADPH +
14 H+ Palmitic + 7CO2 + 6H2O + 8Coenz A +14NADP
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Regulation of LIPOGENESIS
1. Nutritional state = main factor
- excess CHO, pyruvate,lactate, acetyl
CoA stored as fat
- rate is high in well-fed state;
depressed in DM
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Regulation of LIPOGENESIS
2. ACETYL CoA CARBOXYLASE
- most important enzyme
- activated from an inactive dimer to
an active polymeric form by
CITRATE
- regulated by glucagon, epinephrine,insulin
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INSULIN
Ability to depress the level of intracellularcAMPinhibits LIPOLYSIS in adiposereduces the concentration of plasma FFA and
long chain acylCoA
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INSULIN
Depress cAMP inhibits lipolysis
plasma FFA
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LIPID METABOLISM
1. fatty acid synthesis
2.fatty acid activation and oxidation
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FATTY ACID OXIDATIONNOT THE SIMPLEREVERSEOF FATTY ACID SYNTHESIS
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Fatty acid oxidation
Involves Acyl CoA derivatives catalyzed byseparate enzymes
NAD+ and FAD+
Generates ATP
Aerobic process
mitochondria
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Fatty acid oxidation
FFA unesterified state
- 1. converted to active intermediate
( Acyl-CoA synthetase or Thiokinase)- 2. Long chain acylCoA enters
mitochondria by Carnitine Palmitoyl
Transferase I ACYLCARNITINE
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Enzyme systems
FA converted to active FA (acyl-CoA) by acylCoA synthetase( ATP and CoA)
Carnitine palmitoyltransferase 1 (outer
mitochondrial membrane)
Carnitine-acylcarnitine translocase
Carnitine palmitoyl transferase 11
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Fatty acid oxidation
FFA-
3. Acylcarnitine enters inner
membrane BETA OXIDATION
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BETA oxidation Fatty acid
FATTY acid oxidase- mitochondrial matrix- acyl CoA Acetyl CoA
Steps:1.Removal of 2 H+ from 2() , 3() C
- requires FADtransenoyl-CoA +FADH
2. Water added to saturate double bond 3-hydroxyacyl-CoA
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Beta oxidation of FA
Steps:3. 3-Hydroxy derivative undergoes
dehydrogenation 3-Ketoacyl CoA- involves NAD+
4. 3-Ketoacyl CoA split at 2,3 position(nz.Thiolase) Acetyl CoA + new Acyl CoA2 carbons shorter re enters oxidative
pathway.
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B t
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Betaoxidation of fattyacids
FATES of Acetyl CoA formed
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yby beta Oxidation
1. From glycolysis oxidized to CO2 and H2Ovia citric acid cycle
2. Precursor for synthesis of cholesterol and
other steroids
3. In the liver, it forms ketone bodies
( acetone, acetoacetate,
3-hydroxybutyrate)
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Oxidation of FA with ODD #
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Carbon
Acetyl CoA + Propionyl CoA
Succinyl CoA
(constituent of citric acid cycle)
*Propionyl residue is the only part of a FA that is glucogenic
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Oxidation of FA produces a
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plarge quantity of ATP
A.Transport in the respiratory chain ofelectrons from FADH2 and NADH yields 5high energy phosphates for each of the first 7
acetyl CoA formed by Beta oxidation ofPALMITATE
( 7 x5 = 35)
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Oxidation of FA produces a
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plarge quantity of ATP
2. A total of 8 mol of acetyl CoA formed andeach give rise to 12 mol of ATP on oxidationin the citric acid cycle
( 8 X 12 = 96)
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-Oxidation and Synthesis
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y