Lipid Chemistry - Bio Synthesis of Fatty Acid

8/4/2019 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



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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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2. Acetyl group attacks the methylene groupof the malonyl residue

CO2

3- ketoacyl enzyme


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3. 3-Ketoacyl group= reduced,dehydrated,reduced again

corresponding acylS- enzymes


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4. sequence repeated 6X

16-carbon acyl radical assembled

Thioesterase

FREE PALMITATE


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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



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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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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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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

Lipid Chemistry - Bio Synthesis of Fatty Acid

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Lipid Chemistry - Bio Synthesis of Fatty Acid