Metabolism of Lipids 1

8/2/2019 Metabolism of Lipids 1

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METABOLISM OF LIPIDS:DIGESTION OF LIPIDS. TRANSPORT

FORMS OF LIPIDS


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PHYSIOLOGICAL ROLE OF LIPIDS

Energetic role(fuelmolecules)Components of membranes(structural role)Precursors for many

hormones(steroids)Signal molecules(prostaglandins)Protective role(lipids

surround important organs)Enzyme cofactors(vitamin K)Electron carriers(ubiquinone)Insulation againsttemperature extremes


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TRIACYLGLYCEROLS ARE HIGHLYCONCENTRATED ENERGY STORES

Triacylglycerols (TGs) and glycogen -two major forms of stored energy

TGs which are more efficient energystores because:

(1) They are stored in an anhydrous form(2) Their fatty acids are more reducedthan monosaccharides.


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Fat breakdownabout 50 % of energy in liver, kidney and skeletal

muscles up to 95 % of energy cardiac muscleFats are the major source of energy for:fasting animal organism in diabetes

1 g of triacylglycerols stores more than six times

as much energy as a 1 g of glycogen Glycogen reserves are depleted in 12 to 24 hours

after eating, triacylglycerols within severalweeks.


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Fatty acids and glycerol -substances that are directly usedas a fuel by mammalian organisms.

Fatty acids (FA) and glycerol formetabolic fuels are obtainedfrom triacylglycerols:

(1) In the diet(2) Stored in adipocytes (fatstorage cells)

Free fatty acids occur only in

trace amounts in cells

For supplying of fatty acids as a fuel for organism, thetriacylglycerols have to be digested


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DIGESTION OF DIETARY LIPIDS

Lipids in diet:

triacylglycerolsphospholipidscholesterol

Digestionin small intestine.

Enzyme pancreaticlipase.Lipase catalyzes hydrolysis at the C1 and C3 positions ofTGs producing free fatty acidsand 2-monoacylglycerol.


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Colipase protein which is present in the intestine and helpsbind the water-soluble lipase to the lipid substrates.

Colipase also activates lipase.

Bile salts (salts of bile acids) are required for lipids digestion.Bile salts are synthesized in the liver from cholesterol.

Taurocholateandglycocholate- the most abundant bile salts.

Amphipathic: hydrophilic (blue) and hydrophobic (black)


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Bilesalts also activates the lipase.

Inadequate production of bile salts results insteatorrhea.


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Dietary phospholipids are degraded byphospholipases

Lysophospho-glycerides areabsorbed and in

the intestinalcells arereesterifiedback to glycero-

phospholipids.

Phospholipasesare synthesized in the pancreas.

Major phospholipase isphospholipase A2(catalyses thehydrolysis of ester bond at C2 of glycerophospholipidsand lysophosphoglycerides are formed).


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Lysophosphoglycerides can act as detergentand therefore in high concentration can

disrupt cellular membranes.Lysophosphoglyceride is normally present incells in low concentration.

Snake venom containphospholipase A

2

andcauses the lysis oferythrocytesmembranes.


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Dietary cholesterol

Most dietary cholesterol is unesterified

Cholesteryl esters are hydrolyzed in the intestine byan intestinal esterase

Free cholesterol is solublized by bile-salt micelles for

absorption After absorption in the intestinal cells cholesterolreact with acyl-CoA to form cholesteryl ester.


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ABSORPTION OF DIETARY LIPIDS

2-monoacylglycerols, fatty acids,lysophosphoglycerides, free cholesterol formmicelles with bile salts.

Lipid absorptionpassive diffusion process.


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Micelles migrate to the microvilli and lipids diffuseinto the cells.

Bile acids are actively absorbed and transferredto the liver via portal vein.

Bile salts can circulate through intestine and liverseveral time per day.


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In the intestinal cells the fatty acids are converted to fattyacyl CoA molecules.

Three of these molecules can combine with glycerol, or two

with monoacylglycerol, to form a triacylglycerols.

CH2

CH

CH2

OH

OH

O C

O

R2 R1 CO SCoA

CH2

CH

CH2

O

OH

O C

O

R2

C

O

R1

HSCoA

CH2

CH

CH2

O

OH

O C

O

R2

C

O

R1

HSCoA

R3 COSCoA

CH2

CH

CH2

O

O

O C

O

R2

C

O

R1

C

O

R3

+ +

++

1.

2.

1-st reaction is catalyzed by monoacylglycerol acyltransferase

2-nd reaction is catalyzed by diacylglycerol acyltransferase


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These lipids assemblewith phospholipids andapoproteins(apolipoproteins) toform spherical

particles calledlipoprotein

Structure:Hydrophobic core:

-TGs,-cholesteryl estersHydrophilic surfaces:-cholesterol,-phospholipids,

-apolipoproteins

TRANSPORT FORMS OF LIPIDS TGs, cholesterol and cholesterol esters are insoluble in waterand cannot be transported in blood or lymph as free molecules


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The main classes of lipoproteins

1.Chylomicrons.

2.Very low density lipoproteins (VLDL).3.Intermediate density lipoproteins (IDL).

4.Low density lipoproteins (LDL).

5.High density lipoproteins (HDL).


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are the largest lipoproteins (180 to 500 nm in diameter)

are synthesized in the ERof intestinal cells

contain 85 % of TGs (it is the main transport form of dietary TGs). apoprotein B-48(apo B-48)is the main protein component

deliver TGs from the intestine (via lymph and blood) to tissues (musclefor energy, adipose for storage).

bind to membrane-bound lipoproteinlipase(at adipose tissue and

muscle), where the triacylglycerols are again degraded into free fattyacids and monoacylglycerol for transport into the tissue

are present in blood only after feeding

Chylomicrons

exocytosisLymphatic

vessel


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VLDL are formed in the liver

contain 50 % of TGs and 22 % of cholesterol

two lipoproteins

apo B-100 and apo E the main transport form of TGs synthesized in the organism (liver)

deliver the TGs from liver to peripheral tissue (muscle for energy,adipose for storage)

bind to membrane-bound lipoproteinlipases(triacylglycerols are againdegraded into free fatty acids and monoacylglycerol)

Apo BApo E

triacylglycerol

cholesteryl esters

phospholipidscholesterol


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Lipoproteinlipase enzyme which is located withincapillaries of muscles and adipose tissue

Function:hydrolyses of TGs of chylomicrons and VLDL.Formed free fatty acids and glycerol pass into the cells

Chylomicrons and VLDL which gave up TGs are called remnantsof chylomicrons and remnants of VLDL

Remnants are rich in cholesterol esters

Remnants of chylomicrons are captured by liver

Remnants of VLDL are also called intermediate density

lipoproteins (IDL)Fate of the IDL:- some are taken by the liver- others are degraded to thelow density lipoproteins (LDL)(by the removal of more triacylglycerol)


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LDL

LDL are formed in the blood from IDL and in liver from IDL(enzyme liver lipase)

LDL are enriched incholesterol andcholesteryl esters(contain about 50 % ofcholesterol)

Protein component - apoB-100

LDL is the majorcarrier of cholesterol(transport cholesterolto peripheral tissue)


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Cells of all organs have LDL receptors

Receptors for LDL are localized in specialized regions calledcoated pits, which contain a specialized protein called clathrin

Apo B-100 on the surface of an LDL binds to the receptor

Receptor-LDL complex enters the cell by endocytosis.

Endocytic vesicle is formed


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Vesicle fuse with lysosomes

Lysosomal lipasesandproteasesdegrade LDL

LDL receptor itself returns to the plasma membrane

Apo B-100 is hydrolyzed to amino acids

Cholesteryl esters are hydrolyzed to free cholesterol and

fatty acidsReleased free cholesterol:

- is incorporated into the membranes or- is reesterified for storage inside the cell by the enzyme

acyl CoA:cholesterol acyltransferase (ACAT)Feedback regulation:

abundance of intracellular cholesterol suppresses thesynthesis of LDL receptors and so the uptake of additionalcholesterol from plasma LDL is blocked

k


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LDL uptake by receptor-mediated endocytosis


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congenital disease when LDL receptor are not synthesized (mutation at asingle autosomal locus)

the concentration of cholesterol in blood markedly increases

severe atherosclerosis is developed (deposition of cholesterol in arteries)

nodules of cholesterol called xanthomas areprominent in skin and tendons

most homozygotes die of coronary artery disease in childhood

the disease in heterozygotes (1 in 500 people) has a milder and more

variable clinical course

Familial hypercholesterolemia

atherosclerosis

xanthomas

HDL


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HDL are formed in the liver and partially in small intestine

contain the great amount of proteins (about 40 %)

pick up thecholesterol fromperipheral tissue,

chylomicrons andVLDL

enzymeacyltransferaseinHDL esterifies

cholesterols,convert it tocholesterol estersand transport tothe liver


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High serum levels of cholesterolcause disease and death bycontributing to development of

atherosclerosisCholesterol which is present in theform of the LDL is so-called "badcholesterol."

Cholesterol in theform of HDL isreferred to as "good

cholesterol

HDLfunctions as ashuttle that movescholesterol

throughout the body


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The ratio of cholesterol in the form of LDL to that in theform of HDL can be used to evaluate susceptibility tothe development of atherosclerosis

LDL/HDL Ratio

For ahealthyperson,theLDL/HDL

ratio is3.5

T t F f Li id


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Transport Forms of Lipids


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LIPID METABOLISM:MOBILIZATION OFTRIACYLGLYCEROLS;

OXIDATION OFGLYCEROL

S d M bili i f


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TGs are delivered to adiposetissue in the form ofchylomicrones and VLDL,hydrolyzed by lipoprotein

lipaseinto fatty acids andglycerol, which are taken upby adipocytes.

Then fatty acids arereesterified to TGs.

TGs are stored in adipocytes. To supply energy demands

fatty acids and glycerol arereleased mobilisation of

TGs.

Storage and Mobilization ofFatty Acids (FA)

adipocyte

l h l (


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TGhydro-

lysis isinhibitedby insulinin fed

state

At low carbohydrate and insulin concentrations (duringfasting), TG hydrolysis is stimulated by epinephrine,norepinephrine, glucagon,andadrenocorticotropic

hormone.


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Lipolysis - hydrolysis oftriacylglycerols by lipases.A hormone-sensitive lipaseconverts TGs to free fattyacids and monoacylglycerolMonoacylglycerol ishydrolyzed to fatty acidand glycerol or by ahormone-sensitive lipaseor

by more specific and moreactive monoacylglycerollipase


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Fatty acids and glycerol diffusethrough the adipocyte membrane andenter bloodstream.

Glycerol is transported via the bloodin free state and oxidized or convertedto glucose in liver. Fatty acids are traveled bound toalbumin. In heart, skeletal muscles and liverthey are oxidized with energy release.

Transport of Fatty Acids and Glycerol

d f Gl l


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Oxidation of Glycerol

Glycerol is absorbed by the liver.

Steps: phosphorylation, oxidation and isomerisation.Glyceraldehyde 3-phosphate is an intermediate in:glycolytic pathway gluconeogenic pathways


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Isomerase


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ATP Generation from Glycerol Oxidation

glycerol

glycerol 3-phosphate - 1 ATPglycerol 3-phosphate - dihydroxyacetonphosphate 2.5ATP (1 NADH)

glyceraldehyde 3-phosphate pyruvate4,5 ATP (1NADH + 2 ATP)

pyruvate acetyl CoA 2.5 ATP (1 NADH)

acetyl CoA in Krebs cycle

10 ATP (3NADH + 1 FADH2 + 1GTP)Total 19,5-1 = 18,5 ATP


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LIPIDMETABOLISM:

FATTY ACIDOXIDATION


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(1) Activation of fatty acids takes placeon the outer mitochondrial membrane

(2) Transport into the mitochondria

(3) Degradation to two-carbonfragments (as acetyl CoA) in themitochondrial matrix(b-oxidationpathway)

Stages of fatty acid oxidation

(1) A ti ti f F tt A id


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(1) Activation of Fatty Acids Fatty acids are converted to CoA thioesters byacyl-CoA synthetase(ATP dependent)

The PPi released is hydrolyzed by apyrophosphataseto 2 Pi

Two phosphoanhydride bonds (two ATP equivalents)are consumed to activate one fatty acid to athioester

(2) Transport of Fatty Acyl CoA into Mitochondria


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The carnitine shuttlesystem.

Fatty acyl CoA is firstconverted to acylcarnitine(enzymecarnitineacyltransferase I(bound tothe outer mitochondrialmembrane).

Acylcarnitine enters the

mitochondria by atranslocase.

The acyl group is transferredback to CoA (enzyme -carnitine acyltransferase II).

(2) Transport of Fatty Acyl CoA into Mitochondria


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Carnitineshuttlesystem

Path ofacyl groupin red


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The b-oxidation pathway (b-carbon atom (C3)is oxidized) degrades fatty acids two carbonsat a time

b

(3) The Reactions of b oxidation


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1.Oxidation of acylCoA by an acyl CoAdehydrogenaseto

give an enoyl CoA

Coenzyme - FAD


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2. Hydration of thedouble bond betweenC-2 and C-3 by enoylCoA hydratasewith

the 3-hydroxyacylCoA (b-hydroxyacylCoA) formation


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3. Oxidation of3-hydroxyacyl CoA to3-ketoacyl CoA by

3-hydroxyacyl CoAdehydrogenase

Coenzyme NAD+


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4. Cleavage of3-ketoacyl CoA by

the thiol group ofa second moleculeof CoA with theformation of

acetyl CoA and anacyl CoAshortened by two

carbon atoms.

Enzyme -b-ketothiolase.


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The shortened acyl

CoA thenundergoes anothercycle of oxidation

The number ofcycles: n/2-1,

where n

thenumber of carbonatoms

Fatty acyl CoA

-Oxidation of


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Fatty acyl CoA-Oxidation ofsaturated fatty

acids


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One round of b oxidation: 4 enzyme stepsproduce acetyl CoA from fatty acyl CoA

Each round generates one molecule each of:FADH2NADH

Acetyl CoAFatty acyl CoA (2 carbons shorter each round)

Fates of the products of b-oxidation:- NADH and FADH2 - are used in ETC- acetyl CoA - enters the citric acid cycle- acyl CoA undergoes the next cycle of oxidation

ATP Generation from Fatty Acid Oxidation


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ATP Generation from Fatty Acid Oxidation

The balanced equation for oxidizing one palmitoylCoA by seven cycles of b oxidation

Palmitoyl CoA + 7 HS-CoA + 7 FAD+ + 7 NAD+ + 7 H2O

8 Acetyl CoA + 7FADH2 + 7 NADH + 7 H+

ATP generated

8 acetyl CoA 10x8=807 FADH2 7x1.5=10.5

7 NADH 7x2.5=17.5108 ATP

ATP expended to activate palmitate -2

Net yield: 106 ATP

Net yield of ATP per one oxidized palmitate

Palmitate (C15H31COOH) - 7 cycles

n/2-1

LIPID METABOLISM


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LIPID METABOLISM:FATTY ACIDOXIDATION


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Odd-chain fatty acidsoccur in bacteria andmicroorganisms

Final cleavage product ispropionyl CoA ratherthan acetyl CoA

Three enzymes convertpropionyl CoA to succinylCoA (citric acid cycleintermediate)

b-OXIDATION OF ODD-CHAIN FATTY ACIDS

Propionyl CoA Is Converted into Succinyl CoA


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Propionyl CoA Is Converted into Succinyl CoA

1.Propionyl CoA is carboxylated to yield the D

isomer of methylmalonyl CoA.The hydrolysis of an ATP is required.Enzyme:propionyl CoA carboxylaseCoenzyme:biotin


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2. The D isomer of methylmalonyl CoA is

racemized to the L isomerEnzyme: methylmalonyl-CoA racemase


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3. L isomer of methylmalonyl CoA is convertedinto succinyl CoA by an intramolecular

rearrangementEnzyme: methylmalonyl CoA mutaseCoenzyme: vitamin B12 (cobalamin)

OXIDATION OF FATTY ACIDS IN


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OXIDATION OF FATTY ACIDS INPEROXISOMES

Peroxisomes -organelles containingenzyme catalase, which catalyzesthe dismutation of hydrogenperoxide into water and molecular

oxygen Acyl CoAdehydrogenasetransfers electronsto O2to yield H2O2

instead ofcapturing the high-energy electrons byETC, as occurs inmitochondrial b-oxidation.

METABOLISM OF


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METABOLISM OFLIPIDS:

SYNTHESIS OFFATTY ACIDS


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Fatty Acid Synthesis

Occurs mainly in liver and adipocytes, inmammary glands during lactation

Occurs in cytoplasm

FA synthesis and degradation occur bytwo completely separate pathways

When glucose is plentiful, large amountsof acetyl CoA are produced by glycolysisand can be used for fatty acid synthesis


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Three stages of fatty acidsynthesis:

A. Transport of acetyl CoA intocytosol

B. Carboxylation of acetyl CoA

C. Assembly of fatty acid chain

A T f A l C A


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A. Transport of Acetyl CoA tothe Cytosol

Acetyl CoA from catabolism ofcarbohydrates and amino acids is

exported from mitochondria via thecitrate transport system

Cytosolic NADH also converted to NADPH

Two molecules of ATP are expended foreach round of this cyclic pathway

Citrate transport


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psystem

Sources of NADPH for Fatty Acid Synthesis


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Sources of NADPH for Fatty Acid Synthesis

1. One molecule of NADPH is generated for eachmolecule of acetyl CoA that is transferred frommitochondria to the cytosol (malic enzyme).

2. NADPH molecules come from the pentosephosphate pathway.

B Carboxylation of Acetyl CoA


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B. Carboxylation of Acetyl CoA

Enzyme:acetyl CoA carboxylase

Prosthetic group - biotin

A carboxybiotin intermediate is formed.ATP is hydrolyzed.The CO2 group in carboxybiotin is transferred toacetyl CoA to form malonyl CoA.

Acetyl CoA carboxylaseis the regulatory enzyme.

C. The Reactions of Fatty Acid Synthesis


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. f F y y Five separate stages:(1) Loadingof precursors via thioester

derivatives(2) Condensationof the precursors(3) Reduction(4) Dehydration(5) Reduction

During the fatty acid synthesis all intermediates are linkedh ll d l ( P H) h h


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to the protein called acyl carrier protein (ACP-SH),whichis the component offatty acyl synthase complex.

The pantothenic acid isa component of ACP.

Intermediates in the

biosynthetic pathwayare attached to thesulfhydryl terminus ofphosphopantotheinegroup.

The elongation phase of fatty acid synthesis starts with


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g p y ythe formation of acetyl ACP and malonyl ACP.

Acetyl transacylaseand malonyl transacylasecatalyze

these reactions.Acetyl CoA + ACP acetyl ACP + CoAMalonyl CoA + ACP malonyl ACP + CoA


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Condensation

reaction.

Acetyl ACP andmalonyl ACP react toform acetoacetylACP.

Enzyme -acyl-malonyl ACPcondensing enzyme.


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Reduction.

Acetoacetyl ACP isreduced to D-3-hydroxybutyryl ACP.

NADPH is thereducing agent

Enzyme: b-ketoacylACP reductase


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Dehydration.

D-3-hydroxybutyrylACP is dehydratedto form crotonyl

ACP(trans-2-enoylACP).

Enzyme:3-hydroxyacyl ACPdehydratase

Reduction.


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Reduction.

The final step in the cycle

reducescrotonyl ACP tobutyryl ACP.

NADPH is reductant.

Enzyme - enoyl ACPreductase.

This is the end of firstelongation cycle (firstround).


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In the second roundbutyryl ACP condenses

with malonyl ACP toform a C6-b-ketoacylACP.

Reduction, dehydration,and a second reductionconvert the C6-b-ketoacyl ACP into a C6-acyl ACP, which is readyfor a third round ofelongation.

Final reaction of FA synthesis


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Rounds of synthesis continue until aC16 palmitoyl group is formed

Palmitoyl-ACP is hydrolyzed by a thioesterase

F na r act on of F synth s s

Acetyl CoA + 7 Malonyl CoA + 14 NADPH + 14 H+

Palmitate + 7 CO2 + 14 NADP+ + 8 HS-CoA + 6 H2O

Overall reaction of palmitate synthesis from

acetyl CoA and malonyl CoA

Organization of Multifunctional Enzyme


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Organization of Multifunctional EnzymeComplexin Eukaryotes

The synthase is dimer with antiparallel subunits.

Each subunit has three domains.

ACP is located in domain 2.Domain 1 contains transacylases, ketoacyl-ACPsynthase(condensing enzyme)

Domain 2 contains acyl carrier protein, b-ketoacylreductase, dehydratase, and enoyl reductase.

Domain 3 contains thioesteraseactivity.


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Fatty Acid Elongation and Desaturation


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Fatty Acid Elongation and Desaturation

The common product of fatty acid synthesis is

palmitate (16:0).

Cells contain longer fatty acids and unsaturatedfatty acids they are synthesized in the

endoplasmic reticulum.The reactions of elongation are similar to the onesseen with fatty acid synthase (new carbons are

added in the form of malonyl CoA).For the formation of unsaturated fatty acids thereare various desaturasescatalizing the formation ofdouble bonds.

THE CONTROL OF FATTY ACID METABOLISM


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Acetyl CoA carboxylaseplays an essential role

in regulating fatty acid synthesis anddegradation.

The carboxylaseis controlled by hormones:glucagon, epinephrine, and insulin.

Another regulatory factors:citrate, palmitoyl CoA, and AMP

Global Regulationd b f bl h h l


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Insulinstimulates fatty acid synthesiscausingdephosphorylation of carboxylase.

Glucagonandepinephrinehave the reverse effect (keep the

carboxylase in the inactive phosphorylated state).

is carried out by means of reversible phosphorylation

Acetyl CoA carboxylaseis switched off by phosphorylation

and activated by dephosphorylation

Protein kinaseisactivated by AMP and

inhibited by ATP.

Carboxylaseisinactivated when theenergy charge is low.

Local Regulation


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Local Regulation

Acetyl CoA carboxylaseis allosterically stimulated bycitrate.

The level of citrate is high when both acetyl CoA and ATPare abundant (isocitrate dehydrogenase is inhibited byATP).

Palmitoyl CoA inhibits carboxylase.

F d t tResponse to Diet


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Fed state:

Insulinlevel is increased

Inhibits hydrolysis of stored TGs Stimulates formation of malonyl CoA, which inhibits

carnitine acyltransferase I

FA remain in cytosol (FA oxidation enzymes are in the

mitochondria)Starvation:

Epinephrine and glucagon are produced and stimulate

adipose cell lipaseand the level of free fatty acids rises Inactivate carboxylase, so decrease formation of malonyl

CoA (lead to increased transport of FA into mitochondriaand activate the b-oxidation pathway)

p

LIPID METABOLISM:BIOSYNTHESIS OF TRIACYLGLYCEROLS


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BIOSYNTHESIS OF TRIACYLGLYCEROLSAND PHOSPHOLIPIDS

Synthesis of Triacylglycerols (TGs)nd Gl c ph sph lipids (GPLs)


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Glycerol 3-phosphate can be obtained either by the

reduction ofdihydroxyecetone phosphate (primarily) orby the phosphorylation of glycerol (to a lesser extent).

and Glycerophospholipids (GPLs)

Formation of phosphatidate


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F m f p pTwo separate acyl transferases (AT)catalyze theacylation of glycerol 3-phosphate.

The first AT(esterification at C1) has preference forsaturated fatty acids;the second AT(esterification at C2) prefers

unsaturated fatty acids.

Phosphatidic acid(phosphatidate)is an


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p (p p )common intermediate in the synthesis ofTGs and GPLs

Phosphatidate can be converted to two precursors:- diacylglycerol (precursor for TGs and neutralphospholipids) - cytidine diphosphodiacylglycerol(CDP-diacylglycerol) (precursor for acidic phospholipids)

Synthesis of TGs and neutral phospholipids


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y p p p

Phosphatidylcholine

Phospha-tidyl-etha-

nolamine

Triacyl-glycerol

Synthesis of TGs


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Diacylglycerol canbe acylated totriacylglycerol (inadipose tissueand liver)

Enzyme:

acyltransferase

Synthesis of TGs

Synthesis of neutral phospholipids


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CDP-choline or CDP-ethanolamine are formed fromCTP by the reaction:

CTP + choline phosphate CDP-choline + PPiCTP + ethanolamine phosphate CDP-ethanolamine + PPi

Synthesis of neutral phospholipids

Diacylglycerol react with CDP-choline or CDP-ethanolamine to formphosphatidylcholineor

phosphatidylethanolamine


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Synthesis of acidic phospholipids


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Phosphatidylinositol can be converted to phosphatidylinositol4,5-biphosphate which is the precursor of the second

messenger inositol 1,4,5-triphosphate


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Interconver-sions ofphosphati-

dylethanol-amine andphospha-tidylserine

Metabolism of Lipids 1

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