4.LIPIDS Anabolism

8/20/2019 4.LIPIDS Anabolism

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4. Lipid Biosynthesis

5. Regulation and pathology oflipid metabolism

Proteins


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+. Transport of Acetyl-!oA from mitochondria to cytoplasm,. "ynthesis of malonyl-!oA

-. #longation - the malonyl-!oA path ay

●condensation step $ %

●reduction step $ %

●dehydration step $ %

●another reduction step $ %

The steps then repeat.

The Fatty A'id "ynthesis Path/ayin*ol*es the follo/ing stages &


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+.Transport of A'etyl(CoA to'ytoplasm


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&. "ynthesis of malonyl-!oA


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-. #longation - the malonyl-

!oA path ay● All the steps of elongation are catalyzedby Fatty A'id "ynthetase

●Fatty Acid "ynthetase is an enzymecomplex that consists from se*en

enzymes.● At the centre of the multi-enzyme

complex an a'yl 'arrier protein 0ACP1 is


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Fatty a'id

synthetase


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Fatty Acid "ynthase prosthetic

groups:

● the second thiol group - of

phosphopantetheine 'binds the gro ing fatty acyl

chain during the condensationand reduction reactions of the

● the first thiol group (

of a 'ysteine residue. Acts as aholding station for acetyl-

or fatty acyl- groups.


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The "teps of elongation stage in fattyacids biosynthesis :

2 Condensation

( – acethyl-transacylase

& – malonyl-transacylase

) – beta-*etoacyl-A!+-synthase

!e'arbo3ilation


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The "teps of elongation stage in fattyacids biosynthesis : 2 Redu'tion $is used ,A + %.

2 !ehydration $is released ater%. 2 Redu'tion $is used again ,A + %.

/ – beta-*etoacyl-A!+-reductase

0 – beta-hydroxyacyl-A!+-dehydrase

1 – enoyl-A!+-reductase


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The "teps of elongation stage in fattyacids biosynthesis :

( Transfer of the a'yl to the first thiol group 0of 'ysteine1 lea*ing

se'ond thiol group a*ailable to pi' up the ne3t malonyl &

6 2 ACP(a'yltransferase

Then a ne molecule of malonyl(CoA

is added and the "ynthetic !ycle is


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●2n Palmiti' A'id biosynthesis se3en!ycles are needed.

●4ne Acetyl-!oA is required.●"e3en 5alonyl-!oA are required

7 – palmitoil-thio-esterase

Finally:


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"ummary of Fatty Acid "ynthesis

6eactions:

● Acetyl-!oA 7 8 5alonyl-!oA 7 (/ ,A + &

9

+almitate 7 8 !4 & 7 (/ ,A + 7 "!oA


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●The Fatty Acid "ynthetase !omplex only ma*espalmitate

●The rest of the fatty acids come from:

o %longation 0for longer saturated a'ids1o !esaturation 0 for unsaturated a'ids1

%longation and desaturation

of fatty a'ids


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#longation of Fatty AcidsFor longer fatty acids there is a fatty acid elongation system localized onthe #6. The same reactions occur as in the "ynthetase' but no ha3e

indi3idual enzymes. +almitate is first acti3ated to palmitoyl-!oA' theninteract ith malonyl-!oA. The ma;or product is stearoyl(CoA.


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esaturation of fatty acid 9"ynthesis of unsaturated Fatty Acid●Ta es pla'e in mi'rosomes in

li*er ●en8yme 2 monoo3igenase


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Biosynthesis of Tria'ylgly'erols

and 9ly'erophospholipids●Tria'ylgly'erols and

9ly'erophospholipids are

synthesi8ed from 'ommonpre'ursors&

●A'ti*e 9ly'erol 09ly'erol(-(phosphate1:

●A'ti*e Fatt A'ids A' l(CoA


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9ly'erol(-(phosphate 'an be formed in t/o/ays&

(. From dihydro3ya'etone phosphate generatedduring glycolysis by the action of the cytosolic ,A -lin*ed gly'erol(-(phosphate dehydrogenase 0li*er adipose tissue1&. From gly'erol by the action of gly'erol inase


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The other precursors of triacylglycerols arefatty a'yl(CoAs ' formed from fatty acids

by a'yl(CoA synthetases


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+hosphatidic acid is a centralintermediate in lipid biosynthesis:

●it can be con3erted either to atria'ylgly'erol or to agly'erophospholipid :

Phosphatidi' a'id

Tria'ylgly'erols 9ly'erophospholipids


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2n the path ay totriacylglycerols:

(. +hosphatidic acid ishydrolyzed to form a ('&-diacylglycerol&. iacylglycerols are thencon3erted into

triacylglycerols byesterification ith a third fattyacyl-!oA.


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"ynthesis of


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"ynthesis of +hosphatidilcholine


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Biosynthesis of Cholesterol●!holesterol is an essential molecule in many

animals' including humans●!holesterol is founded in the structure of many

membranes

●!holesterol is a precursor of steroid hormones3itamin and bile acids:


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>iosynthesis of !holesterol

●Ta*es place in a li3er of adult humans

●>iosynthesis of cholesterol may be di3ided

into three steps:(. +roduction of me3alonic acid from acetyl-!oA

&. "ynthesis of an ?acti3e isoprene@ fromme3alonic acid follo ed by the condensationof the former of squalene


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(. +roduction of me3alonic acid from acetyl-!oA


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A'yl(CoA('holesterol a'yltransferase 0ACAT1 .

●A'yl(CoA'holesterol a'yl transferase0ACAT1. This enzyme catalyzes the

transfer of a fatty acid from coenzyme A tothe hydroxyl group of cholesterol 'con3erting the cholesterol into a more

hydrophobic form.●!holesteryl esters are transported in

secreted lipoprotein particles to othertissues that use cholesterol


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Plasma lipoproteins

●Plasma lipoproteins ' macromolecularcomplexes of specific carrier proteinscalled apoproteins ith 3ariouscombinations of phospholipids'cholesterol' cholesteryl esters' andtriacylglycerols

● iffering combinations of lipids andproteins produce particles of differentdensities' ranging from 3ery lo -densityli o roteins B B to hi h-densit


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Anatomy of a Bipoprotein

The principal lipidcomponents are

triglycerides'

cholesterol' cholesterylesters and

phospholipids. The

hydrophobic core of theparticle is formed by

the triglycerides and

cholesteryl esters. All


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Bipoproteins

arious combinations of lipid and protein produceparticles of different densities. They are:

●chylomicrons'

●3ery lo -density lipoproteins $ B B%'●lo -density lipoproteins $B B%'

●high-density lipoproteins $ B%.

The most distinguishing feature of each

class is the density and relati3e amounts of


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$uman plasma lipoproteinschylomicron B B 2 B B B B

ensity $gCml% DE. 0 E. 0E–(.EE1

(.EE1–(.E(

(.E( –(.E1)

(.E1)–(.&(E

!omponents $G dry eight%

protein & 8 (0 &E 4;255

triglycerides 7- 5; )( (Efree cholesterol & 8 8 7 4

cholesterylesters

) (& &) 4, +,2,;

phospholipids 8 &E && && &&

Apoproteincomposition

A-2' A-22'>-/ ' !-2'!-22' !-222

>-(EE' !-2'!-22' !-222'#

>-(EE' !-2'!-22' !-222'#

>-(EE A-2' A-22'!-2' !-22'!-222' '#


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Chylomi'rons●Chylomi'rons are the

largest of the lipoproteinsand the least dense'containing a high proportionof triacylglycerols $ E- EG%

●!hylomicrons aresynthesized in the

endoplasmic reticulum ofepithelial cells of the smallintestine

●!hylomicrons carry fatty


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ery lo/(density lipoprotein

L!L● B Bs contain a lot of endogenoustriacylglycerols $0E-1EG%' cholesterol andcholesteryl esters' as ell as apo>-(EEand other apoproteins.

●These lipoproteins are synthesized in theli3er and are transported in the blood tomuscle and adipose tissue.


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"tructure of a lo -density lipoprotein$B B%


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$igh(density lipoprotein $!L

● B begins in the li3er and small intestine assmall' protein-rich particles containingrelati3ely little cholesterol and no cholesterylesters

● Bs contain apo!-2 and apo!-22' among

other apolipoproteins ' as ell as the enzymele'ithin('holesterol a'yl transferase0LCAT1' hich catalyzes the formation of

cholesteryl esters from lecithin


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$igh(density lipoprotein $!L

● B collects cholesteryl esters from othercirculating lipoproteins' !hylomicrons and

B Bs

● B returns cholesterol to the li3er for the

synthesis of bile acid and steroid hormones


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6egulation of lipid metabolism

●5etabolism of lipids is depended on dietarysupply of lipids and carbohydrates and on theneuro-hormonal regulation

● A large dietary inta*e of carbohydrate richfood exerts a significant production oftriglycerides and cholesterol

● egetable oils $rich in phospholipids andpoly-unsaturated fatty acids 9 lipotropicfactors% pre3ent an excessi3e accumulation

of cholesterol and its deposition in blood


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6egulation of lipid metabolism

●The lipotropic factors exercise a mar*edeffect on the biosynthesis of phospholipidsand triglycerides. The dietary deficiency oflipotropic factors increase the triglycerideproduction in the organism

●The lipolysis in tissues is depended on theacti3ity of triglyceride lipase

● Adrenaline and noradrenalin' glucagon'

thyroxin' somatotropin act as stimulators of


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6egulation of Triacylglycerols

synthesis●2nsulin promotes the con3ersion ofcarbohydrate into triacylglycerols .

●+eople ith se3ere diabetes mellitus areunable to synthesize fatty acids fromcarbohydrates or amino acids.

●They sho increased rates of fat oxidationand *etone body formation

● As a consequence they lose eight


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+athology of lipid metabolism

●5ost lipid metabolism pathology ismanifest as 2+#6B2+#52A $ele3atedconcentration of lipids in blood% and tissuelipidoses $excessi3e lipid deposition intissues%

● yperlipemia may manifest itself by anincreased concentration of lipoproteinsand chylomicrons

●"econdary yperlipemia are obser3ed in


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Familial hypercholesterolemia

●2n the human genetic disease *no n asfamilial hypercholesterolemia' blood le3els ofcholesterol are extremely high' and afflicted

indi3iduals de3elop se3ere atherosclerosis inchildhood.

●The B B receptor is defecti3e in these

indi3iduals' and the receptor-mediatedupta*e of cholesterol carried by B B does notoccur.

●!onsequently' cholesterol obtained in the dietis not cleared from the bloodH it accumulates


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+athology of lipid metabolism.

Tissue Bipidoses●Lipidoses can arise from defects of theenzymes in3ol3ed in lipids metabolism

●Atheros'lerosis manifested by thedepozition of cholesterol in arterial alls'

hich results in the formation of lipidplagues.B B exhibit atherogenicproperties

●Fatty infiltration of the li*er can be indeficiency in lipotropic factors and excess


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Atheros'lerosis

●Ihen the cholesterol synthesized andobtained in the diet exceeds the amountrequired for the synthesis of membranes' bilesalts' and steroids

pathological accumulations of cholesterol in

blood 3essels $atherosclerotic plaques% cande3elop in humans' resulting in obstruction ofblood 3essels $ atheros'lerosis %.

● eart failure from occluded coronary arteries

T diti l i f 't i 'l d g l 3 d li id i


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Traditional ris fa'tors in'lude age male se3 dyslipidemiahypertension smo ing and diabetes.


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Atherosclerosis


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Atherosclerosis


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Atherosclerosis


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Atherosclerosis


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Atherosclerosis

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4.LIPIDS Anabolism