ch17_yag_asidi_oksidasyonu_yonca_duman

8/3/2019 ch17_yag_asidi_oksidasyonu_Yonca_Duman

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FATTY ACIDCATABOLISM

or

FATTY ACID

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or

-OXIDATIONof FATTY

ACIDS


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In some species and in some tissues,

the acetyl-CoA has alternative fates.

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n ver , ace y - o may n g er p an s , ace y - obe converted to ketone serves primarily as abodies-water-soluble fuels biosynthetic precursor,exported to the brain and only secondarily as fuel.other tissues when glucoseis not available.


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To overcome the relative stability of the C C bonds in a fatty acid,

the carboxyl group at C-1 is activated by attachment to coenzymeA, which allows stepwise oxidation of the fatty acyl group at theC-3, or/ , position hence the name oxidation .

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Cells can obtain fatty acid fuels from three sources:

Fats consumed in the diet, Fats stored in cells as Fats synthesized in onelipid droplets, organ for export to another.

Digest fats obtained Mobilize fats stored in specia- Convert excessin the diet lized tissue (adipose tissue, con- dietaw carbohydrates

sisting of cells called adipo- to fats for export cytes) (transport) to other

tissues

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Triacylglycerols provide more than half the energyrequirements of some organs, particularly the liver , heart ,and resting skeletal muscle .

Stored triacylglycerols are virtually the sole source of energy in hibernating animals and migrating birds .

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Protists obtain fats by consuming organisms lower in thefood chain, and some also store fats as cytosolic lipiddroplets.

Vascular plants mobilize fats stored in seeds duringgermination.


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Various combi-nations of lipidand protein pro-duce particles of different densities,

ranging fromchylomicrons and

very-low-density

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(VLDL)tovery-high-density

lipoproteins(VHDL) ,

which can be sepa-rated by ultra-centrifugation.


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Mobilization of triacylglycerolsstored in adipose tissue. When lowlevels of glucose in the blood trigger

the release of glucagon, (1) the hormo-ne binds its receptor in the adipocytemembrane and thus (2) stimulatesadenylyl cyclase, via a G protein, toproduce cAMP. This activates proteinkinase A (PKA), which phosphorylates(3) the hormone-sensitive lipase and(4) perilipin molecules on the surfaceof the lipid droplet. Phosphorylation of perilipin permits hormone-sensitive

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droplet, where (5) it hydrolyzes tri-acylglycerols to free fatty acids. (6)Fatty acids leave the adipocyte, bindserum albumin in the blood, and arecarried in the blood; they are releasedfrom the albumin and (7) enter amyocyte via a specific fatty acidtransporter. (8) In the myocyte, fattyacids are oxidized to CO 2, and theenergy of oxidation is conserved inATP, which fuels muscle contraction

and other energy requiring metabolismin the myocyte.


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Ail-CoAsentetazlar

i Ya asidi + CoA + ATP Ya ail-CoA + AMP + PP

membran

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Ail-CoAsentetazlar

iD mitokondriyelYa asidi + CoA + ATP Ya ail-CoA + AMP + 2 P

membran

oG 134 kJ mol =

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Fatty acid entry into mitochondria via the acyl-carnitine/carnitine transporter

[ ] [ ]

[ ]

Karnitinail transferaz-I

Membranlar membran membranaras bo luk d yzeyid yzeyi

Kolayla trlm d

membrand yzeyi

Ya ail-CoA + Karnitin Ya ail-karnitin + CoA

Ya ail-karnitin

[ ]

[ ] [ ]

ifzyon membran

Ail karnitin/Karnitin i yzeyitranspoter

Karnitinail transferaz-II

membran membrani yzeyi

i yzeyi

Ya ail-karnitin

Ya ail-karnitin Ya ail-CoA

Mitokondriyelmatrix

+ Karnitin

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Three isozymes of acyl-CoA dehydrogenase,each specific for a range of fatty-acyl chain lengths

Very-long-chain Medium-chain Short-chain(VLCAD) (MCAD) (SCAD) acyl-CoA acyl-CoA acyl-CoA

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dehydrogenase dehydrogenase dehydrogenaseacting on fatty acting on fatty acting on fattyacids of 12 to 18 acids of 4 to 14 acids of 4 to 8 carbons carbons carbons

All three isozymes are flavoproteins with FAD as a prosthetic group.


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+

3 2 n-1 2 3 2 n-3 3

+ +2

Bir turluk -oksidasyonu iin toplam denklem:CH -(CH ) -CoA + CoA + FAD + NAD + H CH -(CH ) -CoA + CH CO S-CoA

+ FADH + NADH + H

O

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+n-2 n-2 n-2 n-2 n3 2 n-1 2 32 2 2 2 2

n-22

(n-2/2) turluk -oksidasyonu iin toplam denklem:

CH -(CH ) -CoA + CoA + FAD + NAD + H CH CO S-CoA +O

+ +n-2 n-2

2 2 2FADH + NADH + H


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+ +12 2 2

122 2 2

Bir turluk -oksidasyonu sonunda:

NADH + H + O NAD + H O

FADH + O FAD + H O

+2

turluk -oksidasyonu sonunda:

NADH + H + O

n 22

n 2 n 2 n 2 n 2

2 2 4 2

+ 2

2 2 2

NAD + H O

FADH + O FAD + H

n 2

2

n 2 n 2 n 2 n 22 4 2 2

O

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Asetil-CoA'nn oksidasyonu iin elektron transferleri ve

oksidatif fosforilenmeler dahil toplam denklem:

n- n-3 2 n-1 2 i2 2

n2

CH -(CH ) -CoA + + O + (2n-4) ADP + (2n-4) PCo

n-222

-CO S-CoA + (2n-4) ATP + H3CH O

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2

Ya asidi oksidasyonunda olu an asetil-CoA lar sitrik asit dngsndeCO ve suya kadar oksitlendi inde toplam tepkime:

n n2 i2 2Asetil-CoA + n O +5n P + 5n ADP CoA + 5n ATP + n H

2 2O + n CO

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2Ya ail-CoA mitokondrilerde CO ve suya kadar

komple oksitlendi inde toplam tepkime:

3n-23 2 n-1 2 i2

3n-22 22

CH -(CH ) -CoA + O + (7n-4) P + (7n-4) ADP

CoA + (7n-4) ATP + H O + n CO

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16 karbonlu doymu ya asidi palmitik asit iin 1 turluk -oksidasyonu:

Palmitoil-CoA + CoA + FAD + NAD + + H 2O Miristoil-CoA +Asetil-CoA + FADH 2 + NADH + H +

16 karbonlu doymu ya asidi palmitik asit iin 7 turluk -oksidasyonu:

Palmitoil-CoA + 7 CoA + 7 FAD + 7 NAD + + 7 H 2O 8 Asetil-CoA +

7 FADH 2 + 7NADH + 7 H+

Palmitoil-CoAnn Asetil-CoA ya oksitlenmesi iin, elektron transferlerive oksidatif fosforillenmeler dahil toplam denklem:

Palmitoil-CoA + 7 CoA + 7O 2 + 28 P i + 28 ADP 8 Asetil-CoA + 28ATP + 7 H 2O

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In hibernatinganimals , fattyacid oxidationprovidesmetabolicenergy, heat,and water allessential forsurvival of ananimal thatneither eatsnor drinks for

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long periods.

Camels obtainwater tosupplement themeager supplyavailable intheir naturalenvironmentby oxidation of fats stored intheir hump.


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1 mol palmitatn CO 2 ve H 2O ya kadar oksitlenmesiyle retilen enerji 108 ATP1 mol palmitatn palmitolil-CoA ya aktifle mesinde harcanan enerji e deeri 2 ATP1 mol palmitatn komple oksitlenmesinin net enerji kazanc 106 ATP

Palmitoil-CoA + 23 O 2 + 108 P i + 108 ADP CoA + 108 ATP + 16 CO 2 + 23 H 2O

reaksiyonu iin standart sebest enerji de iimi G = 9800 kJ/mol

ADP + Pi ATP reaksiyonu iin G = 30.5 kJ/mol

106 30.5 = 3230 kJ/mol

3230100 %33

9800 9800 kJ/moln %33 ATP nin fosfat ba enerjisi olarak korunur.

Hcre ii gerek ko ullarda korunan serbest enerji %60 n zerindedir.

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P i

Oxidation of mono-unsaturated fatty acids


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Oxidation of mono unsaturated fatty acids

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Ail-CoA-sentetaz

Karnitin ail transferaz-I mitokondriyelmembarn

Karnitin ail transferaz-II

Oleat + CoA Oleil-CoA

Oleil-CoA + Karnitin Oleil-karnitin + CoA

Oleil-karnitin + CoA

Mitokondriyelmatriks

Oleil-CoA + Karnitin

3 tur -oksidasyonu 3

Enoil-CoA izomeraz3 2

Oleil-CoA 3 Asetil-CoA + cis- -dodekenoil-CoA

cis- -dodekenoil-CoA trans- -dodekenoil-CoA

tra

5 tur -oksidasyonu2ns- -dodekenoil-CoA 6 Asetil-CoA

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Oxidation of poly-unsaturated fatty acids


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Oxidation of poly-unsaturated fatty acids


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Ail-CoA-sentetaz

Karnitin ail transferaz-I mitokondriyelmembarn

Karnitin ail t

Linoleat + CoA Linoleil-CoA

Linoleil-CoA + Karnitin Linoleil-karnitin + CoA

Linoleil-karnitin + CoA

ransferaz-II

Mitokondriyelmatriks

3 tur -oksidasyonu 3,6

Enoil-CoA izomera3,6

Linoleil-CoA + Karnitin

Linoleil-CoA 3 Asetil-CoA + cis,cis- -dodekedinoil-CoA

ci cis- -dodekedinoil-CoA

z 2 6trans- cis -dodekedinoil-CoA 1 tur -oksidasyonu2 6 4

Ail-CoA dehidrojenaz4 2

trans- ,cis- -dodekedinoil-CoA Asetil-CoA + cis- -dekenoil-CoAcis- -dekenoil-CoA + FAD trans- ,c

4 2

2,4-dienoil-CoAredktaz2 4 + 3 +

Enoil-CoA-izomeraz3 2

is- -dekedienoil-CoA + FADH

trans- ,cis- -dekedienoil-CoA + NADPH + H trans- -dekenoil-CoA + NADP

trans- -dekenoil-CoA trans- -dekenoil

4 tur -oksidasyonu2

-CoAtrans- -dekenoil-CoA 5 Asetil-CoA

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The propionyl-CoA carboxylase reaction.55


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Methylmalonyl-CoA epimerase reaction.


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In the liver

fatty acyl-CoA formed in the cytosol hastwo major pathways open to it:

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-

by enzymes in or triacylglycerols andmitochondria phospholipids by enzymes

in the cytosol


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Inhibition byMalonyl-CoA

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ACC: Acetyl-CoA carboxylase

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Coordinated regulation of fatty acid synthesis and breakdown . When the diet provides a ready source of carbohydrate as fuel, oxidation of fattyacids is unnecessary and is therefore down-regulated. Two enzymes are key to the coordination of fatty acid metabolism: acetyl-CoA carboxylase(ACC) , the first enzyme in the synthesis of fatty acids, and carnitine acyl transferase I , which limits the transport of fatty acids into the mitochon-drial matrix for oxidation.

Ingestion of a high-carbohydrate meal raises the blood glucose level and thus (1) triggers the release of insulin. (2) Insulin-dependent protein phos-phatase dephosphorylates ACC, activating it. (3) ACC catalyzes the formation of malonyI-CoA (the first intermediate of fatty acid synthesis), and (4)malonyl-CoA inhibits carnitine acyltransferase I, thereby preventing fatty acid entry into the mitochondrial matrix.

When blood glucose levels drop between meals, (5) glucagon release activates cAMP-dependent protein kinase (PKA), which (6) phosphorylates andinactivates ACC. The concentration of malonyl-CoA falls, the inhibition of fatty acid entry into mitochondria is relieved, and (7) fatty acids enter themitochondrial matrix and (8) become the major fuel. Because glucagon also triggers the mobilization of fatty acids in adipose tissue, a supply of fattyacids begins arriving in the blood.


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Yksek [NADH] ile inhibisyon

Yksek [Asetil-CoA] ile inhibisyon

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Peroxisomal oxidation in mammals


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Peroxisomal oxidation in mammals

In mammals , high concentrations of fats in the dietresult in increased synthesis of the enzymes o

peroxisomal oxidation in the liver.

Liver peroxisomes do not contain the enzymes o

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the citric acid cycle and cannot catalyze theoxidation of acetyl-CoA to CO 2.

Instead, long-chain or branched fatty acids are

catabolized to shorter-chain products , such ashexanoyl-CoA, which are exported to mitochondriand completely oxidized.


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Memelilerde peroksizomal ya asidioksidasyonu

hekzakosanoik asit (26:0) gibi ok uzun zincirli ya asitleri

ve

fitanik asit ya da pristanik asit gibi dallanm ya asitlerinin (st rnlerinden elde edilir)

oksidasyonunda ilevseldir.

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Zellweger Sendromu

Peroksizom yetersizlii sonucu kandahekzakosaoik asit (26:0) birikimi,

10 yandan kk ocuklarda krlk,davran bozukluklar,

Birka yl iinde lm.

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The oxidation of a


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branched-chain fattyacid (phytanic acid) inperoxisomes . Phytanicacid has a methyl-substituted carbon and

therefore cannot undergo oxidation. Thecombined action of theenzymes shown here

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removes the carboxyl

carbon of phytanic acid,to produce pristanicacid , in which the carbon is unsubstituted ,allowing oxidation.

Notice that oxidation of pristanic acid releasespropionyl-CoA , not

acetyl-CoA .


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Refsum Sendromu

Phytanoyl-CoA hydroxylase enzimindeki birgenetik bozukluk sonucu oluan yetersizlik,

Kanda ok yksek phytanic acid birikimi,Krlk, sarlk.

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Plant peroxisomes and glyoxysomes use acetyl-CoA from -oxidation as a biosynthetic precursor


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E 1: Acyl-CoA dehydrogenase

E 2: Enoyl-CoA hydratase


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2 y y

E 3: L- -hydroxyacyl-CoA dehydrogenase

E 4: Thiolase

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E 4: Thiolase




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Multi Functional Protein


E 4: Thiolase

E 5: D-3-hydroxacyl-CoA epimerase

E6: 3,2-enoyl-CoA isomerase

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Cyt-P 450 ,The oxidation of fatty acids in theendoplasmic reticulum .This alternative to oxidation begins withoxidation of the carbonmost distant from the acarbon the (omega)

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carbon. The substrate is

usually a medium-chainfatty acid; shown here islauric acid (laurate). Thispathway is generally notthe major route foroxidative catabolism of fatty acids.


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KetoneBodies,

Formedin theLiver, Are

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Exportedto OtherOrgans asFuel.

Formation of ketone bodiesfrom acetyl-CoA. Healthy,well-nourished individualsproduce ketone bodies at a


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relatively low rate. Whenacetyl-CoA accumulates (as instarvation or untreated diabetes , for example), thiolase

catalyzes the condensation of two acetyl-CoA molecules toacetoacetyl-CoA, the parentcompound of the three ketone

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bodies. The reactions of ketone

body formation occur in thematrix of liver mitochondria.The six-carbon compound -hydroxy- -methylglutaryI-CoA(HMG-CoA) is also an

intermediate of sterolbiosynthesis, but the enzymethat forms HMG-CoA in thatpathway is cytosolic. HMG-CoA lyase is present only in the

mitochondrial matrix.


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D- -Hydroxy-buty-

rate as a fuel D


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rate as a fuel. D--Hydroxy-butyrate,synthesized in theliver, passes into theblood and thus toother tissues, where itis converted in threesteps to acetyl-CoA.

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It is first oxidized to

acetoacetate, which isactivated withcoenzyme A donatedfrom succinyl-CoA,then split by thiolase.The acetyl-CoA thusformed is used forenergy production.


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Ketone bodyformation and

export from the


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export from theliver. Conditionsthat promotegluconeogenesis(untreated diabetes,severely reducedfood intake) slowthe citric acid cycle

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(by drawing off

oxaloacetate) andenhance theconversion of acetyl-CoA toacetoacetate. Thereleased coenzymeA allows continued oxidation of fattyacids.


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Active pathways:1. Fatty acid oxidation,2. Formation of keton bodies,3. Gluconeogenesis,4. Keton bodies Acetyl-CoA,5. Citric acid cycle,6. Oxidative phosphorylation.


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Diabetic ketosis results when insulin absent. In the absence of insulin, fats are released fromaddipose tissue, and glucose cannot be absorbed by the liver or addipose tissue. The liverdegrades the fatty acids by oxidation cannot process the acetyl CoA, because of a lack of glucose-derived oxaloacetate (OAA). Excess ketone bodies are formed and released into the


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g ( )blood.

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ch17_yag_asidi_oksidasyonu_yonca_duman

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