Oxidation and biosynthesis of fatty acids Flashcards
Stages of Fatty Acid Oxidation
- Activation of fatty acids
- Transport of Fatty Acyl CoA into the matrix of ` mitochondria
- Degradation to two-carbon fragments
Location of activation of fatty acids
outer mitochondrial membrane
Location of degradation to two carbon fragments
mitochondrial matrix
Process of Activation of FA
- FA are converted to CoA thioesters
- PPi released is hydrolysed
- 2 phosphoanhydride bonds are consumed to activate one FA to a thioester
enzyme that catalyzes conversion of FA to CoA thioesters
acyl-CoA synthetase
enzyme that hydrolyses PPi
pyrophosphatase
Reaction involved in Step 1 of FA Oxidation
FA + ATP Acyl adenylate + PPi
Acyl adenylate + HS—CoA Acyl CoA + AMP
Difference of Acyl CoA and Acetyl CoA
Acetyl CoA: R = methyl
Acyl CoA: R= Carbon chain of any length; two carbons shorter than Acetyl CoA
shuttling system used to transport FA into the mitochondria
carnitine shuttle system
Process of Transporting FA into mitochondria
- Fatty acyl CoA is first converted to acylcarnitine
- Acylcarnitine enters mitochondria (matrix side)
- acyl group is transferred back to CoA
enzyme that converts Fatty acyl CoA to acylcarnitine
carnitine acyltransferase I
carnitine acyltransferase I is bound to-
outer mitochondrial membrane
Acylcarnitine enters the mitochondria via-
translocase
enzyme that transfers acyl group back to CoA
carnitine acyltransferase II
B-carbon atom (C3) is oxidized
B-oxidation pathway
Number of atoms degraded in B-oxidation pathway at a time
2
Reactions in B-oxidation pathway
Oxidation
Hydration
Oxidation
Cleavage
Reaction in 1st Oxidation
Acyl CoA trans-Enoyl CoA
enzyme in 1st oxidation
acyl CoA dehydrogenase
coenzyme and oxidizing agent in 1st oxidation
FAD
Reaction in Hydration
trans- Enoyl CoA ——-> L-3-Hydroxyacyl CoA
enzyme in Hyration
enoyl CoA hydratase
alcohol formed in Hydration
L-3-Hydroxyacyl CoA
Reaction in 2nd Oxidation
L-3-Hydroxyacyl CoA ——-> 3-Ketoacyl CoA
enzyme in 2nd Oxidation
3-hydroxyacyl CoA dehydrogenase
coenzyme in 2nd Oxidation
NAD+
ketone formed in 2nd oxidation
3-Ketoacyl CoA
Reaction in Cleavage
3-Ketoacyl CoA ——–> Acyl CoA + Acetyl CoA
Coenzyme and Cofactors in Cleavage
HS-CoA
Enzyme in Cleavage
B-ketothiolase
- shortened by two C atoms
- undergoes another cycle of oxidation
Acyl CoA
will enter other cycles
Acetyl CoA
The formula for number of cycles
n/2 - 1
Each round generates one molecule each of:
FADH2
NADH
Acetyl CoA
Fatty Acyl CoA
Fate of NADH and FADH2 after B-oxidation
used in ETC
Fate of acetyl CoA after B-oxidation
enters TCA
Fate of acyl CoA after B-oxidation
undergoes the next cycle of oxidation
occurrence of Odd Chain fatty acids
bacteria
microorganisms
Final Cleaving product of B-Oxidation of Odd Chain FA
propionyl CoA rather than acetyl CoA
3 enzymes that convert propionyl CoA to succinyl CoA
propionyl CoA carboxylase
methylmalonyl-CoA racemase
cobalamin (Vit B12)
Type of reaction in first step of conversion of Propionyl CoA to succinyl CoA
Carboxylation
Hydrolysis of ATP
reaction in first step of conversion of Propionyl CoA to succinyl CoA
Propionyl CoA ———-> D-Methylmalonyl CoA
Enzyme in first step
propionyl CoA carboxylase
Coenzyme in first step
Cofactor in first step
biotin, ATP
HCO3
Type of reaction in second step of conversion of Propionyl CoA to succinyl CoA
Racemization
reaction in second step of conversion of Propionyl CoA to succinyl CoA
D-Methylmalonyl CoA L-Methylmalonyl CoA
Enzyme in second step of conversion of Propionyl CoA to succinyl CoA
methylmalonyl-CoA racemase
Type of reaction in third step of conversion of Propionyl CoA to succinyl CoA
Izomerization
reaction in third step of conversion of Propionyl CoA to succinyl CoA
L-Methylmalonyl CoA Succinyl CoA
Enzyme in third step of conversion of Propionyl CoA to succinyl CoA
methylmalonyl CoA mutase
Coenzyme in third step of conversion of Propionyl CoA to succinyl CoA
Vitamin B12 (cobalamin)
makes reaction strong through intramolecular rearrangement
cobalamin
fate of Succinyl CoA
TCA
organelles containing enzyme catalase
Peroxisomes
catalyzes the dismutation of hydrogen peroxide into water and molecular oxygen
catalase
FA Synthesis occurs mainly in:
liver
adipocytes
mammary glands during lactation
location of FA Synthesis
cytoplasm
When glucose is plentiful-
large amounts of Acetyl CoA produced
can be used for FA synthesis
3 Stages of FA synthesis
- Transport of acetyl CoA into cytosol
- Carboxylation of Acetyl CoA
- Assembly of FA chain
destination of transport of acetyl CoA
cytosol
Through which acetyl CoA is exported from mitochondria
citrate transport system
Process of Transport of Acetyle CoA to the Cytosol
Acetyl CoA exported from mitochondrial via citrate transport system
Cytosolic NADH also converted to NADPH
number of ATP expended for each round of transport
2
number of NADPH generated for each molecule of acetyl CoA
1
will reduce oxaloacetate to malate
NADH
Process of Carboxylation of Acetyl CoA
carboxybiotin intermediate formed
ATP hydrolyzed
CO2 group in carboxybiotin transferred to acetyl CoA to form malonyl CoA
Reaction in Carboxylation of Acetyl CoA
HCO3 + ATP —–> ADP + Pi
Enz-Biotin —-> Enz-Biotin-COO-
Acetyl CoA ——> Malonyl CoA
5 Separate stages of Assembly of FA chain
- Loading of precursors via thioester derivatives
- Condensation of the precursors
- Reduction
- Dehydration
- Reduction
A protein that is a component of the Fatty acyl synthase complex to which all intermediates of the FA synthesis are linked
almost identical to Acetyl CoA SH
Acyl Carrier Protein
ACP-SH
common component of CoA and ACP
Pantothenic acid
amino acid end of ACP
Serine
prosthetic group of ACP
makes it possible for CoA to attach to ACP
phosphopantotheine
terminus of phosphopantotheine group of ACP where intermediates attach to
sulfhydryl terminus
active form of AcCoA
malonyl CoA
Reaction of Activation of AcCoA to malonyl CoA
Acetyl CoA + HCO3 + ATP —-> malonyl CoA + ADP + Pi + H
Enzyme used in activation of AcCoA
Acetyl CoA carboxylase
start of/ priming stage Elongation phase of FA Synthesis
formation of Acetyl ACP and Malonyl ACP
Reaction of Priming phase
AcCoA + HS-ACP Acetyl ACP + HS-COA
Malonyl CoA + HS-ACP Malonyl ACP + HS-CoA
Reaction of Condensation phase
Acetyl ACP + Malonyl ACP —-> Acetoacetyl ACP + ACP + CO2
Reaction of Reduction phase
Acetoacetyl ACP + NADPH + H+ D-3- hydroxybutyryl ACP + NADP
Reaction of Dehydration phase
D-3-hydroxybutyryl ACP crotonyl ACP + H2O
Reaction of second reduction phase
Crotonyl ACP + NADPH + H —-> Butyryl ACP + NADP
Enzyme of priming phase
Acetyl transacylase
Malonyl transacylase
Enzyme of Condensation phase
Acyl-malonyl ACP condensing enzyme
Enzyme of first reduction phase
B-ketoacyl ACP reductase
Enzyme of dehydration phase
3- Hydroxyacyl ACP dehydratase
Enzyme of second reduction phase
Enoyl ACP reductase
Product of Butyryl ACP and malonyl ACP in second round
C6-B-ketoacyl ACP
Product after Reduction, dehydration, second reduction of C6-B-ketoacyl ACP
C6-acyl ACP
hydrolyzes Palmitoyl ACP
thioesterase
Reaction of hydrolysis
Palmitoyl-ACP + H2O —–> Palmitate + HS-ACP
Overall reaction of palmitate synthesis from AcCoA and malonyl CoA
AcCoA + 7 Malonyl CoA + 14 NADPH + 14 H —–> Palmitate + 7 CO2 + 14 NADP + 8 HS-CoA + 6H2O
a dimer with antiparallel subunits
Fatty acid synthase
Number of domains in each subunits of Fatty acid synthase
3
Domain 1 enzymes
Acetyl Transacylase
Malonyl Transacylase
Ketoacyl-ACP synthase/ Acyl-Malonyl ACP condensing enzyme
Domain 2 enzymes
B-Ketoacyl ACP Reductase
3-Hydroxyacyl ACP Dehydratase
Enoyl ACP Reductase
ACP
Domain 3 enzyme
Thioesterase
common product of fatty acid synthesis
palmitate
location of synthesis of palmitate
ER
catalyze formation of double bonds to form unsaturated fatty acids
desaturases
plays an essential role in regulating FA synthesis and degradation
AcCoA
hormones that control carboxylase
glucagon
epinephrine
insulin
regulatory factors of carboxylase
citrate
palmitoyl CoA
AMP
is carried out by means of reversible phosphorylation
global regulation
is switched off by phosphorylation and activated by dephorsphorylation
AcCoA
stimulates FA synthesis causing dephosphorylation of carboxylase
Insulin
have the reverse effect: keep carboxylase in the inactive phophorylated state
Glucagon and Epinephrine
activates Protein Kinase
AMP
inhibits Proten kinase
ATP
is inactivated when energy charge is low
Carboxylase
allosterically stimulates AcCoA carboxylase
citrate
the level of citrate is high when
AcCoA and ATP are abundant
inhibits carboxylase
Palmitoyl carboxylase
Response to Fed state
Insulin increased
Inhibits hydrolysis of stored TAGs
Stimulations formation of malonyl CoA
FA remain in cytosol
inhibits carnitine acyltransferase I
malonyl CoA
Response to Starvation
Epinephrine and glucagon stimulate adipose cell lipase
Inactivate carboxylase