Fatty acids Metabolism
Fatty acids are used for energy storage for 2 reasons: a) the carbon atom in FA is highly reduced as the more the atom is electronegative relative to other atoms it is bound with, the more it is reduced and as you know that carbon atom has more electronegativity than hydrogen atom. so, carbon atom will drag electrons towards it and increasing its energy. b) FA aren't hydrated so they can pack more closely in storage.
So, fatty acids undergo oxidation to yield energy which is about 9 Kcal/g fat.
Fatty acid can be saturated and unsaturated, in this post we will take about saturated and unsaturated will be in another post.
Beta-oxidation of Fatty acids:
The major catabolism pathway of FA occurs inside mitochondria which is called β-oxidation to produce acetyl CoA, NADH and FADH2.
Before β-oxidation for long chain FA (LCFA) (Saturated form) occurs, LCFA must be transported through membrane of mitochondria.
Steps of translocation of LCFA:
a) LCFA is converted into CoA derivatives by LC fatty acyl CoA synthetase which is found in the outer mitochondrial membrane enzyme so LCFA passes first membrane in form of fatty acyl CoA.
b) Fatty acyl CoA can't pass through inner mitochondrial membrane as it is impermeable to CoA so it is need of carrier protein called carnitine.
c) Acyl group of fatty acyl CoA will be transferred to carnitine to release CoA and form acylcarnitine by help of carnitine palmitoyltransferase I (CPT-I), an enzyme of the outer mitochondrial membrane.
d) Acylcarnitine is transferred inside inner mitochondrial matrix by exchange for free carnitine out of inner mitochondrial matrix.
e) Once acylcarnitine in inner matrix, it reacts with CoA to transfer acyl group to CoA to form fatty acyl CoA and release free carnitine by help of carnitine palmitoyltransferase II (CPT-II), an enzyme of the inner mitochondrial membrane.
Carnitine:
Sources of Carnitine:
It can be obtained from diet of meat products or synthesized from amino acids such as lysine and methionine by enzymatic pathway in liver and kidney not in cardio or skeletal muscles. cardio or skeletal muscle gets their carnitine by uptake of it from blood or diet or endogenous synthesis. (Skeletal muscle contain about 97% of all carnitine in body)
Inhibition of carnitine:
Malonyl CoA inhibits CPT-I, thus preventing the entry of long-chain acyl groups into the mitochondrial matrix.
Carnitine deficiency:
Any error in carnitine will decrease ability of tissue to use LCFAs.
There are many deficiencies in carnitine:
a) Primary carnitine deficiency: is caused by defect in membrane transporter that prevent uptake of carnitine by cardiac and skeletal muscle and kidney. so to treat previous one: carnitine supplementation.
b) Secondary carnitine deficiency: is caused defects in fatty acid oxidation leading to the accumulation of acylcarnitines that are excreted in the urine, decreasing carnitine availability as carnitine is found in form with acyl CoA.
c) Acquired secondary carnitine deficiency can be seen in patient with liver diseases or taking anti seizures valproic acid.
Some defects in mitochondrial oxidation are due to deficiencies in CPT-I and CPT-II.
CPT-I deficiency affects the liver, where an inability to use LCFAs for fuel greatly impairs that tissue’s ability to synthesize glucose during a fast. This can lead to severe hypoglycemia, coma, and death.
CPT-II deficiency can affect the liver and cardiac and skeletal muscle.
The most common (and least severe) form affects skeletal muscle. It leads muscle weakness with myoglobinemia (leading to necrosis and decrease in O2 supply to muscles). Treatment includes avoidance of fasting and getting a diet high in carbohydrates with low in fat (medium-chain TAGs) as it doesn't require carnitine shuttles.
After translocation of LCFA inside mitochondria, β-oxidation for FA is classified into 2 parts:
First part is related to fatty acids with even number of carbon atoms and Second part is related to fatty acid with odd number of carbon atoms.
we will talk about second part latter.
First part: fatty acids are degraded by repeated cycles of oxidation of β-carbon that results in shortening fatty acid chain by 2 carbon atom each cycle.
The Steps of β-oxidation includes:
a) Oxidation process in which fatty acyl CoA is converted into trans 2-enol CoA by Acyl CoA dehydrogenase and FAD+which is reduced into FADH2. (1)
b) Hydration process in which trans 2-enol CoA is converted into 3-hydroxyacyl CoA by 2,3-enol CoA hydratase.
c) Oxidation process in which 3-hydroxyacyl CoA is converted into 3-ketoacyl CoA by 3-hydroxyacyl CoA dehydrogenase and NAD+ is reduced into NADH. (2)
d) Thiolase reaction in which 3-ketoacyl CoA is converted into fatty acyl CoA and acetyl CoA (3) by β-ketoacyl CoA thiolase and adding CoA.
So, 3 important compounds are formed: acetyl CoA, NADH, FADH2.
To calculate No. of acetyl CoA produced each cycle = number of carbons of fatty acid/2 as each cycle, 2 carbon atoms are released in form of acetyl CoA.
To calculate No. of rounds of beta-oxidation, NADH and FADH2 = No. of carbons/2 -1
You know previously that: acetyl CoA will enter TAC cycle to produce 12 ATP while 1 NADH will produce 3 ATP by electron transport chain and 1 FADH2 will produce 2 ATP.
As we know that purpose from β-oxidation of FA is to produce ATP, so yield of ATP from oxidation of FA with even number of carbon atoms = ATP produced - ATP consumed
=12× number of acetyl CoA + 3× No. of NADH + 2 × No. of FADH2 - (2 ATP are used in activation process : converting fatty acid into fatty acyl CoA) .
Suppose you have FA with 16 carbon atoms so to calculate Yield of ATP, follow the steps:
First: 2 ATP are consumed in converting FA into F acyl CoA.
Second: calculate No. of acetyl CoA = No. of C atoms/2 = 16/2 = 8 acetyl CoA.
Third: No. of rounds= No. of carbons/2 -1= 16/8 -1=7 so, 7 NADH2 are produced and also 7 FADH2.
Fourth: Yield of ATP = ATP produced - ATP consumed = 12× number of acetyl CoA + 3× No. of NADH + 2 × No. of FADH2 - 2 ATP = 12×8+3×7+7×2-2=129 ATP.
WAiT FoR us in post relating to medium chain FA, second part of oxidation and unsaturated FA.
SEE u later.
Sources :
Lippincott Biochemistry Reference
https://www.youtube.com/watch?v=__jS-pjzb5k
So, fatty acids undergo oxidation to yield energy which is about 9 Kcal/g fat.
Fatty acid can be saturated and unsaturated, in this post we will take about saturated and unsaturated will be in another post.
Beta-oxidation of Fatty acids:
The major catabolism pathway of FA occurs inside mitochondria which is called β-oxidation to produce acetyl CoA, NADH and FADH2.
Before β-oxidation for long chain FA (LCFA) (Saturated form) occurs, LCFA must be transported through membrane of mitochondria.
Steps of translocation of LCFA:
a) LCFA is converted into CoA derivatives by LC fatty acyl CoA synthetase which is found in the outer mitochondrial membrane enzyme so LCFA passes first membrane in form of fatty acyl CoA.
b) Fatty acyl CoA can't pass through inner mitochondrial membrane as it is impermeable to CoA so it is need of carrier protein called carnitine.
c) Acyl group of fatty acyl CoA will be transferred to carnitine to release CoA and form acylcarnitine by help of carnitine palmitoyltransferase I (CPT-I), an enzyme of the outer mitochondrial membrane.
d) Acylcarnitine is transferred inside inner mitochondrial matrix by exchange for free carnitine out of inner mitochondrial matrix.
e) Once acylcarnitine in inner matrix, it reacts with CoA to transfer acyl group to CoA to form fatty acyl CoA and release free carnitine by help of carnitine palmitoyltransferase II (CPT-II), an enzyme of the inner mitochondrial membrane.
Carnitine:
Sources of Carnitine:
It can be obtained from diet of meat products or synthesized from amino acids such as lysine and methionine by enzymatic pathway in liver and kidney not in cardio or skeletal muscles. cardio or skeletal muscle gets their carnitine by uptake of it from blood or diet or endogenous synthesis. (Skeletal muscle contain about 97% of all carnitine in body)
Inhibition of carnitine:
Malonyl CoA inhibits CPT-I, thus preventing the entry of long-chain acyl groups into the mitochondrial matrix.
Carnitine deficiency:
Any error in carnitine will decrease ability of tissue to use LCFAs.
There are many deficiencies in carnitine:
a) Primary carnitine deficiency: is caused by defect in membrane transporter that prevent uptake of carnitine by cardiac and skeletal muscle and kidney. so to treat previous one: carnitine supplementation.
b) Secondary carnitine deficiency: is caused defects in fatty acid oxidation leading to the accumulation of acylcarnitines that are excreted in the urine, decreasing carnitine availability as carnitine is found in form with acyl CoA.
c) Acquired secondary carnitine deficiency can be seen in patient with liver diseases or taking anti seizures valproic acid.
Some defects in mitochondrial oxidation are due to deficiencies in CPT-I and CPT-II.
CPT-I deficiency affects the liver, where an inability to use LCFAs for fuel greatly impairs that tissue’s ability to synthesize glucose during a fast. This can lead to severe hypoglycemia, coma, and death.
CPT-II deficiency can affect the liver and cardiac and skeletal muscle.
The most common (and least severe) form affects skeletal muscle. It leads muscle weakness with myoglobinemia (leading to necrosis and decrease in O2 supply to muscles). Treatment includes avoidance of fasting and getting a diet high in carbohydrates with low in fat (medium-chain TAGs) as it doesn't require carnitine shuttles.
β-oxidation of medium chain of fatty acids:
Fatty acids (<12 carbon atoms) can cross inner mitochondrial matrix without aid of carnitine, once they are inside cytosol, they are activated into CoA derivatives. Medium chain fatty acids are found in human milk. they are independent on CPT-1, so they aren't inhibited by malonyl CoA.
In mitochondria, there are 4 types of acyl CoA dehydrogenase for either short, medium, long or very long chain of fatty acids. And Deficiency in medium chain fatty acyl CoA dehydrogenase is is one of the most common inborn errors of metabolism and the most common inborn error of fatty acid oxidation, being found in 1:14,000 births worldwide. It results in decreased ability to oxidize fatty acids with six to ten carbons (which accumulate and can be measured in urine), severe hypoglycemia (because the tissues must increase their reliance on glucose), and hypoketonemia (because of decreased production of acetyl CoA). it has been reported that this deficiency can cause sudden infant death syndrome or Reye syndrome. Its treatment is to avoid fasting.
After translocation of LCFA inside mitochondria, β-oxidation for FA is classified into 2 parts:
First part is related to fatty acids with even number of carbon atoms and Second part is related to fatty acid with odd number of carbon atoms.
we will talk about second part latter.
First part: fatty acids are degraded by repeated cycles of oxidation of β-carbon that results in shortening fatty acid chain by 2 carbon atom each cycle.
The Steps of β-oxidation includes:
a) Oxidation process in which fatty acyl CoA is converted into trans 2-enol CoA by Acyl CoA dehydrogenase and FAD+which is reduced into FADH2. (1)
b) Hydration process in which trans 2-enol CoA is converted into 3-hydroxyacyl CoA by 2,3-enol CoA hydratase.
c) Oxidation process in which 3-hydroxyacyl CoA is converted into 3-ketoacyl CoA by 3-hydroxyacyl CoA dehydrogenase and NAD+ is reduced into NADH. (2)
d) Thiolase reaction in which 3-ketoacyl CoA is converted into fatty acyl CoA and acetyl CoA (3) by β-ketoacyl CoA thiolase and adding CoA.
So, 3 important compounds are formed: acetyl CoA, NADH, FADH2.
To calculate No. of acetyl CoA produced each cycle = number of carbons of fatty acid/2 as each cycle, 2 carbon atoms are released in form of acetyl CoA.
To calculate No. of rounds of beta-oxidation, NADH and FADH2 = No. of carbons/2 -1
You know previously that: acetyl CoA will enter TAC cycle to produce 12 ATP while 1 NADH will produce 3 ATP by electron transport chain and 1 FADH2 will produce 2 ATP.
As we know that purpose from β-oxidation of FA is to produce ATP, so yield of ATP from oxidation of FA with even number of carbon atoms = ATP produced - ATP consumed
=12× number of acetyl CoA + 3× No. of NADH + 2 × No. of FADH2 - (2 ATP are used in activation process : converting fatty acid into fatty acyl CoA) .
Suppose you have FA with 16 carbon atoms so to calculate Yield of ATP, follow the steps:
First: 2 ATP are consumed in converting FA into F acyl CoA.
Second: calculate No. of acetyl CoA = No. of C atoms/2 = 16/2 = 8 acetyl CoA.
Third: No. of rounds= No. of carbons/2 -1= 16/8 -1=7 so, 7 NADH2 are produced and also 7 FADH2.
Fourth: Yield of ATP = ATP produced - ATP consumed = 12× number of acetyl CoA + 3× No. of NADH + 2 × No. of FADH2 - 2 ATP = 12×8+3×7+7×2-2=129 ATP.
WAiT FoR us in post relating to medium chain FA, second part of oxidation and unsaturated FA.
SEE u later.
Sources :
Lippincott Biochemistry Reference
https://www.youtube.com/watch?v=__jS-pjzb5k
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