Fatty Acid Oxidation - NEET PG Biochemistry

In the human body, fatty acids are oxidized in a variety of cell structures, including the mitochondria, where only beta-oxidation takes place, the peroxisome, where alpha- and beta-oxidation take place, and the endoplasmic reticulum, where omega-oxidation takes place.

When there is a high energy demand, such as during exercise, beta-oxidation is an important source of metabolic energy. Due to the release of circulating mediators like adrenaline and glucagon, which accelerate lipolysis, these metabolic circumstances cause the release of fatty acids from adipose tissue. When glycogen and gluconeogenic precursors are in short supply, this metabolic pathway meets a significant amount of the energy requirements of skeletal muscle, cardiac muscle, and kidneys. As a result, fatty acid oxidation offers a different, highly effective method of energy synthesis while also protecting muscles from catabolic deterioration. The body has to be cleansed of big, insoluble xenobiotic substances and lipid-based cellular components such sphingolipids and components of the plasma membrane. 

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Fatty Acid Oxidation

Fatty acids get oxidized in peroxisomes, mitochondria and nucleus. Very long-chain fatty acid gets oxidized in peroxisomes. Very short-chain fatty acid gets oxidized in Mitochondria. Short-chain, medium-chain, and long-chain fatty acids get oxidized in both Mitochondria, and peroxisome.

Functions of Peroxisome

They are concerned with very long chain fatty acid oxidation. They are concerned with ether lipid (plasmalogen) synthesis and They are concerned with ⍺ oxidation of branched-chain fatty acids.

β Oxidation

Fatty Acid

CH₃-CH₂-CH₂-CH₂-CH₂-CH₂-CH₂-CH₂-CH₂-CH₂-CH₂-CH₂-CH₂-CH₂-CH₂-CH₂-CH₂-COOH

The carbon atom just before alpha carbon atom is ꞵ carbon atom. When the ꞵ carbon atom is oxidized, it is no more CH2. It becomes COOH (carboxyl group), I.e., we have pre-positioned the functional grp. Which will give us

CH₃-CH₂-CH₂-COOH + CH₃ - COOH

(Acetic acid).

When the acetic acid gets attached to coA, we will call it acetyl CoA.

Acetyl coA

There are two carbon atoms .If there is n carbon containing fatty acid which undergoes ꞵ oxidation will always give n/2 Acetyl CoA because acetyl CoA contains 2 Carbon atoms Product of ꞵ oxidation of fatty acid is always acetyl-CoA molecules Peroxisome - the hydrogen peroxide generation due to ꞵ oxidation is peroxisome

The difference between mitochondrial oxidation and peroxisomal oxidation.:

When oxidation happens in Mitochondria, we remove the hydrogen atom from ꞵ carbon atom and give it to NAD and FAD, which further forms NADH and FADH2. When NADH and FADH2 go through an electron transfer chain, they give rise to ATP.

When oxidation happens in the peroxisome, we remove the hydrogen atom from ꞵ carbon atom and give it to the oxygen molecule. This then forms hydrogen peroxide (H₂O₂). To detoxify hydrogen peroxide, the peroxisome is equipped with catalase enzymes.

Fate of Fatty Acid in a Cell

As soon as fatty acid gets into any cell, irrespective of the final fate of fatty acid, the 1st enzyme to act on this fatty acid will be acetyl CoA synthetase. This acetyl CoA synthetase uses 1 ATP which gets converted to AMP + PPI. This step uses two high energy phosphate and successfully converts fatty acid into acetyl CoA The purpose of acyl CoA synthetase is to trap fatty acid within the cell.Fatty acids are nonpolar substances. It can easily cross a cell membrane and get into cytoplasm. When entered in the cytoplasm, if we don't convert the fatty acid into any another form, the fatty acid concentration inside the cell becomes higher starts getting reflex across the membrane back into the circulation

Acyl CoA with carnitine gives acylcarnitine, and the enzyme is carnitine acyl transferase 1 (rate-limiting enzyme). Acyl carnitine crosses the inner mitochondrial membrane and enters the matrix. Once the acylcarnitine has entered the matrix if you retain the carrier the same carrier will put the acylcarnitine back into cytoplasm. Carnitine acyltransferase 2 releases the carnitine back and converts acylcarnitine to acyl CoA.

Also Read: Mucopolysaccharides : Exceptions, Important Facts

Phases of Fatty Acid Oxidation

• 1st phase: Is n carbon fatty acids goes under ꞵ oxidation to form n/2 acetyl CoA
• 2nd phase: Every acetyl CoA Enters into citric acid Cycle every acetyl CoA molecule. We'll come out as carbon dioxide, and every acetyl CoA will give you 10 ATPs.

Steps of Phase I
Details of Phase 1 - Every Cycle 

• n carbon atoms containing fatty acids on ꞵ oxidation gives you n/2 acetyl CoA.
• For n/2 acetyl CoA, we should go for (n/2 cycles - 1)

Regulation of Fatty Acid Oxidation

The rate limiting enzyme of fatty acid oxidation is CPT1.

Regulation of CPT1

• Stimulators: CPT1 gets stimulated by low energy status indicators (ADP, NAD, FAD, Acyl CoA)
• It gets stimulated by catabolic enzymes, and catabolic enzymes get stimulated by glucagon.
• Inhibitors: CPT1 gets stimulated by high energy status indicators (ATP, NADH, FADH2, INSULIN, MALONYL COA)
• Malonyl CoA is an intermediate of fatty acid synthesis. If it is present in the cell, then this means that the cell is striving hard for fatty acid synthesis, which means it is rich in energy.

Fatty Acid Oxidation Defects

Congenital

• Mutation in the genes for any of the enzymes which are involved in fatty acid oxidation.
  • Carnitine acyl transferase 1(CPT I)
  • Carnitine acyltransferase 2(CPT II)
  • Acyl CoA dehydrogenase 
  • Hydrates 
  • Ꞵ hydroxy acyl CoA dehydrogenase
  • Thiolase

Acquired 

• Jamaican vomiting sickness which is caused by intake of unripe Ackee fruit.
• The toxic principle which is present in unripe ackee fruit is called Hypoglycin.
• Hypoglycin acts by inhibiting medium chain acyl CoA dehydrogenase enzyme.

Fatty Acid Oxidation Defects – Features                                      

• Congenital or acquired are always present with Hypoglycemia because whenever the fatty acid oxidation is defective, energy cannot be produced. Without energy, gluconeogenesis is impaired, and that causes hypoglycemia.
• Fatty acid gets oxidized to form Acetyl CoA. All the Acetyl CoA molecules go into the citric acid cycle by reacting with oxaloacetate and will give rise to 2 carbon-di-oxide.
• If the person is in starvation, all the Oxaloacetate will be used for gluconeogenesis. 
• When acetyl CoA accumulates, it condenses to form ketosis.
• N no. of possibilities are for the formation of hypoglycemia in a neonate that will be accompanied by ketosis.
• If hypoglycemia is because of a fatty acid oxidation defect, there will be no Acetyl CoA and no Ketosis. Therefore, it will be nonketotic hypoglycemia. 
• To support fatty acid synthesis, amino acid oxidation takes place, and wherever amino acid gets oxidized, the amino group will be released as ammonia. So, there will be access to ammonia generation in fatty acid oxidation defects, so they Represent Hyperammonemia.
• When peroxisome starts mediating beta-oxidation, they can oxidize all these fatty acids only till very short-chain fatty acid. They start meditating omega oxidation of very short chain fatty acids, forming a dicarboxylic aciduria.

Odd Chain Fatty Acid Oxidation

When 7 carbon-containing fatty acids are beta oxidized then on the first Cycle, the last two carbon atoms will come out as Acetyl CoA.

• The five carbon-containing fatty acids go to the second Cycle of ꞵ oxidation, where the last two carbon atoms form acetyl CoA.
• Then the remaining three carbon atoms are called propionyl CoA.
• The majority of the products that we get are acetyl CoA molecules.
• Propionyl acid also goes into the citric acid Cycle. It manages to go into the citric acid cycle only when converted to succinyl CoA.
• Propionyl CoA and its enzyme carboxylase convert propionyl CoA to D methyl malonyl CoA. Then this gets converted to L -methyl malonyl CoA with the help of methyl malonyl CoA Racemase. Methyl malonyl mutase (B 12 dependent enzyme) converts it to succinyl CoA.
• B 12. Deficiency causes methylmalonic aciduria. The methylmalonic acid gets incorporated into myelin which causes demyelination. That's why B12 Deficiency presents with neurological manifestation.

Related Biochemistry Articles:

Hypoglycemia 

To maintain blood glucose, we must Stimulate gluconeogenesis to support gluconeogenesis; there should be peripheral lipolysis. In starvation, where there is no insulin when there are excess counter-regulatory hormones, they stimulate hormone-sensitive lipase. During starvation, there is an increase in free fatty acid levels in the serum. The free fatty acid and glycerol, when in the liver, the glycerol will be used as a substrate for gluconeogenesis, and the fatty acid will be oxidized to provide the necessary energy for gluconeogenesis. During starvation, the Acetyl CoA produced can't go under the citric cycle because it requires oxaloacetate, but all the oxaloacetate is used to produce gluconeogenesis. Then the accumulated Acetyl CoA condenses to form ketone bodies.

Diabetes Mellitus

In diabetics, there is absolute insulin deficiency there is peripheral lipolysis. Lipolysis is inevitable by insulin. In diabetes, there is excessive peripheral lipolysis, leading to the formation of glycerol and fatty acids. Therefore, a person loses weight wherever there is the aggression of insulin resistance. 

The fatty acid and glycerol, when in the liver the glycerol, will be used as a substrate for gluconeogenesis. Gluconeogenesis is possible in insulin resistance because glucagon is hyperactive, and the fatty acid will be oxidized to provide the necessary energy for gluconeogenesis. The Acetyl CoA produced can't go under the citric cycle because it requires oxaloacetate, but all the oxaloacetate is used to produce gluconeogenesis. Then the accumulated Acetyl CoA condenses to form ketone bodies conversion of acetyl CoA to ketone bodies:

Whenever acetyl CoA accumulates, two molecules of acetyl CoA condenses each other in the presence of thiolase to form Acetyl acetyl CoA. Then this acetyl acetyl CoA reacts with another molecule of acetyl CoA in the presence of HMG CoA synthase to form HMG CoA Then the enzyme HMG CoA lyase takes of one acetyl CoA which gets recycled back, and that is how HMG CoA then it gets into first ketone body which is Acetoacetate. Acetoacetate On spontaneous decarboxylation forms acetone.In the presence of ꞵ hydroxybutyrate dehydrogenase forms ꞵ hydroxybutyrate using 1 NADH 

Ketone Body Synthesis                     

• Starvation or Hypoglycemia 
  • Excessive peripheral lipolysis 
  • Excessive fatty acid oxidation 
  • Low availability of oxaloacetate 
• Diabetes 
• HMG CoA lyase > HMG CoA Synthase Are rate-limiting enzymes
• Acetoacetate- primary ketone body
• Ketone bodies synthesis is in Liver Mitochondria
• They get utilized in extrahepatic tissues.
• Odd chain fatty acid oxidation will give rise to propionyl CoA then, which will get converted into succinyl CoA then, which will go into the citric acid cycle and then it forms oxaloacetate with the help of succinyl thiokinase. 
• Succinate is not formed from succinyl because succinyl thiokinase is suppressed because of high energy; thus, we require a bypass to form Succinate. We use CoA transferase, which allows succinyl CoA to react with a ketone body(acetoacetate) which forms aceto acetyl CoA.
• The enzyme thus formed is a thiophorase called succinyl CoA acetoacetate CoA transferase.

This is everything that you need to know about fatty acid oxidation  for your biochemistry preparation. For more interesting and informative blog posts like this download the PrepLadder App and keep reading our blog!