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Citric acid cycle is not only a pathway for oxidation of two-carbon units, but is also a major pathway for interconversion of metabolites arising from transamination and deamination of amino acids, and providing the substrates for gluconeogenesis, fatty acid , haem and nucleotide biosynthesis. Because it functions in both oxidative and synthetic processes, it is Amphibolic.

A) Catabolic role- The citric acid cycle is the final common pathway for the oxidation of carbohydrate, lipid, and protein because glucose, fatty acids, and most amino acids are metabolized to acetyl-CoA or intermediates of the cycle. The function of the citric acid cycle is the harvesting of high-energy electrons from carbon fuels.1 acetate unit generates approximately 12 molecules of ATP per turn of the cycle (Figure-1).

 Catabolic role of TCA cycle

Figure-1 – All the major nutrients are completely oxidized in TCA cycle to yield energy.The coenzymes thus reduced in the process of oxidation of substrates are regenerated in the oxidized form through the involvement of electron transport chain.

Portal of entry of nutrients- The nutrients can enter  either at the level of Acetyl co A or at the level of any of intermediates of TCA cycle.  Broadly speaking carbohydrates enter as acetyl Co A through first formation of pyruvate; fatty acids enter eother as acetyl co A (even chain) or Succinyl co A (odd chain fatty acids), whereas amino acids enter at various points in TCA cycle (Figure-2) for complete oxidation or for the synthesis of biological compounds as per need of the cell. The details are as follows-

1) Pyruvate- The major sources of pyruvate are -

a) Glucose- is a representative of carbohydrates,  it is oxidized through glycolysis to produce pyruvate.

Glucose is the major source of pyruvate (Figure-1 and 2).

b) Amino acids- Pyruvate forming amino acids are Glycine, serine, hydroxy proline, threonine, alanine, tryptophan and alanine (Figure-2)

c) Lactate- Pyruvate is formed from lactate under aerobic conditions . The reaction is catalyzed by lactate dehydrogenase.

Pyruvate is subsequently converted to Acetyl co A. The reaction is catalyzed by pyruvate dehydrogenase complex.

2) Acetyl co A- The major sources of Acetyl co A are as follows-

a) Fatty acids- The even chain fatty acids upon oxidation produce acetyl co A.

b) Ketone bodies – Ketone bodies upon breakdown produce acetyl co A.  Thus acetyl co A is both a precursor as well as the end product of metabolism of ketone bodies.

c) Amino acids- Leucine, Lysine, Isoleucine , Tryptophan, Tyrosine and Phenyl alanine produce acetyl co A directly or indirectly (Figure-2).

 Catabolism of amino acids

Figure-2-  The carbon skeleton of various amino acids can gain entry at different points in the TCA cycle for complete oxidation

d)  Acetyl Choline- Upon hydrolysis of acetyl choline acetyl co A is produced.

e) Alcohol- Alcohol is metabolized first to acetaldehyde and then to acetate that is subsequently converted to acetyl co A.

3) α- Keto glutarate- Various amino acids like glutamate, arginine, histidine ,proline and glutamine end up their metabolism forming alpha keto glutarate.

4) Succinyl co A

a) Amino acidsValine, Isoleucine and methionine form Succinyl co A upon catabolism of their carbon skeleton. Valine directly forms Succinyl co A while methionine and Isoleucine first form propionyl co A that is subsequently converted to Succinyl co A (Figure-3).

b) Odd chain fatty acids- Propionyl co A produced from the metabolism of odd chain fatty acids is subsequently converted to Succinyl co A.

c) Side chain of cholesterol- During bile acid synthesis Propionyl co A is produced from the side chain of cholesterol that  gains entry in TCA cycle as Succinyl co A.

 Fate of propionyl co A

Figure-3- Fate of propionyl co A. Propionyl co A is first carboxylated to form D- Methyl malonyl co A, that is is isomerized to form L methyl malnyl coA which is finally converted to Succinyl co A.

5) Fumarate-  Phenyl alanine and tyrosine are Fumarate forming amino acids (Figure-2).

6) Oxaloacetate- Aspartate and Asparagine form Oxaloacetate that can further be utilized for oxidation or glucose production as per need of the body (Figure-2).

Anabolic  role/Significance of TCA cycle intermediates

1) Acetyl co A- It has a central role to play both in the catabolism as well as synthesis of various biological compounds. Acetyl co A is a precursor for the synthesis of-

a) Fatty acids

b) Cholesterol

c) Ketone bodies

d) Steroids

e) Acetyl choline

f) Also used for detoxification of xenobiotics

2) Citrate- Besides acting as a negative allosteric modifier for Phosphofructokinase-1 to inhibit glycolysis, it also regulates pathway of fatty acid biosynthesis by- i) stimulating the activity of  Acetyl co A carboxylase acting as a positive modifier (Citrate converts the enzyme from an inactive dimer to an active polymeric form ) and also -ii) by transporting acetyl co A to the cytoplasm from mitochondrion since the fatty acid synthesis is a cytoplasmic process (Figure-4).

 Role of citrate

Figure-4- Acetyl-CoA is formed from glucose via the oxidation of pyruvate within the mitochondria. However, it does not diffuse readily into the extra mitochondrial cytosol, the principal site of fatty acid synthesis. Citrate, formed after condensation of acetyl-CoA with Oxaloacetate in the citric acid cycle within mitochondria, is translocated into the extra mitochondrial compartment via the tricarboxylate transporter, where in the presence of CoA and ATP it undergoes cleavage to acetyl-CoA and Oxaloacetate catalyzed by ATP-citrate lyase. The acetyl-CoA is then available for malonyl-CoA formation and synthesis to palmitate.

3) Isocitrate-  Dehydrogenation of Isocitrate forms the first link between TCA cycle and electron transport chain. Cytosolic Isocitrate dehydrogenase enzyme activity provides NADPH for the reductive biosynthesis.

4) α- Ketoglutarate - Alpha ketoglutarate forms the  first link between TCA cycle and amino acid metabolism (Figure-5).

Upon transamination, glutamate is produced from alpha keto glutarate. Glutamate can be-

a) Decarboxylated to form GABA (gamma amino butyric acid) which is a neurotransmitter

b) Aminated to form Glutamine which is used for the synthesis of pyrimidine nucleotides.

 Amphibolic role of TCA cycle

Figure-5- Involvement of the citric acid cycle in fatty acid, sterol, haem, purine and pyrimidine  biosynthesis, transamination, and gluconeogenesis.

5) Succinyl co A- It is used for-

a) Utilization of ketone bodies

b) Haem biosynthesis

6) Fumarate- Forms a link between urea cycle and TCA cycle.

7) Malate is used for the transportation of-

a) Oxaloacetate from mitochondrion to cytoplasm for channeling it in to the pathway of gluconeogenesis.

b) For transportation of reducing equivalents from cytoplasm to mitochondrion (Malate Aspartate shuttle).

8) Oxaloacetate- is used not only as a biocatalyst for stimulation of TCA cycle activity but it is also used for-

a) Glucose production in the pathway of gluconeogenesis

b) Formation of Aspartate by transamination

c) Aspartate is further used for the synthesis of purine and pyrimidine nucleotides

d) Aspartate can also be used for the synthesis of Asparagine.

e) Aspartate is also used for urea formation in urea cycle.

Summary of significance of TCA cycle

Role TCA intermediate Significance
a) Catabolic Role Acetyl co A Oxidation of  carbohydrate, fatty acids, amino acids, ketone bodies and alcohol
  TCA cycle intermediates such as Alpha keto glutarate, succinyl co A, Fumarate and oxaloacetate Oxidation of carbon skeleton of various amino acids
Each Acetyl co A yields 12 ATP molecules
b) Anabolic Role Acetyl co A Synthesis of fatty acids, cholesterol, ketone bodies, steroids, acetyl choline and used for detoxification
  Citrate Promotes activity of acetyl co A carboxylase and transports acetyl co A outside the mitochondrial for extra mitochondrial fatty acid synthesis.
  α- Keto glutarate Synthesis of Glutamate, GABA and Glutamine. GABA is a neurotransmitter whereas glutamine is required for pyrimidine biosynthesis.
  Succinyl co A Utilization of ketone bodies and haem biosynthesis
  Fumarate Link between urea and TCA cycles
  Malate Transporter of Oxaloacetate and reducing equivalents
  Oxaloacetate Substrate of gluconeogenesis, forms Aspartate and Asparagine.

Aspartate is needed for purine, pyrimidine and urea synthesis

Clinical Significance

Thus TCA cycle is vital to life due to its amphibolic role, no TCA cycle enzyme deficiency has yet been reported , perhaps this is not compatible with life.

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