Citric acid cycle : Central metabolic cycle and its Significance

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Citric acid cycle is also called Krebs Cycle and Tricarboxylic acid cycle. The citric acid cycle is a aerobic universal Acetyl~coA catabolic cycle. It is a central metabolic cycle. The cycle was first elucidated by scientist “Sir Hans Adolf Krebs” (LT, 1900 to 1981). He shared the Nobel Prize for physiology and Medicine in 1953 with Fritz Albert Lipmann, the father of ATP cycle. For their work in intermediary Metabolism.

citric acid cycle and Kreb cycle animation

Reactions of the Citric acid Cycle:


The acetyl CoA is condensed with Oxaloacetic acid (OAA) it gives Tricarboxylic acid Citric acid. This reaction is catalyzed by Citrate synthase.

Oxaloacetic acid + Acetyl ~ CoA –> Citric acid + HS~CoA

2. Dehydration:

Citric acid self dehydrates into Cis-Aconitate. This reaction is catalyzed by Aconitase.

Citric acid—> Cis-Aconitate + H2O

3. Hydration:

The cis-Aconitate is converted into IsoCitrate by using one water molecule. This reaction is catalyzed by Aconitase.

Cis-Aconitate + H2O –> IsoCitrate

4. Dehydrogenation:

IsoCitrate is converted into Oxalosuccinate. Here two protons (or) two hydrogen atoms are extracted from the Isocitrate by NAD+. This reaction is catalyzed by Isocitrate dehydrogenase.

Isocitrate + NAD –>  Oxalo succinate + NADH + H+

5. Decarboxylation:

Oxalosuccinate is decarboxylated into α-ketoglutarate. This reaction is catalyzed by Isocitrate dehydrogenase.

Oxalosuccinate –> α-ketoglutarate + CO2

6. Dehydrogenation:

α-ketoglutarate is converted into Succinyl~coA by taking one Acetyl~CoA and one molecule of NAD+. This reaction is catalyzed by α-ketoglutarate dehydrogenase.

α-ketoglutarate + Acetyl~CoA + NAD –>  Succinyl~coA + NADH + H+

7. Substrate-level-Phosphorylation:

Succinyl~coA is converted into Succinate. In this reaction one High energy compound is synthesized. Here GDP (or ADP) is converted into GTP (or ATP) by utilizing one phosphoric acid (inorganic acid) molecule. In animals GTP is produced, in case of plants it is ATP. This reaction is catalyzed by Succinyl~coA synthatase.

Succinyl~coA + GDP + Pi –> Succinate + GTP

8. Dehydrogenation:

Succinate is dehydrogenated into Fumarate by using FAD is a Proton acceptor. This reaction is catalysed by Succinate dehydrogenase.

Succinate + FAD –> Fumarate + FADH2

9. Hydration:

Fumarate is hydrated into Malate by taking one water molecule. This reaction is catalyzed by Fumarse.

Fumarate + H2O –> Malate

10. Dehydrogenation:

Malate is dehydrogenated into Oxaloacetic acid by using NAD as a proton acceptor. This reaction is catalyzed by Malate dehydrogenase.

Malate + NAD+ –> Oxaloacetic acid + NADH + H+

Regulation of Citric Acid Cycle:

The capacity of TCA cycle to generate energy for cellular needs is closely regulated by the availability of Substrate and the need of TCA cycle intermediates and demand for ATP.

  1. The formation of citrate from oxaloacetate and acetyl coA is an important part of control (Step 1). ATP acts as an allosteric inhibitor of citrate synthase. Citrate allosterically inhibits PFK, the key enzyme of glycolysis; stimulates Fructose-1,6-bisPhosphatase, a key enzyme of Gluconeogenesis and activates Acetyl CoA carboxylase, key enzyme of Fatty acid synthesis.
  2. Another control point is Isocitrate dehydrogenase reaction (step 3). ADP acts as a positive modifier enhancing the binding of substrate. the substrate binding also has a positive cooperative effect. NADH is an inhibitor and displaces NAD+ from its binding.
  3. α-ketoglutarate dehydrogenase is inhibited by succinyl~coA and NADH.
  4. The regulation of the cycle is by cellular needs of ATP. When the energy charge of the cell is low, as indicated by high level of NAD+ and FAD, the cycle operates at a faster rate. The cycle is tightly coupled to the respiratory chain providing ATP.

Net ATP Calculation of Citric acid cycle:

Step numberReactionsCoenzymeATP generated
Step 4 & 5Isocitrate -> α-ketoglutarateNADH3
Step 6α-ketoglutarate -> Succinyl~coANADH3
Step 7Succinyl ~ coA -> SuccinateGTP or ATP1
Step 8Succinate -> FumarateFADH22
Step 10Malate -> OxaloacetateNADH3

Inhibitors of TCA cycle:

  1. Aconitase is inhibited by Flouro Acetate. This is a non-competitive inhibition.
  2. α-ketoglutarate dehydrogenase is inhibited by Arsinite. This again is a non-competitive inhibition.
  3. Succinate dehydrogenase is inhibited by Malonate. This is a competitive inhibition.

Significance of TCA cycle:

  1. Citric acid cycle is the final common oxidative pathway. Carbohydrates are entering this cycle as Pyruvate and Acetyl~coA. Fatty acids are Broken down into Acetyl~coA which then enters in this cycle. All amino acids after transamination enter into some or other point in this cycle.
  2. In the body oxidation of fat need the help of oxaloacetate. One passage of cycle oxidizes acetyl~coA into two CO2 molecules. Here oxaloacetate acts as true catalyst; it enters into the cycle but is regenerated in the end. The major source of OAA is Pyruvate.
  3. Excess carbohydrates are converted as neutral fat and deposited in adipose tissue. The pathway is Glucose -> Pyruvate -> Acetyl~coA -> Fatty acid. However, fat can’t be converted to Glucose because Pyruvate dehydrogenase reaction is an absolutely irreversible.
  4. Fat is completely broken down in the cycle, and there is no net synthesis of carbohydrates from Fat.
  5. Many amino acids after transamination enter into the citric acid cycle.E.g: Glutamic acid enter at the level of alpha-ketoglutarate, and aspartate enters at OAA level. Those amino acids which are converted as members of TCA cycle can enter the Gluconeogenesis pathway through OAA.
  6. Some amino acids such as Leucine catabolized to Acetyl~coA or not converted to Glucose because Pyruvate to Acetyl~coA reaction is Irreversible. The acetyl~coA molecule either enter the TCA cycle and are completely oxidized, or are channeled into Ketone body formation. Hence, they are called as ketogenic amino acids.
  7. All other pathways such as beta-oxidation of fat (or) glycogen synthesis are either catabolic or anabolic. But TCA cycle is truly amphibolic. It is also called amphiphatic in nature.(Greek word amphi=both, pathos=feeling).
  8. Citric acid cycle acts as a source of precursor of biosynthetic pathways. Example is HEME is synthesized from succinyl~coA and Aspartate from OAA. There is a continuous efflux of four carbon units from the cycle. To counter balance this loss, and to keep the concentrations of the four carbon unit in the cell, anaplerotic reactions are essential. This is called Anaplerotic role of TCA cycle. (Greek work ana=up; plerotikos=to fill). Anaplerotic reactions are “filling up” reactions or influx reactions, which supply 4 carbon units to the TCA cycle.
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