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Citric Acid Cycle- Pathway, Energetics and Significance

During the citric acid cycle, NADH and FADH2 are released in the reduced form while two molecules of carbon dioxide are produced with one GTP/ATP.

Citric Acid Cycle


During the citric acid cycle, NADH and FADH2 are released in the reduced form while two molecules of carbon dioxide are produced along with one GTP/ATP.

The Krebs Cycle (Citric Acid Cycle)

Similar to the conversion of pyruvate into acetyl CoA in the mitochondria, the process takes place in their matrix. Except for succinate dehydrogenase that is embedded in the mitochondrial inner membrane, most citric acid cycle enzymes are soluble. Citric acid cycles are closed cycles in contrast to glycolysis, in which the first-stage compound is recycled at the last stage. It consists of eight redox reactions, dehydration reactions, hydration reactions, and decarboxylation reactions which lead to two carbon dioxide molecules, one GTP/ATP molecule, and reduced forms of FADH2 and NADH2. Due to the need to transfer NADH and FADH2 produced in the system to another pathway, it is an aerobic pathway. By preventing the transfer, the oxidation steps of the citrus acid cycle are also prevented. Although oxygen is not consumed directly by the citric acid cycle, nor is ATP produced directly either.

Processes Involved in the Citric Acid Cycle

Step 1
By combining an acetyl group (from the acetyl CoA) with a four-carbon oxaloacetate molecule, a six-carbon citrate molecule is formed. There is also a sulfhydryl group (-SH) associated with this that diffuses away from the CoA and is combined with another acetyl group. Because of its highly exergonic nature, this step is irreversible. Positive feedback and the availability of ATP control the rate of this reaction. The more ATP there is, the slower the reaction is. Alternatively, if the supply of ATP is low, the rate increases.

Step 2
One water molecule is lost and another is gained in the process of converting citrate into its isomer, isocitrate.

Step 3 and 4
Isocitrate is oxidized in step three. This results in a five-carbon molecule, α-ketoglutarate, along with two electrons and a molecule of CO2, which reduces NAD+ to NADH. ADP also exerts a positive effect on this step, through a negative feedback loop with ATP and NADH. In these steps, both electrons are released, reducing NAD+ to NADH, while carboxyl groups are released, leading to the formation of CO2. After the third step, α-Ketoglutarate is produced, and a succinyl group is produced after the fourth step. Succinyl CoA is formed when a CoA binds to a succinyl group. ATP, succinyl CoA, and NADH act as feedback inhibitors of the enzyme that catalyzes step four.

Step 5
The substitution of phosphate for coenzyme A produces a high-energy bond. The succinyl group on the substrate is converted into succinate when phosphorylation occurs, and either guanine triphosphate (GTP) or ATP are produced. An enzyme can have two different forms, called isoenzymes, depending on the tissue in which it is found. As an example, heart muscle and skeletal muscle absorb large amounts of ATP. These tissues produce ATP. In tissues with an abundance of anabolic pathways, including the liver, the second enzyme form is found. The enzyme generates GTP. Despite being energetically equivalent to ATP, GTP has limited application. Proteins are primarily synthesized from GTP.

Step 6
The sixth step involves converting succinate into fumarate through dehydration. FAD receives two hydrogen atoms as part of the transfer process, producing FADH2. While the electrons in these atoms do not possess enough energy to reduce NAD+, they do possess enough energy to reduce FAD. In contrast to NADH, this carrier is directly linked to the electron transport chain, and therefore does not stay attached to the enzyme. A mitochondrial enzyme is located in the inner membrane of the mitochondrion, which allows it to catalyze this step.

Step 7
During step seven, fumarate is added to water to produce malate. The citric acid cycle ends with the oxidation of malate to produce oxaloacetate. This results in another molecule of NADH being produced.

The Citric Acid Cycle's Products

The citric acid cycle requires two carbon atoms for each acetyl group in a glucose molecule. After each cycle, two carbon dioxide molecules are released, even though the molecules may not contain all of the carbon atoms that have recently been added. When the acetyl carbon atoms are released on later turns of the cycle, all six carbon atoms from the original glucose molecule are eventually incorporated into carbon dioxide. As each turn of the cycle proceeds, one FADH2 molecule and three NADH molecules are formed. After these carriers have completed aerobic respiration, ATP molecules will be formed. Each cycle also produces one GTP or ATP molecule. Citric acid cycle is an amphibolic cycle (both catabolic and anabolic) in that it synthesizes several intermediate compounds that are necessary for the synthesis of non-essential amino acids.


In combination with oxidative phosphorylation, ETC oxidizes 3 NADH to produce 9ATP. FADH2 results in 2ATP being formed. A single substrate phosphorylation occurs. A single acetyl CoA produces 12 ATP.


  • Glucose, fats, and amino acids are all oxidized in Kreb's cycle or the citric acid cycle.
  • Many animals must obtain their energy from other sources than glucose.
  • The Krebs cycle starts with amino acids (metabolic products of proteins). Pyruvate and other intermediates are created as pyruvate is produced during deamination. By deamination, alanine becomes pyruvate, glutamate becomes -ketoglutarate, and aspartate becomes oxaloacetate.
  • Acyl CoA is created during the Krebs cycle after fatty acids undergo -oxidation.
  • In the Krebs cycle, acetyl CoA is formed from fatty acids through -oxidation. An abundance of energy is released after nutrients are completely oxidized.
  • This enzyme is involved in gluconeogenesis, lipogenesis, and amino acid interconversion.
  • It is possible to synthesize amino acids, nucleotides, cytochromes, chlorophylls, etc., from many intermediate compounds.
  • Citric acid cycles rely heavily on vitamins. Niacin, riboflavin, thiamine, and pantothenic acid as cofactors for several enzymes (FAD, NAD), as well as coenzyme A.
  • For physical and chemical work, Krebs cycle regulation depends on the availability of NAD+ and the utilization of ATP.
  • Neurological damage is related to genetic defects of Krebs cycle enzymes.Damage to liver cells can have a significant impact on biological processes because the liver performs most of them. Convulsions and coma are symptoms of hyperammonaemia in liver diseases. The reason for this is due to the reduced ATP production caused by glutamate production, which forms glutamine alongside the withdrawal of α -ketoglutarate.
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Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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