The Krebs Cycle, its Steps, and the Role of ATP and AMP

The Krebs Cycle is referred to as the Citric Acid Cycle or tricarboxylic acid (TCA) cycle and is the second stage of cellular respiration. It is a fundamental metabolic pathway that happens in the mitochondria of eukaryotic cells.

The Krebs Cycle:

The image indicated the eight steps of the Krebs Cycle
The image indicated the eight steps of the Krebs Cycle/image credit

The Krebs Cycle is referred to as the Citric Acid Cycle or tricarboxylic acid (TCA) cycle and is the second stage of cellular respiration. It is a fundamental metabolic pathway that happens in the mitochondria of eukaryotic cells. It plays a pivotal role in the aerobic respiration of cells, which generates energy by oxidizing acetyl-CoA. Carbohydrates, fats, and proteins breakdown to produce acetyl-CoA

Overview of the Steps of the Krebs Cycle:

The Steps of the Krebs Cycle are as follows;

1. Acetyl-CoA Entry:

With the entry of acetyl-CoA, a two-carbon molecule, into the mitochondria, the cycle begins. Acetyl-CoA is formed in the first stage of cellular respiration through glycolysis from the breakdown of glucose and the conversion of pyruvate.

2. Combination with Oxaloacetate:

 In this step, acetyl-CoA combines with a four-carbon molecule called oxaloacetate, which forms citrate, a six-carbon compound.

3. Isomerization and Decarboxylation:

Citrate now undergoes isomerization and subsequently forms decarboxylation reactions, leading to the release of two molecules of carbon dioxide (CO2). During this process, citrate is transformed into a five-carbon compound called alpha-ketoglutarate.

4. Further Decarboxylation:

Further, alpha-ketoglutarate undergoes decarboxylation and releases another molecule of CO2 forming a four-carbon compound called succinyl-CoA. During this step, NADH (nicotinamide adenine dinucleotide, reduced) is also produced.

5. Substrate-level Phosphorylation:

In this step, succinyl-CoA undergoes substrate-level phosphorylation, which transfers a phosphate group to ADP and forms ATP. The result of this reaction is the formation of succinate.

6. Reduction of FAD:

Now succinate is oxidized to fumarate, and FAD (flavin adenine dinucleotide) is reduced to form FADH2.

7. Hydration:

 In this step fumarate undergoes hydration, being catalyzed by an enzyme, to form malate.

8. Regeneration of Oxaloacetate:

In the last step, malate is further oxidized to regenerate oxaloacetate. This step also witnesses the reduction of NAD+ to NADH.

Reaction of the Krebs Cycle:

The overall reaction of the Krebs Cycle can be summarized and represented as follows:

Acetyl-CoA + 3 NAD+ + FAD + ADP + Pi + 2 H2O → 2 CO2 + 3 NADH + FADH2 + ATP + 3 H+ + CoA

The cycle completes with the regeneration of oxaloacetate that gets, ready to combine with another acetyl-CoA molecule. In the final stage of cellular respiration, the electrons carried by NADH and FADH2 produced during the Krebs Cycle are then used in the electron transport chain to generate ATP in oxidative phosphorylation.

Roles of ATP and AMP:

Adenosine triphosphate (ATP) and adenosine monophosphate (AMP) play vital roles in regulating the Krebs Cycle or Citric Acid Cycle. These molecules serve as indicators of the energy level within a cell and help in coordinating metabolic processes. The levels of ATP and AMP activate feedback mechanisms that influence the activity of key enzymes in the Krebs Cycle.

1. Energy Status and ATP Levels:

High levels of ATP mean a well-energized cell, which indicates sufficient energy available for cellular processes. In this state, the cell may downregulate ATP-producing pathways to avoid unnecessary energy production. The Krebs Cycle is very sensitive to ATP levels. When ATP concentrations are high certain enzymes are inhibited in the cycle. For example, the enzyme isocitrate dehydrogenase (IDH), a key regulatory enzyme in the cycle, is inhibited by high ATP levels.

2. AMP and Activation of Krebs Cycle:

When cellular energy levels are low, ATP is being rapidly utilized, and adenosine monophosphate (AMP) levels increase. Elevated AMP levels serve as an indicator of energy depletion. In response to low ATP and high AMP levels, certain enzymes in the Krebs Cycle are activated. For example, increased levels of AMS stimulate Isocitrate dehydrogenase.

3. AMP-Activated Protein Kinase (AMPK):

AMP also activates an important cellular energy sensor known as AMP-activated protein kinase (AMPK). After being activated, AMPK starts various responses to restore cellular energy balance. One of its activities is to enhance the catabolic pathways that generate ATP, including the promotion of the Krebs Cycle. AMPK phosphorylates enzymes and transcription factors, that gives rise to ATP production and conservation.

4. Integration with Other Pathways:

The regulation of the Krebs Cycle by ATP and AMP is part of the cellular coordination of energy metabolism. These molecules coordinate with other pathways, such as glycolysis and fatty acid oxidation, to maintain energy homeostasis.

The levels of ATP and AMP serve as important signals for the regulation of the Krebs Cycle. High ATP levels inhibit certain enzymes in the cycle, preventing unnecessary ATP production when energy levels are sufficient. On the other hand, elevated AMP levels activate the cycle, promoting ATP generation to meet the cellular energy demand. This dynamic regulation ensures that the Krebs Cycle responds to the energy needs of the cell and contributes to overall cellular energy homeostasis.


In conclusion, the Krebs Cycle is an important component of cellular respiration, providing the necessary electrons and energy-rich molecules (NADH and FADH2) for the electron transport chain to produce ATP, the main component of cellular energy. Click to get your Gift

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1 Comment

  • February 18, 2024 at 8:13 pm

    […] are also specific. The three principal stages of aerobic respiration include glycolysis, the Krebs cycle (or citric acid cycle), and the electron transport […]


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