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TCA Cycle (Tricarboxylic Acid Cycle): Biochemistry, Metabolism, Enzymes

TCA Cycle (Tricarboxylic Acid Cycle): Biochemistry, Metabolism, Enzymes

Edited By Irshad Anwar | Updated on Jul 02, 2025 06:59 PM IST

What Is The TCA Cycle?

The TCA cycle is also called the Krebs or citric acid cycle. It is one of the most basic metabolic pathways of cellular respiration. The process is the second step in aerobic respiration in the mitochondrial matrix of eukaryotic cells. The TCA cycle is the pathway through which the complete oxidation of acetyl-CoA, originating from carbohydrates, fats, and proteins, takes place into carbon dioxide and energy.

Overview Of The TCA Cycle

The TCA cycle is an aerobic pathway that produces high-energy electron carriers, NADH and FADH2, crucial for the production of ATP in the electron transport chain. The cycle functions as a closed loop, regenerating at the end of its starting molecule, oxaloacetate. As such, it is constantly regenerated so that the cycle may continue so long as supplies of acetyl-CoA are available.

Steps Of The TCA Cycle

Now, there are a total of eight major steps involved in the cycle of the TCA cycle, each of which is catalyzed by specific enzymes. These include citrate formation—one in which acetyl-CoA is combined with the four-carbon compound oxaloacetate to form the six-carbon compound citrate while releasing the CoA group—and isomerization, where citrate is converted into isocitrate in a two-step process involving the loss, followed by the gain, of a water molecule.

  1. Oxidative Decarboxylation: Isocitrate gets oxidized into alpha-ketoglutarate by releasing one carbon dioxide molecule and reducing NAD+ into NADH. The catalyst of this reaction is isocitrate dehydrogenase.

  2. Further Decarboxylation: Alpha-ketoglutarate is oxidized while reducing NAD+ into NADH, and another carbon dioxide molecule is released, together with the formation of a four-carbon compound known as succinyl-CoA, catalyzed by alpha-ketoglutarate dehydrogenase.

  3. Substrate-Level Phosphorylation: Succinyl-CoA is converted to succinate, and a phosphate group is transferred to ADP to produce ATP (or GTP).

  4. Oxidation of Succinate: In this step, succinate gets oxidized to form fumarate, with two hydrogen atoms transferred to FAD to result in FADH2.

  5. Hydration: A water molecule is added to fumarate, converting it to malate.

  6. Final Oxidation: Malate gets oxidized to again result in oxaloacetate, producing another NADH in the process.

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End Products Of The TCA Cycle

The products of each cycle of the TCA are:

  1. 6 NADH: Those are the high-energy electron carriers that will feed into the electron transport chain.

  2. 2 FADH2: Another electron carrier

  3. 2 ATP; IP: Those are products of substrate-level phosphorylation.

  4. 4 CO2: It is carbon dioxide, a waste product in the cycle.

Importance Of The TCA Cycle

There are several reasons that the TCA cycle is important :

  1. Energy production: It generates NADH and FADH2 for ATP synthesis on the electron transport chain.

  2. Biosynthesis: The TCA cycle intermediates act as precursors in the synthesis of amino acids, nucleotides, and other biomolecules.

  3. Production of Carbon Dioxide: Carbon dioxide is generated in this cycle and is exhaled out from the body through respiration.

TCA Cycle Regulation

The TCA cycle is strictly regulated so the rate of energy production within the cell can be adjusted to the metabolic needs of the cell. Regulation of the TCA cycle exists at several key enzymes, including :

  1. Citrate Synthase: Controls entry of acetyl-CoA into the cycle.

  2. Isocitrate Dehydrogenase: It is inhibited by the levels of NADH and ATP. Thus, it makes isocitrate's conversion to alpha-ketoglutarate controlled.

  3. Alpha-Ketoglutarate Dehydrogenase: The same type of control occurs for this enzyme as for isocitrate dehydrogenase. This is to maintain energy production in balance with the availability of substrates.

The Connection Between Glycolysis And The TCA Cycle

The TCA cycle is also directly linked with glycolysis because the products of the latter get converted into acetyl-CoA. As soon as the glycolysis has taken place in the cytoplasm, pyruvate is transported into the mitochondria, where it undergoes oxidation decarboxylation to produce acetyl-CoA. This acetyl-CoA then enters the TCA cycle for further oxidation and thus energy production.

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Frequently Asked Questions (FAQs)

1. What is the main function of the TCA cycle?

 The major role of the TCA cycle is to oxidize acetyl-CoA to carbon dioxide, reducing NAD+ and FAD to NADH and FADH2. Ultimately, in the electron transport chain, this results in the production of ATP.

2. Within the cell, where is the TCA cycle located?

 In eukaryotic cells, the TCA cycle is located in the matrix of the mitochondria.

3. How many molecules of ATP are made directly from one turn of the TCA cycle?

 On one turn of the TCA cycle, one molecule of GTP, or ATP, is directly generated via substrate-level phosphorylation.

4. What happens to the carbon dioxide produced by the TCA cycle?

 The carbon dioxide produced by the TCA cycle is released from the cell and finally leaves the body through exhalation by the animal during respiration.

5. How is the TCA cycle controlled?

Key enzymes in the TCA cycle are regulated, responding to the levels of substrates and products to ensure that the cycle runs efficiently in response to the requirements for energy in the cell.

6. What is the net energy yield of one turn of the TCA cycle?
One turn of the TCA cycle produces 3 NADH, 1 FADH2, and 1 GTP (equivalent to ATP). However, the cycle itself doesn't directly produce ATP in large quantities. Its main role is to generate reduced coenzymes (NADH and FADH2) for the electron transport chain.
7. What is the role of NAD+ in the TCA cycle?
NAD+ serves as an electron acceptor in several steps of the TCA cycle. It's reduced to NADH by accepting electrons from substrates, particularly during the oxidative decarboxylation reactions catalyzed by isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase. The NADH produced then carries these high-energy electrons to the electron transport chain.
8. How does the TCA cycle differ in C3 and C4 plants?
In C3 plants, the TCA cycle operates similarly to other organisms. In C4 plants, the cycle is modified in bundle sheath cells to support the increased demand for carbon skeletons used in the C4 pathway. The cycle may be more flexible, with some steps bypassed to produce specific intermediates needed for C4 metabolism.
9. What is the role of fumarase in the TCA cycle?
Fumarase catalyzes the reversible hydration of fumarate to malate in the TCA cycle. This step is important for the cycle's continuity and also plays a role in the malate-aspartate shuttle, which helps transfer reducing equivalents between the mitochondria and cytosol.
10. How does the TCA cycle contribute to fatty acid synthesis?
The TCA cycle contributes to fatty acid synthesis by producing citrate, which can be exported from the mitochondria to the cytosol. In the cytosol, citrate is cleaved by ATP citrate lyase to produce acetyl-CoA, the building block for fatty acid synthesis.
11. What is the TCA cycle and why is it important?
The TCA cycle, also known as the Krebs cycle or citric acid cycle, is a series of chemical reactions in cellular respiration that generates energy from the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. It's crucial because it produces NADH and FADH2, which are used in the electron transport chain to generate ATP, the cell's energy currency.
12. Why is the TCA cycle considered amphibolic?
The TCA cycle is considered amphibolic because it functions in both catabolic (breakdown) and anabolic (biosynthesis) processes. It breaks down acetyl-CoA for energy production while also providing precursors for various biosynthetic pathways, such as amino acid synthesis.
13. How does the TCA cycle contribute to the electron transport chain?
The TCA cycle contributes to the electron transport chain by producing NADH and FADH2. These reduced coenzymes carry high-energy electrons to the electron transport chain, where they are used to generate a proton gradient that drives ATP synthesis through oxidative phosphorylation.
14. What is the significance of α-ketoglutarate in the TCA cycle?
α-Ketoglutarate is a key intermediate in the TCA cycle. It undergoes oxidative decarboxylation to form succinyl-CoA, producing NADH. Additionally, α-ketoglutarate serves as an important link between carbon and nitrogen metabolism, as it can be converted to glutamate, a crucial amino acid precursor.
15. What is the importance of malate in the TCA cycle?
Malate plays several important roles in the TCA cycle. It's oxidized to oxaloacetate in the final step of the cycle, regenerating the starting compound. Malate can also be exported from the mitochondria to the cytosol via the malate-aspartate shuttle, helping to transfer reducing equivalents across the mitochondrial membrane.
16. Where does the TCA cycle occur in plant cells?
In plant cells, the TCA cycle takes place in the matrix of mitochondria. This is the same location as in animal cells, highlighting the conserved nature of this metabolic pathway across different organisms.
17. What is the role of lipoic acid in the TCA cycle?
Lipoic acid is an important cofactor in the TCA cycle. It's a component of the α-ketoglutarate dehydrogenase and pyruvate dehydrogenase complexes. Lipoic acid helps transfer acyl groups and electrons during the oxidative decarboxylation reactions catalyzed by these enzyme complexes.
18. How does oxygen availability affect the TCA cycle in plants?
Oxygen availability significantly affects the TCA cycle in plants. Under normal aerobic conditions, the cycle operates fully. However, under hypoxic (low oxygen) conditions, such as in waterlogged roots, the cycle is modified. Some steps may be bypassed, and alternative pathways like fermentation may be activated to maintain energy production.
19. How does the TCA cycle adapt during seed germination in plants?
During seed germination, the TCA cycle adapts to support the rapid growth and energy demands of the developing seedling. In oil-rich seeds, the glyoxylate cycle, a modified version of the TCA cycle, becomes active to convert stored lipids into carbohydrates. As the seedling develops, the full TCA cycle becomes more prominent to support increased energy production.
20. What is the first step of the TCA cycle?
The first step of the TCA cycle is the condensation of acetyl-CoA with oxaloacetate to form citrate. This reaction is catalyzed by the enzyme citrate synthase and is often considered the pace-setting step of the cycle.
21. Why is oxaloacetate considered both a substrate and a product of the TCA cycle?
Oxaloacetate is both a substrate and a product because it's consumed in the first step of the cycle when it combines with acetyl-CoA to form citrate, but it's also regenerated in the last step when malate is oxidized. This regeneration allows the cycle to continue.
22. What role does aconitase play in the TCA cycle?
Aconitase catalyzes the second step of the TCA cycle, converting citrate to isocitrate via a cis-aconitate intermediate. This isomerization step is crucial for the subsequent oxidative decarboxylation reactions in the cycle.
23. What is substrate-level phosphorylation in the TCA cycle?
Substrate-level phosphorylation in the TCA cycle occurs during the conversion of succinyl-CoA to succinate, catalyzed by succinyl-CoA synthetase. This reaction produces GTP (or ATP in some organisms) directly, without involving the electron transport chain.
24. How does succinate dehydrogenase differ from other TCA cycle enzymes?
Succinate dehydrogenase is unique among TCA cycle enzymes because it's the only enzyme that's also part of the electron transport chain (Complex II). It catalyzes the oxidation of succinate to fumarate, reducing FAD to FADH2 in the process, and directly transfers electrons to the ubiquinone pool.
25. How does the TCA cycle regulate itself?
The TCA cycle regulates itself through feedback inhibition. High levels of ATP and NADH inhibit key enzymes like citrate synthase and isocitrate dehydrogenase. Additionally, the availability of substrates (acetyl-CoA and oxaloacetate) and the energy state of the cell (ATP/ADP ratio) also regulate the cycle's activity.
26. How does the TCA cycle differ in plants during the day versus night?
In plants, the TCA cycle operates differently during day and night. During the day, when photosynthesis is active, the cycle may be partially suppressed as the plant uses light energy. At night, the cycle becomes more active to provide energy through respiration. Some steps may be bypassed during the day to produce precursors for biosynthesis.
27. How does citrate synthase control the entry of acetyl-CoA into the TCA cycle?
Citrate synthase controls the entry of acetyl-CoA into the TCA cycle by being allosterically inhibited by ATP and NADH. When energy levels are high (indicated by high ATP and NADH), the enzyme's activity decreases, slowing down the cycle. This regulation helps match energy production with cellular energy demands.
28. How does isocitrate dehydrogenase regulate the TCA cycle?
Isocitrate dehydrogenase is a key regulatory enzyme in the TCA cycle. It's allosterically activated by ADP and inhibited by ATP and NADH. This regulation allows the enzyme to respond to the cell's energy state, increasing or decreasing the flux through the cycle as needed.
29. How does the TCA cycle contribute to the plant's response to stress?
The TCA cycle contributes to plant stress response by providing precursors for the synthesis of stress-related compounds. For example, it produces α-ketoglutarate, which can be converted to proline, an osmolyte that helps plants tolerate drought and salinity stress. The cycle's flexibility also allows plants to adjust their metabolism under different stress conditions.
30. How does the TCA cycle connect to glycolysis?
The TCA cycle connects to glycolysis through the conversion of pyruvate to acetyl-CoA. Pyruvate, the end product of glycolysis, is transported into the mitochondria and oxidatively decarboxylated to form acetyl-CoA, which then enters the TCA cycle.
31. How does the TCA cycle contribute to gluconeogenesis?
The TCA cycle contributes to gluconeogenesis by providing oxaloacetate, which can be converted to phosphoenolpyruvate, a key intermediate in glucose synthesis. This process, known as anaplerosis, replenishes TCA cycle intermediates that have been withdrawn for biosynthetic processes.
32. What is anaplerosis and why is it important for the TCA cycle?
Anaplerosis refers to the replenishment of TCA cycle intermediates that have been withdrawn for biosynthetic processes. It's important because it maintains the cycle's ability to function continuously. Anaplerotic reactions often involve the carboxylation of pyruvate or phosphoenolpyruvate to form oxaloacetate.
33. How does the glyoxylate cycle relate to the TCA cycle in plants?
The glyoxylate cycle is a variation of the TCA cycle found in plants, particularly in seeds during germination. It allows plants to convert acetyl-CoA from fatty acid breakdown into glucose. The glyoxylate cycle shares some enzymes with the TCA cycle but bypasses the CO2-generating steps, allowing for net carbon conservation.
34. What is the role of CoA in the TCA cycle?
Coenzyme A (CoA) plays a crucial role in the TCA cycle. It's involved in the formation of acetyl-CoA, the starting substrate of the cycle, and in the conversion of α-ketoglutarate to succinyl-CoA. CoA helps transfer acyl groups and is essential for the energy-yielding reactions of the cycle.
35. What is the connection between the TCA cycle and amino acid metabolism?
The TCA cycle is closely connected to amino acid metabolism. Several TCA cycle intermediates serve as precursors for amino acid synthesis (e.g., α-ketoglutarate for glutamate). Conversely, amino acids can be catabolized to form TCA cycle intermediates, allowing them to enter the cycle as an energy source.
36. What is the significance of the irreversible steps in the TCA cycle?
The irreversible steps in the TCA cycle, catalyzed by citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase, are significant because they help drive the cycle forward and are often regulatory points. These steps make the overall cycle effectively irreversible under physiological conditions.
37. What is the role of thiamine pyrophosphate (TPP) in the TCA cycle?
Thiamine pyrophosphate (TPP) is a crucial coenzyme in the TCA cycle. It's required for the activity of the α-ketoglutarate dehydrogenase complex, which catalyzes the oxidative decarboxylation of α-ketoglutarate to succinyl-CoA. TPP helps in the transfer of the two-carbon unit during this reaction.
38. How does the TCA cycle interact with the electron transport chain in plant mitochondria?
The TCA cycle interacts closely with the electron transport chain in plant mitochondria. It produces NADH and FADH2, which donate electrons to the chain. Additionally, succinate dehydrogenase (Complex II) is both a TCA cycle enzyme and a component of the electron transport chain, directly linking the two processes.
39. What is the importance of isocitrate in the TCA cycle?
Isocitrate is a key intermediate in the TCA cycle. Its oxidation by isocitrate dehydrogenase is an important regulatory point in the cycle. This step produces NADH and is one of the irreversible reactions that drive the cycle forward. Isocitrate can also be used in other metabolic pathways, such as the glyoxylate cycle in plants.
40. How does the plant cell coordinate the TCA cycle with photosynthesis?
Plants coordinate the TCA cycle with photosynthesis through various regulatory mechanisms. During the day, when photosynthesis is active, the TCA cycle may be partially suppressed as the plant uses light energy. The cycle can be modified to produce precursors for biosynthesis rather than focusing on energy production. At night, the cycle becomes more active for energy production through respiration.
41. What is the role of biotin in the TCA cycle?
Biotin is a coenzyme involved in carboxylation reactions. While not directly part of the TCA cycle, it's crucial for anaplerotic reactions that replenish cycle intermediates. For example, biotin is required for the activity of pyruvate carboxylase, which converts pyruvate to oxaloacetate, an important anaplerotic reaction.
42. How does the TCA cycle contribute to nitrogen assimilation in plants?
The TCA cycle contributes to nitrogen assimilation in plants by providing carbon skeletons for amino acid synthesis. Specifically, α-ketoglutarate from the cycle can be aminated to form glutamate, a key amino acid and nitrogen carrier in plants. This links carbon metabolism from the TCA cycle with nitrogen metabolism.
43. What is the significance of the malate-aspartate shuttle in relation to the TCA cycle?
The malate-aspartate shuttle is important for transferring reducing equivalents (electrons) from the cytosol to the mitochondria. It uses malate, a TCA cycle intermediate, to carry electrons across the mitochondrial membrane. This shuttle helps maintain the NAD+/NADH balance in different cellular compartments and supports the continued operation of the TCA cycle.
44. What is the role of succinyl-CoA synthetase in the TCA cycle?
Succinyl-CoA synthetase catalyzes the conversion of succinyl-CoA to succinate in the TCA cycle. This reaction is coupled to the formation of GTP (or ATP in some organisms) through substrate-level phosphorylation. It's the only step in the cycle that directly produces a high-energy phosphate compound without involving the electron transport chain.
45. How does the TCA cycle contribute to the production of secondary metabolites in plants?
The TCA cycle contributes to the production of secondary metabolites in plants by providing precursors and energy. For example, citrate can be used in the synthesis of certain flavonoids, while α-ketoglutarate is a precursor for some alkaloids. The energy and reducing power generated by the cycle also support various biosynthetic pathways for secondary metabolites.
46. What is the importance of the α-ketoglutarate dehydrogenase complex in the TCA cycle?
The α-ketoglutarate dehydrogenase complex catalyzes the oxidative decarboxylation of α-ketoglutarate to succinyl-CoA, producing NADH. This is one of the irreversible steps in the cycle and a key regulatory point. The complex is sensitive to the energy state of the cell and can be inhibited by high levels of NADH and succinyl-CoA.
47. How does the TCA cycle in plants respond to changes in carbon dioxide levels?
The TCA cycle in plants can respond to changes in CO2 levels. Under elevated CO2, there may be an increase in the activity of certain TCA cycle enzymes to support increased biomass production. Conversely, under low CO2 conditions, the cycle may be modified to conserve carbon, with some intermediates diverted to other pathways like photorespiration.

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