Kreb Cycle (Citric Acid Cycle, or TCA cycle (tricarboxylic acid cycle)), is a central metabolic pathway where the sequence of biochemical reactions releases energy stored in the form of ATP. The Krebs Cycle takes place in the mitochondria. The Krebs Cycle was discovered by Hans Krebs.
The cycle starts with acetyl-CoA which is derived from carbohydrates, fats, and proteins. It enters the cycle and gets converted into citrate, a six-carbon molecule. In this article, we will cover the Krebs cycle, its location, steps, and significance.
What is Kreb Cycle?
Kreb cycle is a series of biochemical reactions in a closed loop. The TCA cycle plays a central role in cell metabolism as it receives products from various substrates. The TCA cycle is involved in both anabolic and catabolic processes and is a tightly regulated cycle. The end products after each turn of the cycle are one GTP or ATP molecule, three NADH molecules, and one FADH2 molecule. These are required to transfer electrons to the mitochondrial respiratory chain, also known as the electron transport chain (ETC).
Where Does Kreb Cycle Takes Place?
- In eukaryotes: The citric acid cycle takes place in the matrix of the mitochondria.
- In prokaryotes: It takes place in the protoplasm.
- Pyruvate is produced in the cytosol of the cell. Pyruvate is converted to acetyl CoA and is transported to the mitochondrial matrix, the innermost part of the mitochondria.
Krebs Cycle Diagram
The citric acid cycle or Krebs cycle is given below showing all its steps:
Kreb Cycle is a Part of Cellular Respiration
The Kreb cycle in cellular respiration is a catabolic reaction and takes place within the cell. It is a four-stage process in which glucose is oxidized to carbon dioxide and oxygen is reduced to water. In this process, energy is released that is stored in the form of ATP molecules. Each molecule of glucose produces 36 to 38 ATPs. The 4 stages of cellular respiration are as follows:
Stage 1: Glycolysis
The glycolysis takes place in the cytoplasm of the cell. Partial oxidation of glucose(6- carbon molecule) takes place from two molecules of pyruvate (3-carbon molecule). In this reaction, ATP is produced, and NAD is converted to NADH.
Stage 2: Pyruvate oxidation
Pyruvate, formed during glycolysis, enters the mitochondria matrix and undergoes oxidative decarboxylation to form two molecules of acetyl CoA. In this reaction, the Pyruvate dehydrogenase enzyme acts as a catalyst. Carbon dioxide and NADH are produced in this step.
Stage 3: Kreb cycle
In the mitochondrial matrix, Acetyl CoA reacts with oxaloacetate to form citrate(6 carbon). In this process, 2 molecules of CO2 are released, oxaloacetate is recycled, and the energy is stored in the form of ATP and other high-energy compounds like NADH and FADH.
Stage 4: Oxidative phosphorylation
The NADH and FADH2 generated in the preceding stages transfer their electrons to the electron transport chain, located on the inner mitochondrial membrane. NAD and FAD are regenerated and oxygen is reduced to water.
Kreb Cycle Steps
The Krebs cycle is a series of chemical reactions that occur in the mitochondria of cells. The steps of the Kreb cycle are as follows:
Step 1: The cycle starts with the entry of a two-carbon acetyl group derived from acetyl-CoA combined with a four-carbon compound oxaloacetate. Six-carbon molecule known as citrate is formed. The reaction is catalyzed by the enzyme citrate synthase.
Step 2: Isocitrate, the isomer of Citrate is formed. It is a hydration reaction and is catalyzed by the enzyme aconitase.
Step 3: Isocitrate undergoes an oxidative decarboxylation reaction, realizing a molecule of carbon dioxide (CO2) and producing NADH. This step is catalyzed by the enzyme isocitrate dehydrogenase.
Step 4: Isocitrate is oxidized to alpha-ketoglutarate. Carbon dioxide and NADH are produced in this step, which is catalyzed by the enzyme alpha-ketoglutarate dehydrogenase complex.
Step 5: Alpha-ketoglutarate is oxidized. Carbon dioxide and NADH are produced. Guanosine diphosphate (GDP) is phosphorylated to form guanosine triphosphate (GTP), which gets converted into ATP. The reaction is catalyzed by the enzyme alpha-ketoglutarate dehydrogenase complex.
Step 6: Alpha-ketoglutarate is converted to succinyl-CoA, and one molecule of NADH is produced. The reaction is catalyzed by the alpha-ketoglutarate dehydrogenase complex.
Step 7: Succinyl-CoA reacts with a molecule of guanosine diphosphate (GDP), and forms one molecule of guanosine triphosphate (GTP) and succinate. The reaction is catalyzed by the enzyme succinyl-CoA synthetase.
Step 8: Succinate is oxidized to fumarate, and FADH2 (Flavin adenine dinucleotide) is produced. The reaction is catalyzed by the enzyme succinate dehydrogenase, which is also a part of the electron transport chain.
Step 9: Fumarate is hydrated to malate. The reaction is catalyzed by the enzyme fumarase.
Step 10: Malate is oxidized to oxaloacetate, and one molecule of NADH is produced. The reaction is catalyzed by the enzyme malate dehydrogenase.
The cycle can begin again if more molecule of acetyl-CoA is available.
Krebs Cycle Enzymes
In eukaryotic cells, the enzymes orchestrating the citric acid cycle reactions reside within the mitochondria's matrix, with exceptions like succinate dehydrogenase and aconitase, found in the inner mitochondrial membrane. A shared feature among these enzymes is their dependence on Mg2+ for catalytic activity.
The citric acid cycle involves several enzymatic steps, each facilitated by a specific enzyme:
- Citrate synthase
- Aconitase
- Isocitrate dehydrogenase
- α-ketoglutarate dehydrogenase
- Succinyl-CoA synthetase
- Succinate dehydrogenase
- Fumarase
- Malate dehydrogenase
Regulation of Krebs Cycle
Regulation of the TCA cycle occurs at three distinct points and includes the three following enzymes:
- Citrate synthase
- Isocitrate dehydrogenase
- Alpha-ketoglutarate dehydrogenase.
Kreb Cycle Products
The Calvin cycle produces products which can be classified into - intermediate products and end products.
Intermediate Products of Krebs Cycle
The intermediate products help in the continuation of the cycle and act as key molecules for other biosynthetic pathways. The intermediate products formed in the Kreb cycle are:
- Citrate (Citric acid)
- Isocitrate
- Oxoglutarate
- Succinyl- CoA
- Succinate
- Fumarate
- Malate
- Oxaloacetate (oxaloacetic acid)
They help in the generation of energy-rich molecules such as ATP, NADH, and FADH2, which play an important role in cellular respiration and energy production.
End Products of TCA or Kreb Cycle
The citric acid cycle in one round or one molecule of acetyl CoA produces the following end products:
(I) 2 molecules of CO2 are released. Removal of CO2 or decarboxylation of citric acid takes place at two places:
- In the formation of α ketoglutarate (5C) from isocitrate (6C).
- In the conversion of α ketoglutarate (5C) to succinyl CoA (4C).
(II) In the formation of succinyl CoA from succinate succinyl CoA one ATP is produced.
(III) NAD+ are reduced to NADH and 1 FAD+ is converted to FADH2 in the following reactions:
- Isocitrate to α ketoglutarate → NADH
- α ketoglutarate to succinyl CoA → NADH
- Succinate to fumarate → FADH2
- Malate to Oxaloacetate → NADH
Two cycles are required per glucose molecule as 2 pyruvate molecule produces 2 acetyl molecule through oxidative decarboxylation. A single molecule of NADH gives 2-3 ATPs and one FADH2 gives 2 ATPs on oxidation in the electron transport chain. Therefore,
Kreb cycle on complete oxidation of glucose produces 4 CO2, 6 NADH, 2 FADH2, and 2 ATPs.
Krebs Cycle Equation/Reaction
2Acetyl CoA + 6NAD+ + 2FAD + 2 ADP + 2Pi +2 H2O → 4CO2 + 6NADH + 2FADH2 + 2ATP + 2CoA
Krebs Cycle Summary
Location - Takes place in the mitochondria of eukaryotic cells and the protoplasm of prokaryotic cells.
Steps of the Krebs Cycle - The various steps involved are:
- Acetyl-CoA Formation
- Acetyl-CoA combines with oxaloacetate to form citrate.
- Isomerization
- Citrate is converted to isocitrate.
- Decarboxylation
- Isocitrate undergoes oxidative decarboxylation to form α-ketoglutarate, releasing CO2 and producing NADH.
- Second Decarboxylation
- α-ketoglutarate is decarboxylated to form succinyl-CoA, releasing CO2 and producing NADH.
- Succinyl-CoA Formation
- Succinyl-CoA is produced from α-ketoglutarate, generating GTP/ATP and NADH.
- Succinate Formation
- Succinyl-CoA is converted to succinate, producing FADH2.
- Fumarate Formation
- Succinate is oxidized to form fumarate, generating FADH2.
- Malate Formation
- Fumarate is hydrated to form malate.
- Regeneration of Oxaloacetate
- Malate is oxidized to regenerate oxaloacetate, producing NADH.
End Product - 4CO2, 6 NADH, 2 FADH2, and 2 ATPs.
Krebs Cycle Function
The various important functions of Krebs Cycle are:
- Generation of high-energy molecules like ATP through oxidative phosphorylation.
- Production of electron carriers NADH and FADH2, which transfer electrons to the electron transport chain.
- Oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins to release energy.
- Synthesis of intermediates like citrate, α-ketoglutarate, succinyl-CoA, and oxaloacetate for various metabolic pathways.
- Removal of carbon dioxide as a waste product through decarboxylation reactions.
Importance of Kreb Cycle
- Energy Production: Energy-rich molecule in the form of ATP is produced in the Kreb cycle
- Krebs cycle is the final pathway of oxidation of glucose, fat, and amino acids.
- Generation of NADH and FADH2: These molecules act as electron carriers in subsequent steps of cellular respiration.
- Biosynthesis of Intermediates: The Krebs cycle produces intermediate compounds important for various biosynthetic pathways in the cell. For example, oxaloacetate can be used for gluconeogenesis, and alpha-ketoglutarate can be utilized for amino acid synthesis.
- The genetic defects of Krebs's cycle enzymes are linked with neural damage.
- Succinyl-CoA produced in the Krebs cycle is associated with the synthesis of hemoglobin and myoglobin.
- The Kreb cycle is regulated by the supply of NAD+ and utilization of ATP in the physical and chemical work.
- Many animals use nutrients other than glucose as a source of energy.
- Vitamins like Riboflavin, niacin, thiamin, and pantothenic acid are part of various enzyme cofactors (FAD, NAD) and coenzyme A.
Conclusion - Krebs Cycle or Citric Acid Cycle
The Krebs Cycle, also known as the Citric Acid Cycle or TCA cycle (tricarboxylic acid cycle), serves as a central metabolic pathway, releasing energy stored in the form of ATP. This citric cycle occurs within the mitochondria. Beginning with acetyl-CoA derived from carbohydrates, fats, and proteins, it ultimately generates energy-rich molecules like ATP, NADH, and FADH2. The Krebs Cycle is an integral part of cellular respiration, contributing to the oxidation of glucose, fatty acids, and amino acids. Its importance lies in energy production, the synthesis of intermediates for various metabolic pathways, and its association with neural function and hemoglobin synthesis.
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