The Citric Acid Cycle, Tricarboxylic Acid (TCA), or Krebs Cycle is a complex set of chemical reactions that occur in living organisms, including humans, to generate energy from the oxidation of carbohydrates, proteins, and fats. Discovered by Sir Hans Adolf Krebs in 1937, the Krebs Cycle is an essential component of cellular metabolism, providing the energy required for the normal functioning of cells. In this article, we will delve into the history, intermediates, steps, applications, products, and enzymes of the Krebs Cycle, providing a comprehensive overview of this important biological process.
The Krebs Cycle History
The Krebs Cycle was discovered by Sir Hans Adolf Krebs in 1937, for which he was awarded the Nobel Prize in Physiology or Medicine in 1953. Krebs, a German-born biochemist, worked at the University of Sheffield, where he conducted his research on the energy metabolism of living cells. His discovery of the Krebs Cycle marked a significant milestone in the understanding of the biochemical processes that occur in living organisms.
Intermediates of Krebs Cycle
The Krebs Cycle is a cyclic pathway that involves a series of chemical reactions, starting with the oxidation of acetyl-CoA to form citrate, which is the first intermediate of the cycle. The intermediates of the Krebs Cycle are as follows:
Citrate:
The Krebs Cycle produces citrate when acetyl-CoA reacts with oxaloacetate. Citrate is used in the biosynthesis of fatty acids and cholesterol.
Isocitrate:
Isocitrate dehydrogenase oxidizes isocitrate to produce alpha-ketoglutarate, which is also an intermediate in the biosynthesis of amino acids and regulates gene expression.
Alpha-Ketoglutarate:
Isocitrate dehydrogenase oxidizes isocitrate to produce alpha-ketoglutarate. Alpha-ketoglutarate serves as an intermediate in the biosynthesis of amino acids and plays a role in regulating gene expression.
Succinyl-CoA:
Alpha-ketoglutarate dehydrogenase oxidizes alpha-ketoglutarate to produce succinyl-CoA. This reaction forms an intermediate in the biosynthesis of porphyrins and heme, which are crucial components of hemoglobin.
Succinate:
Succinyl-CoA synthetase converts succinyl-CoA to succinate, producing succinate. Succinate plays a role in the biosynthesis of heme and chlorophyll and regulates gene expression.
Fumarate:
Succinate dehydrogenase converts succinate to fumarate, producing fumarate. Biosynthesis of amino acids uses fumarate as an intermediate, and gene expression regulation involves it as well.
Malate:
Fumarase hydrates fumarate to produce malate. Biosynthesis of amino acids and nucleotides involves this compound as an intermediate.
Oxaloacetate:
Malate dehydrogenase oxidizes malate to produce oxaloacetate, which is the last intermediate of the Krebs Cycle. Amino acids and nucleotides are synthesized using this intermediate, and it plays a role in regulating gene expression.
These intermediates are essential for the production of ATP, the main energy currency of the cell. They also play a role in other metabolic pathways, such as the biosynthesis of amino acids, nucleotides, and heme.
Steps involved in Krebs Cycle
A specific enzyme catalyzes each of the eight steps involved in the Krebs Cycle:
- Formation of Citrate: The enzyme citrate synthase catalyzes the condensation of acetyl-CoA with oxaloacetate to form citrate in the first step.
- Isomerization of Citrate to Isocitrate: The enzyme aconitase catalyzes the isomerization of citrate to isocitrate, which constitutes the second step.
- Oxidation of Isocitrate: The enzyme isocitrate dehydrogenase catalyzes the oxidation of isocitrate to α-ketoglutarate in the third step.
- Decarboxylation of α-Ketoglutarate: The enzyme α-ketoglutarate dehydrogenase catalyzes the decarboxylation of α-ketoglutarate to form succinyl-CoA in the fourth step.
- Formation of Succinate: The enzyme succinyl-CoA synthetase catalyzes the formation of succinate and the transfer of a phosphate group from succinyl-CoA to GDP, resulting in the formation of GTP. Later, GTP is converted to ATP.
- Fumarate formation: The enzyme succinate dehydrogenase catalyzes the oxidation of succinate to form fumarate in the sixth step.
- Formation of Malate: Fumarase catalyzes the conversion of fumarate to malate by hydration.
- Oxaloacetate formation: Malate dehydrogenase catalyzes the oxidation of malate to form oxaloacetate in the final step.
Krebs Cycle Diagram
The Citric Acid Cycle Applications
The Citric Acid Cycle has several applications in different fields, including biochemistry, medicine, and food science. The following are some of the most significant applications of the Citric Acid Cycle:
- Biochemical research: The Citric Acid Cycle is a crucial component of cellular metabolism, and its study has helped researchers to understand the energy metabolism of living cells. It has also provided insights into the biosynthesis of various biomolecules, such as amino acids and nucleotides.
- Medical research: The Citric Acid Cycle has several medical applications, including the diagnosis and treatment of diseases. For example, several inborn errors of metabolism affect the enzymes of the Krebs Cycle, leading to various medical conditions.
- Food science: The food industry utilizes the Citric Acid Cycle for the production of various food additives, including citric acid, which acts as a preservative and enhances flavor. Furthermore, it is employed in the fermentation of alcoholic beverages and the creation of bread.
Products of Citric acid cycle
The products of the Citric Acid Cycle are ATP, NADH, FADH2, and CO2. The following are the products of each step of the Krebs Cycle:
- Formation of Citrate: CoA-SH and citrate are the products of this step.
- Isomerization of Citrate to Isocitrate: No products are formed in this step.
- Oxidation of Isocitrate: NADH, CO2, and α-ketoglutarate are the products of this step.
- Decarboxylation of α-Ketoglutarate: CO2, NADH, and succinyl-CoA are the products of this step.
- Formation of Succinate: GTP and succinate are the products of this step.
- Fumarate formation: FADH2 and fumarate are the products of this step.
- Formation of Malate: No products are formed in this step.
- Formation of Oxaloacetate: NADH and oxaloacetate are the products of this step.
Enzymes of Krebs Cycle
The Krebs Cycle involves the action of eight enzymes, each of which is responsible for catalyzing a specific step in the cycle. The following are the enzymes of the Krebs Cycle and the steps they catalyze:
- Citrate synthase: Catalyzes the condensation of acetyl-CoA with oxaloacetate to form citrate.
- Aconitase: Catalyzes the isomerization of citrate to isocitrate.
- Isocitrate dehydrogenase: Catalyzes the oxidation of isocitrate to α-ketoglutarate.
- α-ketoglutarate dehydrogenase: Catalyzes the decarboxylation of α-ketoglutarate to form succinyl-CoA.
- Succinyl-CoA synthetase: Catalyzes the transfer of a phosphate group from succinyl-CoA to GDP to form GTP and the formation of succinate.
- Succinate dehydrogenase: Catalyzes the oxidation of succinate to form fumarate.
- Fumarase: Catalyzes the hydration of fumarate to form malate.
- Malate dehydrogenase: Catalyzes the oxidation of malate to form oxaloacetate.
In conclusion, the Citric Acid Cycle is a crucial component of cellular metabolism, and its study is essential for understanding the energy metabolism of living cells. Several biosynthetic pathways use its intermediates and its products essential for ATP production. The cycle has several medical and industrial applications, making it a vital area of study in biochemistry and other related fields.