[Biology Class Notes] on Krebs Cycle Pdf for EXAM

The Krebs cycle or Citric acid cycle is a series of enzyme-catalyzed reactions occurring in the mitochondrial matrix, where acetyl-CoA is oxidized to form carbon dioxide and coenzymes are reduced, which generate ATP in the electron transport chain.

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Krebs cycle was named after Hans Krebs, who postulated the detailed cycle. He was awarded the Nobel prize in 1953 for his contribution.

It is a series of eight-step processes, where the acetyl group of acetyl-CoA is oxidized to form two molecules of [CO_{2}] and in the process, one ATP is produced. Reduced high-energy compounds, NADH, and [FADH_{2}] are also produced.

Two molecules of acetyl-CoA are produced from each glucose molecule so two turns of the Krebs cycle are required which yields four [CO_{2}], six NADH, two FADH₂, and two ATPs.

Krebs Cycle is a Part of Cellular Respiration

Cellular respiration is a catabolic reaction taking place in the cells. It is a biochemical process by which nutrients are broken down to release energy, which gets stored in the form of ATP, and waste products are released. In aerobic respiration, oxygen is required.

Cellular respiration is a four-stage process. In the process, glucose is oxidized to carbon dioxide and oxygen is reduced to water. The energy released in the process is stored in the form of ATPs. 36 to 38 ATPs are formed from each glucose molecule.

The Four Stages are

Glycolysis: Partial oxidation of a glucose molecule to form 2 molecules of pyruvate. This process takes place in the cytosol.

Formation of Acetyl CoA: Pyruvate formed in glycolysis enters the mitochondrial matrix. It undergoes oxidative decarboxylation to form two molecules of Acetyl CoA. The reaction is catalyzed by the pyruvate dehydrogenase enzyme.

[2Pyruvate + 2NAO^{-} + 2CoA^{-} overset{ Pyruvate dehydrogenase }{rightarrow} 2 Acetyl CoA + 2NADH + C0_{2}]

Krebs Cycle (TCA or Citric Acid Cycle): It is the common pathway for complete oxidation of carbohydrates, proteins, and lipids as they are metabolized to acetyl coenzyme A or other intermediates of the cycle. The Acetyl CoA produced enters the Tricarboxylic acid cycle or Citric acid cycle. Glucose is fully oxidized in this process. The acetyl CoA combines with oxaloacetate (4C) to form citrate (6C). In this process, 2 molecules of [CO_{2}] are released and oxaloacetate is recycled. Energy is stored in ATP and other high-energy compounds like NADH and [FADH_{2}].

Electron Transport System and Oxidative Phosphorylation: ATP is generated when electrons are transferred from the energy-rich molecules like NADH and [FADH_{2}] produced in glycolysis, citric acid cycle, and fatty acid oxidation to molecular [O_{2}] by a series of electron carriers. [O_{2}] is reduced to [H_{2}O]. It takes place in the inner membrane of mitochondria.

Krebs Cycle Steps

It is an eight-step process. The Krebs cycle takes place in the matrix of mitochondria under aerobic conditions.

Step 1: The first step is the condensation of acetyl CoA with oxaloacetate (4C) to form citrate (6C), coenzyme A is released. The reaction is catalyzed by citrate synthase.

Step 2: Citrate is turned to its isomer, isocitrate. The enzyme aconitase catalyzes this reaction. 

Step 3: Isocitrate undergoes dehydrogenation and decarboxylation to form ?-ketoglutarate (5C). A molecular of [CO_{2}] is released. Isocitrate dehydrogenase catalyzes the reaction. It is an NAD+-dependent enzyme. NAD+ is converted to NADH.

Step 4: α-ketoglutarate (5C) undergoes oxidative decarboxylation to form succinyl CoA (4C). The reaction is catalyzed by the α-ketoglutarate dehydrogenase enzyme complex. One molecule of [CO_{2}] is released and NAD+ is converted to NADH.

Step 5: Succinyl CoA is converted to succinate by the enzyme succinyl CoA synthetase. This is coupled with substrate-level phosphorylation of GDP to form GTP. GTP transfers its phosphate to ADP forming ATP.

Step 6: Succinate is oxidized to fumarate by the enzyme succinate dehydrogenase. In the process, FAD is converted to [FADH_{2}].

Step 7: Fumarate gets converted to malate by the addition of one [H_{2}O]. The enzyme catalyzing this reaction is fumarase.

Step 8: Malate is dehydrogenated to form oxaloacetate, which combines with another molecule of acetyl CoA and starts the new cycle. Hydrogens removed get transferred to NAD+ forming NADH. Malate dehydrogenase catalyzes the reaction.

Krebs Cycle Summary

Location: Krebs cycle occurs in the mitochondrial matrix

Krebs Cycle Reactants: Acetyl CoA, which is produced from the end product of glycolysis, i.e. pyruvate and it condenses with 4 carbon oxaloacetate, which is generated back in the Krebs cycle.

Krebs Cycle Products

Each citric acid cycle forms the following products:

1. In the conversion of isocitrate (6C) to α-ketoglutarate (5C)

2. In the conversion of α-ketoglutarate (5C) to succinyl CoA (4C)

1. Isocitrate to α-ketoglutarate → NADH

2. α-ketoglutarate to succinyl CoA → NADH

3. Succinate to fumarate → [FADH_{2}]

4. Malate to Oxaloacetate → NADH

Notes that 2 molecules of Acetyl CoA are produced from oxidative decarboxylation of 2 pyruvates so two cycles are required per glucose molecule.

To summarize, for complete oxidation of a glucose molecule, the Krebs cycle yields [ 4 CO_{2}, 6NADH, 2 FADH_{2} ], and 2 ATPs.

Each molecule of NADH can form 2-3 ATPs and each FADH₂ gives 2 ATPs on oxidation in the electron transport chain.

Krebs Cycle Equation

To sum up,

[ 2  Acytyl  CoA + 6 NAO^{-} + 2 FAD + 2ADP + 2P_{i} + 2H_{2}0  rightarrow  4CO_{2} + 6 NADH + 2FADH_{2} + 2ATP + CoA ]

Significance of Krebs Cycle

• The Krebs cycle or Citric acid cycle is the final pathway of oxidation of glucose, fats, and amino acids.

• Amino acids (metabolic product of proteins) are deaminated and get converted to pyruvate and other intermediates of the Krebs cycle. They enter the cycle and get metabolized e.g. alanine is converted to pyruvate, glutamate to α-ketoglutarate, aspartate to oxaloacetate on deamination.

• Many intermediate compounds are used in the synthesis of amino acids, nucleotides, cytochromes, chlorophylls, etc.

• Vitamins play an important role in the citric acid cycle. Riboflavin, niacin, thiamin, and pantothenic acid a part of various enzymes cofactors (FAD, NAD) and coenzyme A.

• As most of the processes occur in the liver to a significant extent, damage to liver cells has a lot of repercussions. Hyperammonemia occurs in liver diseases and leads to convulsions and coma. This is due to reduced ATP generation as a result of the withdrawal of α-ketoglutarate and the formation of glutamate, which forms glutamine.