The Krebs Cycle, also known as the Citric Acid Cycle, is a fundamental metabolic pathway within cellular respiration. It plays a critical role in energy production by oxidizing acetyl-CoA to carbon dioxide and transferring energy-rich electrons to carrier molecules. Understanding the Krebs Cycle is essential for students preparing for the Collegeboard AP Biology exam, as it forms the backbone of cellular energetics and bioenergetic processes.

Key Concepts

Overview of the Krebs Cycle

The Krebs Cycle is the second stage of cellular respiration, following glycolysis and preceding the electron transport chain. Occurring in the mitochondrial matrix of eukaryotic cells, the cycle completes the oxidative degradation of carbohydrates, fats, and proteins into carbon dioxide and high-energy electron carriers. This cyclical process is anaerobic, meaning it does not require oxygen directly, although it is dependent on the availability of oxygen to serve as the final electron acceptor in the electron transport chain.

Step-by-Step Mechanism

Formation of Citrate: The cycle begins with the condensation of acetyl-CoA (a 2-carbon molecule) with oxaloacetate (a 4-carbon molecule) to form citrate (a 6-carbon molecule). This reaction is catalyzed by the enzyme citrate synthase.
Isomerization to Isocitrate: Citrate undergoes isomerization to form isocitrate through the intermediate formation of cis-aconitate, catalyzed by aconitase.
Oxidative Decarboxylation to α-Ketoglutarate: Isocitrate is oxidized and decarboxylated to α-ketoglutarate (a 5-carbon molecule) by isocitrate dehydrogenase, producing NADH and releasing CO₂.
Oxidative Decarboxylation to Succinyl-CoA: α-Ketoglutarate undergoes a similar oxidative decarboxylation to succinyl-CoA (a 4-carbon molecule linked to Coenzyme A) via α-ketoglutarate dehydrogenase, generating another molecule of NADH and releasing CO₂.
Conversion to Succinate: Succinyl-CoA is converted to succinate by succinyl-CoA synthetase, coupled with the synthesis of GTP (or ATP) from GDP and inorganic phosphate.
Oxidation to Fumarate: Succinate is oxidized to fumarate by succinate dehydrogenase, producing FADH₂ in the process.
Hydration to Malate: Fumarate is hydrated to malate by fumarase through the addition of a water molecule.
Oxidation to Oxaloacetate: Malate is oxidized to oxaloacetate by malate dehydrogenase, generating a final molecule of NADH and completing the cycle.

Energy Yield and Molecular Outputs

Each turn of the Krebs Cycle yields the following high-energy molecules:

3 NADH molecules
1 FADH₂ molecule
1 GTP (or ATP) molecule
2 CO₂ molecules

These electron carriers (NADH and FADH₂) donate electrons to the electron transport chain, leading to the production of ATP through oxidative phosphorylation. The GTP (or ATP) produced can be used directly for cellular work. The cycle’s regeneration of oxaloacetate ensures its continuity, allowing for the ongoing oxidation of acetyl-CoA.

Anaplerotic Reactions

Anaplerotic reactions are biosynthetic pathways that replenish Krebs Cycle intermediates that have been extracted for biosynthesis. For instance, the conversion of pyruvate to oxaloacetate by pyruvate carboxylase is a critical anaplerotic reaction, ensuring that the cycle remains functional even when intermediates are diverted for anabolic purposes.

Regulation of the Krebs Cycle

The Krebs Cycle is tightly regulated to meet the cell's energy demands. Key regulatory points include:

Citrate Synthase: Inhibited by high levels of ATP and NADH, signaling sufficient energy availability.
Isocitrate Dehydrogenase: Activated by ADP and inhibited by ATP and NADH, responding to the cell’s energy needs.
α-Ketoglutarate Dehydrogenase: Similar to isocitrate dehydrogenase, it is regulated by energy charge indicators like ATP and NADH.

Integration with Other Metabolic Pathways

The Krebs Cycle serves as a hub for various metabolic pathways. Amino acids can be converted into cycle intermediates, fatty acids can be broken down into acetyl-CoA, and carbohydrates are funneled into the cycle through glycolysis. This integration allows for the efficient utilization of diverse nutrients to produce energy and synthesize essential biomolecules.

Chemical Equations Involved

The overall chemical equation for one turn of the Krebs Cycle is: $$ \text{Acetyl-CoA} + 3 \text{NAD}^+ + \text{FAD} + \text{GDP} + \text{P}_i + 2 \text{H}_2\text{O} \rightarrow 2 \text{CO}_2 + 3 \text{NADH} + \text{FADH}_2 + \text{GTP} + \text{CoA} $$

This equation summarizes the substrates consumed and the products generated during the cycle, highlighting the cycle’s role in energy production and carbon dioxide release.

Historical Context and Discovery

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. His work elucidated the steps of this critical metabolic pathway, significantly advancing our understanding of cellular respiration and energy metabolism.

Clinical Relevance

Dysfunction in the Krebs Cycle can lead to various metabolic disorders. For example, deficiencies in enzymes like aconitase or isocitrate dehydrogenase can result in impaired energy production, contributing to conditions such as Leigh syndrome and certain cancers. Understanding the Krebs Cycle is also essential in fields like biochemistry and medicine, where metabolic pathways are targeted for therapeutic interventions.

Comparison Table

Aspect	Krebs Cycle	Glycolysis
Location	Mitochondrial matrix	Cytoplasm
Oxygen Requirement	Indirectly requires oxygen	Anaerobic
Carbon Dioxide Produced	2 molecules per cycle	None
ATP Yield	1 GTP (≈1 ATP) per cycle	2 ATP per glucose molecule
Electron Carriers	3 NADH, 1 FADH₂ per cycle	2 NADH per glucose molecule
Primary Function	Oxidation of Acetyl-CoA, energy production	Breakdown of glucose, initial energy extraction

Summary and Key Takeaways

The Krebs Cycle is a central metabolic pathway in cellular respiration, occurring in the mitochondrial matrix.
It oxidizes acetyl-CoA to carbon dioxide, producing NADH, FADH₂, and GTP/ATP.
Key regulatory enzymes ensure the cycle responds to the cell’s energy needs.
The cycle is interconnected with various metabolic pathways, facilitating efficient energy and biomolecule production.
Understanding the Krebs Cycle is crucial for comprehending broader cellular energetics and metabolic disorders.

Examiner Tip

Tips

Mnemonic for Cycle Steps: "Can I Keep Selling Sex For Money, Officer?" stands for Citrate, Isocitrate, α-Ketoglutarate, Succinyl-CoA, Succinate, Fumarate, Malate, Oxaloacetate.
Visual Learning: Draw the cycle repeatedly to reinforce each step and its enzymes.
Understand, Don’t Memorize: Focus on the purpose of each step and how it connects to energy production and other metabolic pathways for better retention.

Did You Know

The Krebs Cycle not only plays a vital role in energy production but also provides key intermediates for the synthesis of amino acids and other biomolecules. Additionally, certain cancer cells can hijack the cycle to support their rapid growth, a phenomenon known as the Warburg effect. This connection between metabolism and cancer has opened new avenues for targeted cancer therapies.

Common Mistakes

Error 1: Confusing the location of the Krebs Cycle with glycolysis.
Incorrect: "The Krebs Cycle occurs in the cytoplasm."
Correct: "The Krebs Cycle occurs in the mitochondrial matrix."
Error 2: Forgetting the regeneration of oxaloacetate.
Incorrect: "The cycle stops after producing ATP."
Correct: "The cycle regenerates oxaloacetate, allowing it to continue."
Error 3: Miscounting the carbon atoms released as CO₂.
Incorrect: "Only one CO₂ is released per cycle."
Correct: "Two CO₂ molecules are released per cycle."

FAQ

What is the main purpose of the Krebs Cycle?

The main purpose of the Krebs Cycle is to generate high-energy electron carriers (NADH and FADH₂) and GTP/ATP, which are used in the electron transport chain to produce ATP, the cell’s primary energy currency.

Where does the Krebs Cycle take place in the cell?

The Krebs Cycle occurs in the mitochondrial matrix of eukaryotic cells.

Is the Krebs Cycle aerobic or anaerobic?

The Krebs Cycle itself is anaerobic as it does not directly require oxygen. However, it is dependent on oxygen indirectly because the electron transport chain, which uses the electron carriers produced in the cycle, requires oxygen as the final electron acceptor.

How many ATP molecules are produced per glucose molecule in the Krebs Cycle?

Per glucose molecule, the Krebs Cycle runs twice, producing a total of 2 GTP (≈2 ATP) molecules.

What role do NADH and FADH₂ play in the Krebs Cycle?

NADH and FADH₂ are electron carriers produced during the Krebs Cycle. They transport high-energy electrons to the electron transport chain, where their energy is used to produce ATP through oxidative phosphorylation.

1. Natural Selection

1.1 Speciation

1.1.1 Allopatric and Sympatric Speciation

1.1.2 Reproductive Isolation

1.2 Evidence of Evolution

1.2.1 Fossil Record

1.2.2 Comparative Anatomy

1.2.3 Molecular Biology

1.3 Introduction to Natural Selection

1.3.1 Darwin's Theory

1.3.2 Adaptation

1.4 Natural Selection