Glycolysis, Krebs Cycle, and Oxidative Phosphorylation

Introduction

Key Concepts

1. Glycolysis

Glycolysis is the initial pathway of cellular respiration, occurring in the cytoplasm of the cell. It involves the breakdown of one molecule of glucose ($C_6H_{12}O_6$) into two molecules of pyruvate ($C_3H_4O_3$). This ten-step process can be divided into two phases: the investment phase and the payoff phase.

• Investment Phase: Requires the investment of 2 ATP molecules to phosphorylate glucose and convert it into fructose-1,6-bisphosphate.
• Payoff Phase: Produces 4 ATP molecules and 2 NADH molecules through substrate-level phosphorylation and the reduction of NAD⁺.

The net gain from glycolysis is 2 ATP molecules and 2 NADH molecules per glucose molecule. Pyruvate produced in glycolysis serves as the substrate for the Krebs cycle under aerobic conditions.

2. Krebs Cycle (Citric Acid Cycle)

The Krebs Cycle takes place in the mitochondrial matrix and completes the oxidation of organic molecules derived from carbohydrates, fats, and proteins. Each acetyl-CoA molecule, derived from pyruvate via the link reaction, enters the cycle and undergoes a series of reactions that regenerate oxaloacetate, the cycle's starting molecule.

• Energy Investment: The conversion of pyruvate to acetyl-CoA produces 1 NADH and 1 CO₂ per pyruvate molecule.
• Cycle Reactions: Each turn of the cycle produces 3 NADH, 1 FADH₂, and 1 GTP (or ATP) through substrate-level phosphorylation, along with the release of 2 CO₂ molecules.

Given that each glucose molecule generates 2 acetyl-CoA molecules, the Krebs Cycle turns twice per glucose, effectively doubling its outputs.

3. Oxidative Phosphorylation

Oxidative phosphorylation encompasses the electron transport chain (ETC) and chemiosmosis, occurring in the inner mitochondrial membrane. This stage utilizes the high-energy electrons carried by NADH and FADH₂ to generate ATP.

• Electron Transport Chain: Electrons are transferred through a series of protein complexes (Complex I to IV) and mobile carriers, releasing energy used to pump protons ($H^+$) into the intermembrane space, creating a proton gradient.
• Chemiosmosis: The established proton gradient fuels ATP synthase to produce ATP from ADP and inorganic phosphate ($P_i$). This process is driven by the flow of protons back into the mitochondrial matrix.

The final electron acceptor in the ETC is molecular oxygen ($O_2$), which combines with electrons and protons to form water ($H_2O$). Oxidative phosphorylation is responsible for producing the majority of ATP during cellular respiration, approximately 34 ATP molecules per glucose.

Integration of the Three Stages

The three stages of cellular respiration are interconnected, forming a continuous pathway for energy extraction from glucose:

1. Glycolysis breaks down glucose into pyruvate, yielding ATP and NADH.
2. Pyruvate is converted to acetyl-CoA, which enters the Krebs Cycle, producing more NADH, FADH₂, and ATP.
3. NADH and FADH₂ donate electrons to the ETC, driving oxidative phosphorylation and generating a substantial amount of ATP.

This seamless integration ensures efficient energy production and highlights the cell's ability to harness different stages for maximum ATP yield.

Energy Yield and Efficiency

The complete oxidation of one glucose molecule yields a total of approximately 38 ATP molecules:

• Glycolysis: 2 ATP (net) + 2 NADH
• Link Reaction: 2 NADH
• Krebs Cycle: 2 ATP + 6 NADH + 2 FADH₂
• Oxidative Phosphorylation: Approximately 34 ATP from NADH and FADH₂

However, the actual ATP yield may vary due to the efficiency of mitochondrial transport systems and the usage of the proton gradient for other cellular processes.

Regulation of Cellular Respiration

Cellular respiration is tightly regulated to meet the cell's energy demands and maintain homeostasis. Key regulatory points include:

• Hexokinase: Catalyzes the first step of glycolysis, inhibited by its product, glucose-6-phosphate.
• Pyruvate Dehydrogenase: Controls the conversion of pyruvate to acetyl-CoA, regulated by product inhibition from NADH and acetyl-CoA.
• Isocitrate Dehydrogenase and α-Ketoglutarate Dehydrogenase: Enzymes in the Krebs Cycle, activated by ADP and inhibited by ATP and NADH.

These regulatory mechanisms ensure that ATP production aligns with the cell's energy requirements, preventing unnecessary metabolic flux.

Fermentation: An Anaerobic Alternative

In the absence of oxygen, cells can undergo fermentation to regenerate NAD⁺ from NADH, allowing glycolysis to continue:

• Lactic Acid Fermentation: Pyruvate is reduced to lactate, regenerating NAD⁺. Common in muscle cells during intense exercise.
• Alcoholic Fermentation: Pyruvate is converted to ethanol and CO₂, regenerating NAD⁺. Occurs in yeast and some plant cells.

Fermentation yields only 2 ATP molecules per glucose, highlighting its lower efficiency compared to aerobic respiration.

ATP Production Summary

The efficiency of ATP production through cellular respiration can be summarized as follows:

Comparison Table

Summary and Key Takeaways