Citric Acid Cycle (Krebs Cycle) Cheat Sheet

The Citric Acid Cycle (CAC), also known as the Krebs Cycle or TCA cycle, is the second stage of cellular respiration. It occurs in the mitochondria, oxidizing pyruvate derivatives to generate ATP, NADH, and FADH2, which are crucial for energy production and biosynthetic pathways.

Core Principles

• Occurs in the mitochondrial matrix.
• Pyruvate is first converted to Acetyl-CoA (2 carbons).
• Acetyl-CoA enters the cycle, combining with oxaloacetate (4 carbons) to form citrate (6 carbons).
• The cycle involves eight enzyme-catalyzed steps.
• Key outputs include ATP (via substrate-level phosphorylation), NADH, and FADH2.
• Carbon dioxide (CO2) is released as a waste product.
• Regenerates oxaloacetate to continue the cycle.
• Provides precursors for anabolic pathways (e.g., amino acid synthesis).

Action Steps

• Transport pyruvate into the mitochondria.
• Oxidize pyruvate to Acetyl-CoA, producing NADH and CO2.
• Combine Acetyl-CoA with oxaloacetate to form citrate.
• Proceed through the eight enzymatic steps of the cycle.
• Generate ATP, NADH, and FADH2 at specific steps.
• Release CO2 during oxidative steps.
• Regenerate oxaloacetate to accept new Acetyl-CoA.
• Utilize NADH and FADH2 in oxidative phosphorylation for further ATP synthesis.

Formulas

• Pyruvate (3C) + CoA -> Acetyl-CoA (2C) + CO2 + NADH
• Acetyl-CoA (2C) + Oxaloacetate (4C) -> Citrate (6C)
• Net yield per Acetyl-CoA (1 cycle): 1 ATP, 3 NADH, 1 FADH2
• Net yield per Glucose (2 cycles): 2 ATP, 6 NADH, 2 FADH2

Key Terms

• Acetyl-CoA: A 2-carbon molecule that enters the citric acid cycle, derived from pyruvate oxidation.
• Oxaloacetate: A 4-carbon molecule that combines with Acetyl-CoA to start the cycle and is regenerated at the end.
• Citrate: A 6-carbon molecule formed when Acetyl-CoA combines with oxaloacetate; the first intermediate.
• NADH: An electron carrier molecule that captures high-energy electrons during oxidation reactions; used in oxidative phosphorylation.
• FADH2: Another electron carrier molecule, capturing electrons; used in oxidative phosphorylation.
• Substrate-level phosphorylation: Direct synthesis of ATP from a high-energy intermediate molecule.
• Mitochondrial matrix: The innermost compartment of the mitochondrion, where the CAC takes place.

Pro Tips

• Remember that the cycle's intermediates are versatile and feed into other metabolic processes.
• The NADH and FADH2 produced are the primary energy currency generators for the subsequent electron transport chain.
• High ATP and NADH levels signal sufficient energy, leading to cycle inhibition.

Pitfalls to Avoid

• Confusing the yield per pyruvate molecule versus per glucose molecule.
• Forgetting that the cycle occurs within the mitochondria.
• Overlooking the role of CAC intermediates in biosynthesis.
• Not recognizing that ATP is generated via both substrate-level phosphorylation (in CAC) and oxidative phosphorylation (using CAC products).

Real World Examples

• Cellular energy production: The CAC is central to generating the majority of ATP during aerobic respiration, powering all cellular activities.
• Amino acid synthesis: Intermediates like alpha-ketoglutarate and oxaloacetate can be diverted to synthesize various amino acids needed by the cell.
• Fatty acid synthesis: Acetyl-CoA, a key product feeding into the CAC, is also the primary building block for fatty acids.

Timeline

• Step 1: Pyruvate (3C) is oxidized to Acetyl-CoA (2C), producing NADH and CO2.
• Step 2: Acetyl-CoA combines with Oxaloacetate (4C) to form Citrate (6C).
• Step 3: Citrate is isomerized to Isocitrate (6C).
• Step 4: Isocitrate is oxidized and decarboxylated to alpha-ketoglutarate (5C), producing NADH and CO2.
• Step 5: Alpha-ketoglutarate is oxidized and decarboxylated to Succinyl-CoA (4C), producing NADH and CO2.
• Step 6: Succinyl-CoA is converted to Succinate (4C), producing ATP (or GTP) via substrate-level phosphorylation.
• Step 7: Succinate is oxidized to Fumarate (4C), producing FADH2.
• Step 8: Fumarate is hydrated to Malate (4C).
• Step 9: Malate is oxidized to Oxaloacetate (4C), producing NADH and regenerating the cycle starter.

People

• Hans Krebs: Nobel laureate who elucidated the citric acid cycle.

Quiz

• Where does the Citric Acid Cycle primarily occur?: Mitochondrial matrix
• What molecule combines with Acetyl-CoA to start the cycle?: Oxaloacetate
• Which of the following is NOT a direct product of the Citric Acid Cycle per Acetyl-CoA molecule?: Oxygen (O2)