Lecture19

Overview of the Citric Acid Cycle (CAC)

• The citric acid cycle (TCA or Krebs cycle) is essential for converting carbohydrates, fats, and proteins into carbon dioxide, water, and energy.

• The cycle generates NADH and FADH2, which are crucial for ATP production through oxidative phosphorylation.

Stages of the Citric Acid Cycle

Stage 1: Formation of Citrate

• Key Steps:

  • Acetyl CoA (2C) combines with Oxaloacetate (4C) to form Citrate (6C) [catalyzed by citrate synthase].

  • Importance of induced fit mechanism in citrate synthase prevents unwanted reactions before the active site is closed.

  • This stage undergoes two oxidative decarboxylations, releasing two CO2 molecules.

Stage 1: Conversion and Decarboxylation Steps

• Conversion of Citrate to Isocitrate via Aconitase (involves dehydration and rehydration).

• Isocitrate to -Ketoglutarate via Isocitrate Dehydrogenase:

  • Reaction:

    • Isocitrate + NAD+ → -Ketoglutarate + CO2 + NADH

  • First generation of high-energy electrons (NADH).

• -Ketoglutarate to Succinyl CoA via -Ketoglutarate Dehydrogenase Complex:

• Keto to succ coa via KDC

  • Reaction:

    • -Ketoglutarate + CoA + NAD+ → Succinyl CoA + CO2 + NADH

  • Similar to Pyruvate Dehydrogenase (PDH) complex.

Stage 2: Regeneration of Oxaloacetate

• Formation of Succinate from Succinyl CoA via Succinyl-CoA Synthetase:

  • Reaction generates ATP (or GTP) through substrate-level phosphorylation.

• Fumarate Formation from Succinate via Succinate Dehydrogenase:

  • Reaction generates FADH2.

• Hydration to Malate via Fumarase

• Oxaloacetate Production from Malate via Malate Dehydrogenase:

  • Reaction:

    • Malate + NAD+ → Oxaloacetate + NADH + H+

Key Reactions and Their Energetics

• Each step has specific energy implications (ΔG values) reflecting its exergonic or endergonic nature. Example:

  • Citrate synthase step is highly exergonic (−31.4 kJ/mol).

Regulation of the Citric Acid Cycle

• Control Points:

  • Key control points include oxidative decarboxylations (Isocitrate and -Ketoglutarate Dehydrogenases).

  • Inhibitors and activators:

    • Isocitrate Dehydrogenase is inhibited by NADH and ATP, activated by ADP.

    • -Ketoglutarate Dehydrogenase is inhibited by succinyl CoA and NADH.

Importance of Cycle Intermediates

• Biosynthetic Precursor Role:

  • Intermediates can be extracted for biosynthesis; oxaloacetate must be replenished.

  • Key replenishing reactions are termed anaplerotic reactions (e.g., pyruvate carboxylase converts pyruvate to oxaloacetate).

Glyoxylate Cycle in Plants

• Similar to TCA but prevents decarboxylations, allowing conversion of fats to glucose.

• Uses enzymes like isocitrate lyase and malate synthase.

Citric Acid Cycle and Cancer Connections

• Metabolites from the TCA cycle influence mitochondrial function and gene expression in cancer cells.

• Citrate can suppress cancer proliferation, while others promote tumorigenesis.

Summary of Key Questions

• What are the significant decarboxylation reactions?

• What enzymes are responsible and how is their activity regulated?

• How is NADH, FADH2, and ATP generated?

• Why can’t fatty acids directly convert to glucose?

• What is the significance of the glyoxylate cycle in glucose synthesis?

These key points provide insight into the citric acid cycle's structure, function, and regulation in cellular metabolism, essential for the BMB 3110 course.