(1) Metabolism | The Krebs Cycle

Overview of the Krebs Cycle

  • Also known as the Tricarboxylic Acid (TCA) Cycle or Citric Acid Cycle.

  • Developed by Hans Krebs.

Glycolysis Recap

  • Conversion of glucose into pyruvate through the glycolysis pathway.

  • Results in the formation of 2 pyruvates from 1 glucose molecule.

    • Yield: 2 NADH, 2 net ATP.

Transition to Krebs Cycle

  • Pyruvate Transport:

    • Enter mitochondria where it undergoes conversion to Acetyl CoA.

    • This process generates 2 NADH and releases 2 CO2 via decarboxylation.

    • Carried out by the Pyruvate Dehydrogenase Complex (E1, E2, E3).

Starting the Krebs Cycle

  • Key Participants:

    • Acetyl CoA: 2-carbon structure.

    • Oxaloacetate (OAA): 4-carbon fragment.

    • Reaction: Acetyl CoA + OAA → Citrate (6-carbon molecule).

    • Enzyme: Citrate Synthase.

Mnemonic for Intermediates

  • Citrate is Krebs' Starting Substrate for Making Oxaloacetate:

    • C: Citrate

    • A: Alpha-ketoglutarate

    • S: Succinyl CoA

    • S: Succinate

    • F: Fumarate

    • M: Malate

    • O: Oxaloacetate

Enzymatic Steps and Regulation

1. Citrate Synthase

  • Highly regulated enzyme.

  • Promoted by low ATP/ADP and high acetyl CoA.

  • Inhibited by high ATP, NADH, citrate, and succinyl CoA.

2. Aconitase

  • Converts citrate to isocitrate (isomerization).

  • Reversible reaction.

  • Inhibited by fluoroacetate (found in rat poison).

3. Isocitrate Dehydrogenase

  • Converts isocitrate to alpha-ketoglutarate (decarboxylation, loss of CO2).

  • Generates 1 NADH.

  • Inhibited by high ATP and NADH; stimulated by ADP and calcium.

4. Alpha-Ketoglutarate Dehydrogenase

  • Converts alpha-ketoglutarate to succinyl CoA (another decarboxylation).

  • Generates 1 NADH.

  • Similar regulation to isocitrate dehydrogenase: inhibited by succinyl CoA, ATP, NADH; stimulated by calcium.

5. Succinyl CoA Synthetase

  • Converts succinyl CoA to succinate.

  • Generates GTP (which can be converted to ATP by ADP).

  • Reaction Type: Substrate-level phosphorylation.

6. Succinate Dehydrogenase

  • Converts succinate to fumarate.

  • Part of the electron transport chain (Complex II).

  • Generates 1 FADH2.

  • Associated with pheochromocytoma when mutated.

7. Fumarase

  • Converts fumarate to malate (reversible addition of water).

  • Deficiency can lead to leiomyomas (smooth muscle tumors).

8. Malate Dehydrogenase

  • Converts malate back to oxaloacetate, generating 1 NADH.

  • Reversible and plays a role in gluconeogenesis.

Overall Yield from One Turn of the Krebs Cycle

  • Product Summary (from 2 Acetyl CoA):

    • 4 CO2 (2 lost per cycle)

    • 6 NADH

    • 2 FADH2

    • 2 ATP (via substrate-level phosphorylation)

Important Connections and Implications

  • High ATP, NADH signals inhibit the cycle, while high ADP and calcium signal for activation.

  • Importance of alpha-ketoglutarate in histone demethylase function and its link to tumor growth with metabolic mutations.

  • The Krebs cycle feeds into the electron transport chain for maximum ATP production through oxidative phosphorylation.

Conclusion

  • The Krebs cycle is a crucial metabolic pathway deeply interconnected with energy production and cellular metabolism, showcasing a complex regulation that ensures energy homeostasis within cells.