Overview
This lecture covers the Krebs cycle (also known as the citric acid or tricarboxylic acid cycle), including its intermediates, key enzymes, regulation, and products.
Krebs Cycle Overview
- The Krebs cycle occurs in the mitochondria and is central to cellular aerobic respiration.
- Pyruvate from glycolysis is converted to acetyl-CoA, which combines with oxaloacetate to form citrate.
- One cycle processes one acetyl-CoA; since one glucose makes two pyruvates, the cycle runs twice per glucose.
Key Intermediates & Mnemonic
- Intermediates in order: Citrate, Isocitrate, α-Ketoglutarate, Succinyl-CoA, Succinate, Fumarate, Malate, Oxaloacetate.
- Mnemonic: “Citrate Is Krebs’ Starting Substrate For Making Oxaloacetate.”
Major Enzymes & Steps
- Citrate synthase: Combines acetyl-CoA and oxaloacetate to make citrate; highly regulated, irreversible.
- Aconitase: Converts citrate to isocitrate; reaction is reversible.
- Isocitrate dehydrogenase: Converts isocitrate to α-ketoglutarate; produces NADH, releases CO₂, irreversible.
- α-Ketoglutarate dehydrogenase: Converts α-ketoglutarate to succinyl-CoA; produces NADH, releases CO₂, irreversible.
- Succinyl-CoA synthetase: Converts succinyl-CoA to succinate; produces GTP (then ATP by substrate-level phosphorylation).
- Succinate dehydrogenase (Complex II): Converts succinate to fumarate; produces FADH₂; part of the electron transport chain.
- Fumarase: Converts fumarate to malate.
- Malate dehydrogenase: Converts malate to oxaloacetate; produces NADH.
Regulation of the Cycle
- Citrate synthase: Inhibited by ATP, NADH, citrate, and succinyl-CoA; stimulated by ADP.
- Isocitrate dehydrogenase: Inhibited by ATP; stimulated by ADP and Ca²⁺.
- α-Ketoglutarate dehydrogenase: Inhibited by NADH and succinyl-CoA; stimulated by Ca²⁺.
Cycle Products (per glucose, i.e., 2 cycles)
- 6 NADH, 2 FADH₂, 2 ATP (by substrate-level phosphorylation), 4 CO₂.
Clinical Connections
- Mutations or inhibitors (e.g., fluoroacetate, mutations in succinate dehydrogenase or fumarase) can cause cell dysfunction or tumors (gliomas, pheochromocytoma, leiomyomas).
- α-Ketoglutarate is a cofactor for histone demethylase, influencing gene expression; disruptions can lead to cancer.
Key Terms & Definitions
- Krebs cycle (Citric acid cycle) — Sequence of reactions that oxidize acetyl-CoA to CO₂ and generate NADH, FADH₂, and ATP.
- Substrate-level phosphorylation — Direct ATP (or GTP) formation from ADP (or GDP) using energy from a substrate.
- Dehydrogenase — Enzyme catalyzing redox reactions, often producing NADH or FADH₂.
- Decarboxylation — Removal of CO₂ from a molecule.
- Aconitase — Enzyme isomerizing citrate to isocitrate.
- Succinate dehydrogenase — Enzyme functioning in both the Krebs cycle and electron transport chain (Complex II).
Action Items / Next Steps
- Memorize the order of intermediates using the provided mnemonic.
- Review and understand regulation of key enzymes (citrate synthase, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase).
- Practice drawing the cycle and noting where products are formed.