Overview
This lecture reviews the Krebs cycle (also called the citric acid or tricarboxylic acid cycle), its regulation, main steps, and the products generated per glucose molecule.
Introduction & Key Concepts
- Krebs cycle is also known as the citric acid cycle or tricarboxylic acid (TCA) cycle, discovered by Hans Krebs.
- Glycolysis converts glucose (6C) into two pyruvates (3C each), generating 2 NADH and 2 net ATP.
- In oxygen presence, pyruvate enters mitochondria, is converted to acetyl-CoA, producing 2 NADH and 2 CO2.
Cycle Intermediates & Mnemonics
- Acetyl-CoA (2C) combines with oxaloacetate (4C) to form citrate (6C).
- Mnemonic for intermediates: Citrate Is Krebs' Starting Substrate For Making Oxaloacetate (Citrate, Isocitrate, α-Ketoglutarate, Succinyl-CoA, Succinate, Fumarate, Malate, Oxaloacetate).
Enzymes & Regulation
- Citrate Synthase: Irreversible; inhibited by ATP, NADH, citrate, and succinyl-CoA; stimulated by ADP.
- Aconitase: Reversible isomerization; inhibited by fluoroacetate (rat poison).
- Isocitrate Dehydrogenase: Irreversible; produces NADH and CO2; inhibited by ATP; stimulated by ADP and Ca²⁺.
- α-Ketoglutarate Dehydrogenase: Irreversible; produces NADH and CO2; inhibited by NADH and succinyl-CoA; stimulated by Ca²⁺.
- Succinyl-CoA Synthetase: Converts succinyl-CoA to succinate; produces GTP (converted to ATP via substrate-level phosphorylation).
- Succinate Dehydrogenase: Produces FADH2; reversible; part of ETC (Complex II); mutations can cause pheochromocytoma.
- Fumarase: Converts fumarate to malate; reversible; deficiency can cause leiomyomas.
- Malate Dehydrogenase: Converts malate to oxaloacetate; produces NADH; reversible.
Regulation & Clinical Connections
- High ATP/NADH inhibits cycle; high ADP/Ca²⁺ stimulates.
- Mutations in α-ketoglutarate dehydrogenase can impair gene expression via histone demethylase, leading to certain tumors (e.g., gliomas).
- Certain enzyme deficiencies or toxins can impact the cycle and result in disease.
Products Per Glucose (2 cycles)
- 4 CO2, 6 NADH, 2 FADH2, 2 ATP (via substrate-level phosphorylation).
- NADH and FADH2 feed into the electron transport chain to produce further ATP via oxidative phosphorylation.
Key Terms & Definitions
- Acetyl-CoA — 2-carbon molecule entering the Krebs cycle.
- Oxaloacetate — 4-carbon molecule, combines with acetyl-CoA to start the cycle.
- NADH/FADH2 — Electron carriers produced in the cycle, used in ETC.
- Substrate-level phosphorylation — Direct formation of ATP (or GTP) from energetically favorable reactions.
- Oxidative phosphorylation — Production of ATP using energy from NADH/FADH2 via the ETC.
Action Items / Next Steps
- Review enzyme regulation points and intermediates of the Krebs cycle.
- Memorize the mnemonic for cycle intermediates.
- Prepare for quiz on cycle steps, enzyme names, products, and regulation.