Biochemistry
Krebs Cycle
Citric acid cycle — central metabolic hub, generating electron carriers and CO₂
The Krebs cycle (also citric acid cycle, TCA cycle) is the central metabolic pathway of aerobic respiration. Located in mitochondrial matrix. Acetyl-CoA (from carbohydrate, fat, protein breakdown) enters; oxidized completely to CO₂. 8 enzymatic steps; 3 NAD⁺ → NADH, 1 FAD → FADH₂, 1 GDP → GTP per cycle. Electron carriers (NADH, FADH₂) feed electron transport chain. Discovered by Hans Krebs (1937; Nobel 1953). Hub of metabolism: many other pathways feed in or branch out (amino acid synthesis, gluconeogenesis, etc.).
- LocationMitochondrial matrix
- InputAcetyl-CoA (2 carbons)
- Per cycle output2 CO₂, 3 NADH, 1 FADH₂, 1 GTP
- Steps8 enzymatic reactions
- DiscoveredHans Krebs, 1937 (Nobel 1953)
- NamesKrebs cycle = citric acid cycle = TCA cycle
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Why Krebs matters
- Energy. Central to ATP production.
- Metabolism. Hub for all macronutrients.
- Biosynthesis. Intermediates for amino acid, lipid synthesis.
- Cancer. Some cancers rewire Krebs metabolism.
- Diabetes. Altered metabolism.
- Mitochondrial diseases. Disorders of Krebs/ETC.
- Education. Foundational biochemistry.
Common misconceptions
- Krebs makes most ATP. ETC + ATP synthase makes most.
- Krebs uses oxygen directly. O₂ used by ETC, not Krebs.
- Krebs only for glucose. All major fuels.
- Cycle goes one direction. Some intermediates can leave for biosynthesis.
- All steps do same thing. Each step distinct.
- Krebs makes CO₂ from glucose carbons. Yes; but indirect via pyruvate.
Frequently asked questions
How does the Krebs cycle work?
8 enzymatic steps that completely oxidize acetyl-CoA to CO₂. Acetyl-CoA (2C) joins oxaloacetate (4C) → citrate (6C). Citrate gradually oxidized through cycle; loses 2 CO₂; regenerates oxaloacetate. Per cycle: 2 CO₂ released, 3 NADH made, 1 FADH₂, 1 GTP. NADH/FADH₂ go to electron transport chain → ATP synthesis. Oxaloacetate ready for next cycle.
What's acetyl-CoA?
2-carbon unit attached to coenzyme A. Generated from: pyruvate (from glycolysis), fatty acids (β-oxidation), some amino acids. Enters Krebs cycle when joined to oxaloacetate. Major metabolic intermediate. Accumulation indicates excess fuel — pushes biosynthesis (fatty acid synthesis from acetyl-CoA).
How many ATPs per glucose?
Total cellular respiration. Glycolysis: 2 ATP, 2 NADH. Pyruvate to acetyl-CoA: 2 NADH (per glucose, since 2 pyruvates). Krebs: 2 cycles × (3 NADH + 1 FADH₂ + 1 GTP) = 6 NADH + 2 FADH₂ + 2 GTP. Electron transport: ~30 ATP from all NADH/FADH₂. Total: ~36-38 ATP per glucose (theoretical; ~30 actual due to leaks).
What's the connection to electron transport?
Krebs cycle generates NADH and FADH₂ — electron carriers. These feed electron transport chain (in inner mitochondrial membrane). Electrons passed to O₂ via complexes I-IV; H⁺ pumped across membrane; H⁺ flows back through ATP synthase → makes ATP. Krebs cycle's main contribution: electron carriers, not direct ATP. Combined with ETC: oxidative phosphorylation.
How is Krebs regulated?
Multiple control points. (1) Citrate synthase: inhibited by ATP, NADH, citrate (when energy abundant). (2) Isocitrate dehydrogenase: rate-limiting; activated by ADP, inhibited by NADH and ATP. (3) α-ketoglutarate dehydrogenase: similar regulation. (4) Substrate availability: if energy needed, cycle accelerates. Tightly regulated to match energy demand.
What feeds into Krebs?
All major fuels converge on acetyl-CoA. Glucose → pyruvate (glycolysis) → acetyl-CoA. Fatty acids → β-oxidation → acetyl-CoA. Amino acids → various intermediates (some → acetyl-CoA, some → α-KG, etc.). All fuel oxidation routes converge on Krebs cycle. Reverse: cycle intermediates can leave for biosynthesis (oxaloacetate → glucose; α-KG → amino acids).
What if oxygen absent?
Krebs cycle stops. Without O₂, electron transport stops. NADH accumulates; can't be reoxidized. Krebs cycle requires NAD⁺ — when depleted, halts. Cell switches to fermentation: glycolysis only, regenerating NAD⁺ via lactate or ethanol. Far less ATP per glucose (2 vs 30). Reason: aerobic > anaerobic energy.