Krebs Cycle

Krebs Cycle

🟢 Lite — Quick Review (1h–1d)

Rapid summary for last-minute revision before your exam.

The Krebs cycle (citric acid cycle / TCA cycle) runs in the mitochondrial matrix and oxidises acetyl-CoA to two CO₂ molecules, harvesting 3 NADH, 1 FADH₂, and 1 GTP per turn. The eight enzymes in order are: citrate synthase, aconitase, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase complex, succinyl-CoA synthetase, succinate dehydrogenase, fumarase, and malate dehydrogenase. The three physiologically irreversible steps are catalysed by citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase. Net yield per acetyl-CoA = 10 ATP (3 × 2.5 + 1 × 1.5 + 1 GTP). High-yield pointers: substrate-level phosphorylation in this cycle yields GTP, not ATP; succinate dehydrogenase is Complex II of the ETC; the cycle is amphibolic (both catabolic and anabolic).

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🟡 Standard — Regular Study (2d–2mo)

Standard content for students with a few days to months.

Overall Reaction

Acetyl-CoA + 3 NAD⁺ + FAD + GDP + Pi + 2 H₂O → 2 CO₂ + 3 NADH + FADH₂ + GTP + CoA + 3 H⁺. Two carbons enter as acetyl-CoA and two leave as CO₂; the remaining energy is conserved in reduced cofactors and a high-energy phosphate.

Step-by-Step Pathway

• Citrate synthase: Acetyl-CoA + oxaloacetate → citrate + CoA. The committed step; driven by hydrolysis of the thioester bond.
• Aconitase: Citrate ⇌ isocitrate (via cis-aconitate). Iron–sulphur cluster enzyme; stereospecific dehydration/rehydration.
• Isocitrate dehydrogenase: Isocitrate → α-ketoglutarate + CO₂ + NADH. First CO₂ released; NAD⁺-dependent mitochondrial isoform is the principal TCA regulator.
• α-Ketoglutarate dehydrogenase complex: α-KG → succinyl-CoA + CO₂ + NADH. A multi-enzyme complex analogous to pyruvate dehydrogenase, requiring TPP, lipoate, FAD, NAD⁺, CoA. Second CO₂ released.
• Succinyl-CoA synthetase (succinate thiokinase): Succinyl-CoA + GDP + Pi → succinate + GTP + CoA. The only substrate-level phosphorylation in the cycle; GTP is converted to ATP by nucleoside diphosphate kinase.
• Succinate dehydrogenase: Succinate → fumarate + FADH₂. The only TCA enzyme embedded in the inner mitochondrial membrane (Complex II); receives electrons via FAD, not NAD⁺. Malonate is a classical competitive inhibitor.
• Fumarase (fumarate hydratase): Fumarate + H₂O → malate. Stereospecific hydration.
• Malate dehydrogenase: Malate + NAD⁺ → oxaloacetate + NADH. Oxaloacetate regeneration closes the cycle.

Energy Yield

Source	Per acetyl-CoA	ATP equivalent
3 NADH	3 × 2.5	7.5
1 FADH₂	1 × 1.5	1.5
1 GTP	1 × 1	1.0
Total		10 ATP

Per glucose (2 acetyl-CoA entering), the cycle alone produces 20 ATP, excluding the 2 ATP consumed during the preceding steps.

Anaplerosis and Cataplerosis

The cycle is amphibolic — intermediates are siphoned off for biosynthesis: oxaloacetate and malate for gluconeogenesis, citrate for cytosolic acetyl-CoA / fatty acid synthesis, succinyl-CoA for heme synthesis, and α-ketoglutarate for glutamate and purine precursors. Replenishment (anaplerosis) of oxaloacetate is achieved by pyruvate carboxylase, PEP carboxykinase, and glutamate dehydrogenase; deficiency of pyruvate carboxylase causes fasting hypoglycaemia.

NEET PG Question Patterns

• Identify the enzyme catalysing a specific step.
• Choose cofactors of the α-ketoglutarate dehydrogenase complex (TPP, lipoate, FAD, NAD⁺, CoA — remember “Tender Loving Care For Nancy CoA”).
• Distinguish GTP vs ATP, FADH₂ vs NADH, and Complex II identification.
• State the inhibitor–enzyme pair (arsenite → α-KG dehydrogenase; malonate → succinate dehydrogenase).

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🔴 Extended — Deep Study (3mo+)

Comprehensive coverage for students on a longer study timeline.

Regulatory Architecture

The cycle is governed by substrate availability, product inhibition, and allosteric control. Isocitrate dehydrogenase is activated by ADP/Ca²⁺ and inhibited by ATP and NADH. α-Ketoglutarate dehydrogenase is suppressed by its products (NADH, succinyl-CoA) and by Ca²⁺-mediated signalling in muscle. High NADH/NAD⁺ and ATP/ADP ratios slow the cycle, matching flux to oxidative phosphorylation demand — a phenomenon called respiratory control.

Amphibolic Connections

• Cataplerotic exit of citrate (via ATP-citrate lyase) supplies cytosolic acetyl-CoA for fatty acid and cholesterol biosynthesis; this is the mechanistic link between glucose excess and lipogenesis.
• Succinyl-CoA withdrawal for δ-aminolaevulinic acid synthesis is the rate-limiting prelude to haem biosynthesis.
• Oxaloacetate transamination gives aspartate, essential for the urea cycle, purine and pyrimidine rings.

Inhibitors and Toxins

• Arsenite binds the dithiol groups of lipoamide, blocking both α-KG dehydrogenase and pyruvate dehydrogenase — the biochemical basis of arsenic poisoning.
• Fluoroacetate is converted to fluorocitrate, which inhibits aconitase, producing citrate accumulation (mechanism of action in toxicology MCQs).
• Malonate is a classical competitive inhibitor of succinate dehydrogenase (succinate → fumarate).

Common Errors

1. Stating that the cycle produces ATP directly — it produces GTP; ATP arises only via nucleoside diphosphate kinase.
2. Calling succinate dehydrogenase Complex III — it is Complex II of the ETC and does not pump protons.
3. Assuming O₂ is a substrate of the cycle — O₂ is consumed only downstream, at Complex IV.
4. Forgetting that the two carbons lost as CO₂ in a given turn are derived from the oxaloacetate (not the incoming acetyl-CoA), although net flux over multiple turns is balanced.

Worked Example

A 25-year-old presents with acute arsenical poisoning. Predict: (a) the two dehydrogenase complexes inhibited, and (b) the metabolic intermediates that accumulate. Answer: (a) α-Ketoglutarate dehydrogenase and pyruvate dehydrogenase; (b) α-ketoglutarate and pyruvate accumulate, with secondary lactate rise due to NADH-mediated shift to anaerobic glycolysis.

Practice Prompts

1. Calculate ATP yield per glucose through the TCA cycle alone and justify each multiplier for NADH vs FADH₂.
2. Explain how removal of oxaloacetate for gluconeogenesis during prolonged fasting is replenished and name the anaplerotic enzymes involved.

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