Citric Acid Cycle — Revision Notes

⚡ 30-Second Revision

Location: — Mitochondrial matrix (eukaryotes).
Input: — Acetyl-CoA (2C) + Oxaloacetate (4C).
Output per Acetyl-CoA: — 3 NADH, 1 FADH2, 1 GTP ($\approx$ 1 ATP), 2 CO2.
Key Enzymes: — Citrate synthase, Isocitrate dehydrogenase, $\alpha$-Ketoglutarate dehydrogenase, Succinyl-CoA synthetase, Succinate dehydrogenase.
Substrate-level phosphorylation: — Succinyl-CoA $\rightarrow$ Succinate (produces GTP).
Oxidative decarboxylation: — Isocitrate $\rightarrow$ $\alpha$-Ketoglutarate; $\alpha$-Ketoglutarate $\rightarrow$ Succinyl-CoA (produces CO2 and NADH).
Amphibolic: — Both catabolic and anabolic (precursors for amino acids, fatty acids, heme).
Oxygen dependence: — Indirectly aerobic (requires NAD+/FAD regeneration by ETS, which needs O2).

2-Minute Revision

The Citric Acid Cycle, also known as the Krebs cycle or TCA cycle, is the central hub of aerobic respiration, occurring in the mitochondrial matrix. It begins when a two-carbon Acetyl-CoA molecule condenses with a four-carbon oxaloacetate to form citrate.

Through a series of eight enzyme-catalyzed reactions, the two carbons from Acetyl-CoA are completely oxidized and released as two molecules of carbon dioxide. The primary energy harvest from this cycle is in the form of high-energy electron carriers: 3 NADH and 1 FADH2 per Acetyl-CoA.

These carriers will then donate their electrons to the Electron Transport System for massive ATP production. Additionally, 1 GTP (equivalent to 1 ATP) is produced directly via substrate-level phosphorylation.

The cycle is crucial because it regenerates oxaloacetate, allowing continuous processing of Acetyl-CoA. It's also amphibolic, providing intermediates for biosynthesis of amino acids, fatty acids, and heme, making it a vital link between catabolism and anabolism.

5-Minute Revision

The Citric Acid Cycle (CAC), or Krebs cycle, is the second major stage of aerobic respiration, taking place within the mitochondrial matrix. It's a cyclic pathway that completely oxidizes the acetyl group of Acetyl-CoA, derived from glucose, fatty acids, and amino acids. The cycle starts with the condensation of Acetyl-CoA (2C) and oxaloacetate (4C) to form citrate (6C), catalyzed by citrate synthase. Citrate then undergoes isomerization to isocitrate (6C).

The first oxidative decarboxylation occurs when isocitrate is converted to $\alpha$-ketoglutarate (5C) by isocitrate dehydrogenase, releasing CO2 and producing NADH. The second oxidative decarboxylation converts $\alpha$-ketoglutarate (5C) to succinyl-CoA (4C) by the $\alpha$-ketoglutarate dehydrogenase complex, releasing another CO2 and producing NADH. These two steps account for the complete oxidation of the two carbons from Acetyl-CoA.

Next, succinyl-CoA is converted to succinate (4C) by succinyl-CoA synthetase, producing 1 GTP (which can be converted to ATP) via substrate-level phosphorylation – the only direct ATP production in the cycle.

Succinate is then oxidized to fumarate (4C) by succinate dehydrogenase (Complex II of the ETS), producing FADH2. Fumarate is hydrated to malate (4C) by fumarase, and finally, malate is oxidized back to oxaloacetate (4C) by malate dehydrogenase, producing the third NADH and regenerating the starting molecule.

Overall Yield per Acetyl-CoA: 3 NADH, 1 FADH2, 1 GTP, 2 CO2. These NADH and FADH2 molecules are the primary energy yield, as they fuel the Electron Transport System for oxidative phosphorylation. The cycle's amphibolic nature means its intermediates (like citrate, $\alpha$-ketoglutarate, oxaloacetate, succinyl-CoA) are crucial precursors for various biosynthetic pathways, including amino acids, fatty acids, and heme.

Regulation primarily occurs at the irreversible steps, with high energy signals (ATP, NADH) inhibiting and low energy signals (ADP) activating the cycle.

Prelims Revision Notes

1
Location: — Occurs in the mitochondrial matrix (eukaryotes). Succinate dehydrogenase is in the inner mitochondrial membrane.
2
Starting Molecule: — Acetyl-CoA (2C) condenses with Oxaloacetate (4C).
3
First Product: — Citrate (6C).
4
Key Intermediates (in order): — Citrate $\rightarrow$ Isocitrate $\rightarrow$ $\alpha$-Ketoglutarate $\rightarrow$ Succinyl-CoA $\rightarrow$ Succinate $\rightarrow$ Fumarate $\rightarrow$ Malate $\rightarrow$ Oxaloacetate.
5
CO2 Release: — Two molecules of CO2 are released per Acetyl-CoA, at the Isocitrate dehydrogenase and $\alpha$-Ketoglutarate dehydrogenase steps.
6
NADH Production: — Three molecules of NADH are produced per Acetyl-CoA at: Isocitrate $\rightarrow$ $\alpha$-Ketoglutarate, $\alpha$-Ketoglutarate $\rightarrow$ Succinyl-CoA, and Malate $\rightarrow$ Oxaloacetate.
7
FADH2 Production: — One molecule of FADH2 is produced per Acetyl-CoA at: Succinate $\rightarrow$ Fumarate (catalyzed by Succinate dehydrogenase).
8
GTP/ATP Production: — One molecule of GTP (equivalent to ATP) is produced per Acetyl-CoA at: Succinyl-CoA $\rightarrow$ Succinate (Substrate-level phosphorylation, catalyzed by Succinyl-CoA synthetase).
9
Regenerated Molecule: — Oxaloacetate is regenerated to continue the cycle.
10
Amphibolic Nature: — Intermediates serve as precursors:

* $\alpha$-Ketoglutarate: Amino acids, purines. * Succinyl-CoA: Porphyrins, heme. * Oxaloacetate: Amino acids, pyrimidines, gluconeogenesis. * Citrate: Fatty acids, cholesterol (after transport to cytoplasm).

1
Oxygen Dependence: — Indirectly aerobic. Requires NAD+ and FAD regeneration by the Electron Transport Chain, which uses oxygen as the final electron acceptor.
2
Regulation: — Key enzymes (Citrate synthase, Isocitrate dehydrogenase, $\alpha$-Ketoglutarate dehydrogenase) are inhibited by ATP, NADH, succinyl-CoA and activated by ADP, Ca2+.

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Citrate
Isocitrate
Ketoglutarate ($\alpha$-Ketoglutarate)
Succinyl-CoA
Succinate
Fumarate
Malate
Oxaloacetate