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A Closer look at the citric acid cycle

Respiration Overview

In the chemical structures, red type traces the fate of the two carbon atoms that enter the cycle via acetyl CoA (step 1), and blue type indicates the two carbons that exit the cycle as CO₂ in step 3 and step 4. (The red labeling goes only through step 5 because the succinate molecule is symmetrical; the two ends cannot be distinguished from each other.) Notice that the carbon atoms that enter the cycle from acetyl CoA do not leave the cycle in the same turn. They remain in the cycle, occupying a different location in the molecules on their next turn, after another acetyl group is added. As a consequence, the oxaloacetate that is regenerated at step 8 is composed of different carbon atoms each time around. In eukaryotic cells, all the citric acid cycle enzymes are located in the mitochondrial matrix except for the enzyme that catalyzes step 6, which resides in the inner mitochondrial membrane. Carboxylic acids are represented in their ionized forms, as —COO^–, because the ionized forms prevail at the pH within the mitochondrion. For example, citrate is the ionized form of citric acid.

1. Acetyl CoA adds its two-carbon acetyl group to oxaloacetate, producing citrate.
2. Citrate is converted to its isomer, isocitrate, by removal of one water molecule and addition of another.
3. Isocitrate is oxidized, reducing NAD⁺ to NADH. Then the resulting compound loses a CO₂ molecule.
4. Another CO₂ is lost, and the resulting compound is oxidized, reducing NAD⁺ to NADH. The remaining molecule is then attached to coenzyme A by an unstable bond.
5. CoA is displaced by a phosphate group, which is transferred to GDP, a molecule with functions similar to ATP that, in some cases, is used to generate ATP.
6. Two hydrogens are transferred to FAD, forming FADH₂ and oxidizing succinate.
7. Addition of a water molecule rearranges bonds in the substrate.
8. The substrate is oxidized, reducing NAD⁺ to NADH and regenerating oxaloacetate.