The main aim of the citric acid cycle is to generate energy from the electrons harvested from sugar molecules like glucose.

Upon entering the citric acid cycle, acetyl-CoA goes through a series of reactions losing its acetyl group as carbon dioxide.

During the oxidative steps of the cycle, the electrons are transferred to NAD⁺, generating NADH.

GTP produced from the conversion of succinyl-CoA to succinate is readily converted to ATP.

In the next reaction, the electrons from succinate oxidation are used to reduce FAD to FADH₂.

Thus, each turn of the TCA cycle generates two CO₂ molecules, three NADH, one FADH₂, and one ATP.

The cycle must go around twice since oxidation of each glucose molecule generates two pyruvates.

Therefore, for every glucose molecule oxidized, the citric acid cycle generates four CO₂, six NADH, two FADH₂, and two ATP molecules.

The coenzymes—NADH and FADH₂—generated from the TCA cycle are utilized during oxidative phosphorylation to produce more ATP.

The citric acid cycle is termed an amphibolic pathway as it operates both anabolically and catabolically. The cyclic reactions balance the flux of the substrates to provide an optimal concentration of NADH and ATP to the cell.

Regulation of Citric Acid Cycle

The citric acid cycle is regulated in several ways, including feedback inhibition, regulation of enzyme activities, and associated anaplerotic or cataplerotic pathways.

The primary substrate of the TCA cycle—acetyl CoA—is produced by the action of pyruvate dehydrogenase (PDH) complex. When produced in excess, acetyl CoA can inhibit the PDH complex. In addition, the high concentration of products, NADH and ATP can also strongly inhibit the PDH complex activity, subsequently inhibiting the citric acid cycle.

Similarly, the enzymes citrate synthase, isocitrate dehydrogenase, and ɑ-ketoglutarate dehydrogenase may undergo allosteric regulation via products and intermediate compounds, such as NADH, ATP, and succinyl CoA, generated during the TCA cycle.

Recycling of TCA Cycle Intermediates

In case of excess production, the TCA cycle intermediates are channeled to other pathways via a process called cataplerosis, where they act as precursors for biosynthesis. These supplied intermediates are called cataplerotic molecules. However, under conditions of limited availability, the TCA cycle can accept the intermediate metabolites from other pathways to keep the cycle running. This mechanism is termed anaplerosis, and the supplied compounds are called anaplerotic molecules.

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