The Krebs Cycle, also known as the Citric Acid Cycle or the tricarboxylic acid (TCA) cycle, is a metabolic pathway central to cellular energy production. This cyclical series of enzyme-catalyzed reactions is where the final breakdown of carbohydrates, fats, and proteins occurs to generate usable energy. In eukaryotic cells, the entire process takes place within the mitochondrial matrix. The cycle’s primary purpose is to capture the energy stored in nutrient molecules by transferring it to specific carrier molecules.
The Role of the Krebs Cycle in Cellular Energy Production
The Krebs Cycle is the aerobic link connecting the initial breakdown of glucose (glycolysis) to the final stage of energy generation (oxidative phosphorylation). Before the cycle begins, the three-carbon molecule pyruvate must be prepared. This preparatory step, called oxidative decarboxylation, converts pyruvate into the two-carbon molecule Acetyl-Coenzyme A (Acetyl-CoA). This conversion is catalyzed by the Pyruvate Dehydrogenase Complex, generating a molecule of NADH and releasing one carbon atom as carbon dioxide. The resulting Acetyl-CoA acts as the fuel input for the cycle.
The overall function of the cycle is to take the two carbons from the acetyl group and oxidize them to two molecules of carbon dioxide. This chemical breakdown releases high-energy electrons and protons, which are accepted by the carrier molecules NAD+ and FAD. The goal is to load these carriers, NADH and FADH2, with energy to power the final production of Adenosine Triphosphate (ATP).
The Eight Principal Steps of the Cycle
The Krebs Cycle consists of eight enzyme-catalyzed steps that result in the regeneration of the starting molecule. The cycle begins with the condensation of the two-carbon Acetyl-CoA molecule with the four-carbon starting molecule, oxaloacetate. This reaction is catalyzed by citrate synthase and produces the six-carbon compound, citrate.
In the second step, citrate is rearranged through an isomerization reaction to form isocitrate. The third step marks the first of two oxidative decarboxylation reactions, converting isocitrate to \(\alpha\)-ketoglutarate. During this process, a carbon atom is released as carbon dioxide, and the first molecule of NADH is produced.
The fourth step is the second oxidative decarboxylation, converting the five-carbon \(\alpha\)-ketoglutarate into the four-carbon compound succinyl-CoA. This reaction releases a second molecule of carbon dioxide and generates the second NADH molecule. Following this, succinyl-CoA is converted to succinate in the fifth step, which generates energy directly through substrate-level phosphorylation.
Substrate-level phosphorylation results in the production of a Guanosine Triphosphate (GTP) molecule, which is chemically equivalent to ATP. The sixth step involves the oxidation of succinate to fumarate, reducing the electron carrier FAD to FADH2. The enzyme catalyzing this step, succinate dehydrogenase, is the only cycle enzyme embedded in the inner mitochondrial membrane.
Fumarate is then converted to malate in the seventh step through the addition of a water molecule. The cycle concludes with the eighth step, where malate is oxidized back to oxaloacetate, the original four-carbon molecule required to start a new turn. This regeneration step produces the third and final molecule of NADH, completing the loop.
Energy Yield and Regulatory Control
Per single turn of the Krebs Cycle, the oxidation of one acetyl group yields a specific set of high-energy products. The net output is three molecules of NADH, one molecule of FADH2, and one molecule of GTP (an ATP equivalent). In addition, two molecules of carbon dioxide are released as metabolic waste products, representing the complete oxidation of the two carbons that entered as Acetyl-CoA.
The significance of the NADH and FADH2 molecules lies in their role as electron carriers for the final stage of cellular respiration, the Electron Transport Chain (ETC). They deposit their high-energy electrons onto the protein complexes of the ETC, which drives the creation of a proton gradient across the inner mitochondrial membrane. The energy stored in this gradient is then harnessed by ATP synthase to generate the cell’s ATP supply through oxidative phosphorylation.
The speed of the Krebs Cycle is managed by the cell’s energy demands through allosteric control. The cycle is regulated primarily at three points, involving the enzymes citrate synthase, isocitrate dehydrogenase, and \(\alpha\)-ketoglutarate dehydrogenase. When the cell has an abundance of energy, high concentrations of ATP and NADH act as inhibitors to slow the cycle. Conversely, when the cell’s energy charge is low, high concentrations of ADP and NAD+ act as activators, signaling the need for more energy production. The availability of the substrate Acetyl-CoA also plays a role, as the cycle cannot proceed without the input molecule.