The Krebs cycle, also known as the Citric Acid Cycle or TCA cycle, is a central metabolic pathway in nearly all living organisms. This series of enzyme-catalyzed reactions is fundamental to cellular respiration, the process by which cells extract energy from nutrients. The cycle occurs within the mitochondrial matrix, the inner compartment of mitochondria, which are often referred to as the “powerhouses” of the cell.
Setting the Stage for Energy Production
Before the Krebs cycle can begin, nutrient molecules like glucose, fats, and proteins must be converted into an entry molecule, Acetyl-CoA. Glucose, for instance, first undergoes glycolysis in the cell’s cytoplasm, breaking down into two molecules of pyruvate. Each pyruvate then moves into the mitochondrial matrix and is transformed into Acetyl-CoA.
This conversion of pyruvate to Acetyl-CoA is a process called oxidative decarboxylation, catalyzed by the pyruvate dehydrogenase complex. During this reaction, one carbon atom from pyruvate is released as carbon dioxide, and high-energy electrons are captured in a molecule called NADH. Acetyl-CoA, a two-carbon molecule, then becomes the main fuel that directly enters the Krebs cycle, linking glycolysis with subsequent energy-generating steps. Fatty acids also enter the cycle by being degraded into Acetyl-CoA through a process called beta-oxidation, while amino acids can be deaminated and converted into pyruvate, Acetyl-CoA, or other cycle intermediates.
Inside the Cycle: Key Transformations
The Krebs cycle is a closed loop, regenerating its starting molecule to continue with new fuel. The cycle begins when two-carbon Acetyl-CoA combines with four-carbon oxaloacetate to form six-carbon citrate. This initial step is catalyzed by the enzyme citrate synthase.
Citrate then undergoes a series of transformations through eight steps, involving enzymes. During these reactions, carbon atoms are rearranged, and several oxidation steps occur. These oxidation steps release carbon dioxide as a waste product, with two CO2 molecules produced per turn.
These oxidation reactions transfer high-energy electrons to carrier molecules NAD+ and FAD, reducing them to NADH and FADH2. For each Acetyl-CoA molecule entering the cycle, three molecules of NADH and one molecule of FADH2 are produced. The cycle culminates with the regeneration of oxaloacetate, ready to accept another Acetyl-CoA molecule and continue energy production.
The Grand Energy Payoff and Beyond
The Krebs cycle’s energetic significance lies in the high-energy electron carriers it produces: NADH and FADH2. These molecules do not directly provide ATP; instead, they shuttle their high-energy electrons to the electron transport chain. This chain, on the inner mitochondrial membrane, generates most ATP through oxidative phosphorylation.
As NADH and FADH2 donate their electrons to the electron transport chain, protein complexes facilitate electron movement. This electron flow drives proton pumping from the mitochondrial matrix into the intermembrane space, creating a proton gradient across the inner mitochondrial membrane. This electrochemical gradient represents stored energy, much like water behind a dam.
The protons then flow back into the mitochondrial matrix through the enzyme ATP synthase, which harnesses this flow to synthesize ATP from ADP and inorganic phosphate. ATP yield can vary, but each NADH molecule typically contributes to about 2.5 ATP, and each FADH2 molecule yields approximately 1.5 ATP. This makes the electron transport chain, powered by the Krebs cycle’s outputs, the primary ATP-generating stage of cellular respiration.
Beyond its main role in energy generation, the Krebs cycle also serves as a hub for other metabolic pathways. Intermediate molecules within the cycle can be used as building blocks for other cellular components. For example, intermediates can be converted into amino acids, the building blocks of proteins, or contribute to the synthesis of fatty acids and cholesterol. The cycle also plays a role in the formation of heme, a component of hemoglobin in red blood cells. This dual function highlights the Krebs cycle’s central position in cellular metabolism, supporting both energy production and biosynthesis.