The Krebs Cycle, also known as the Citric Acid Cycle or the Tricarboxylic Acid (TCA) Cycle, is a central metabolic pathway for all aerobic organisms. This series of chemical reactions is a fundamental component of cellular respiration, the process by which cells break down nutrients to generate energy. Its primary function is to complete the oxidation of carbon atoms derived from carbohydrates, fats, and proteins, preparing chemical energy for later capture.
Setting the Stage: Inputs and Location
The cycle requires a specific two-carbon molecule called Acetyl-Coenzyme A (Acetyl-CoA) to begin. Acetyl-CoA is primarily generated from pyruvate, the end product of glycolysis, through a reaction that also releases carbon dioxide. The body can also produce Acetyl-CoA from other macronutrients; fatty acids are broken down via beta-oxidation, and certain amino acids can be converted into this entry molecule. In eukaryotic cells, the entire sequence of the Krebs Cycle takes place within the mitochondrial matrix, which contains all the necessary enzymes and coenzymes.
The Immediate Molecular Products
The main purpose of the Krebs Cycle is to systematically extract energy from Acetyl-CoA and capture it in various forms, generating four distinct molecular products per turn. Acetyl-CoA enters the cycle by combining with oxaloacetate (a four-carbon compound) to form citrate (a six-carbon molecule). During the subsequent reactions, the two carbon atoms from Acetyl-CoA are fully oxidized and released as two molecules of carbon dioxide (\(\text{CO}_2\)).
This \(\text{CO}_2\) is considered a waste product that the organism eventually exhales. Simultaneously, the energy released from the chemical rearrangement is captured by two types of electron carrier molecules. Specifically, three molecules of Nicotinamide Adenine Dinucleotide (\(\text{NADH}\)) and one molecule of Flavin Adenine Dinucleotide (\(\text{FADH}_2\)) are produced during each turn of the cycle. These molecules are reduced, meaning they have accepted high-energy electrons, making them energy-rich temporary storage units.
A small amount of direct energy is also generated in the form of one molecule of Adenosine Triphosphate (\(\text{ATP}\)) or Guanosine Triphosphate (\(\text{GTP}\)). This single \(\text{ATP}\) or \(\text{GTP}\) molecule is produced directly within the cycle through a process called substrate-level phosphorylation. Although this direct yield is minimal compared to the final energy output of cellular respiration, it provides immediate energy currency to the cell. Therefore, the immediate output for every Acetyl-CoA molecule is three \(\text{NADH}\), one \(\text{FADH}_2\), two \(\text{CO}_2\), and one \(\text{ATP}\) or \(\text{GTP}\).
Maximizing Energy Yield: The Role of Electron Carriers
The true energy yield of the Krebs Cycle is not found in the single molecule of \(\text{ATP}\) it produces, but in the high number of high-energy electron carriers generated. The three \(\text{NADH}\) and one \(\text{FADH}_2\) molecules created during each turn contain the vast majority of the chemical energy extracted from the original Acetyl-CoA. These reduced coenzymes are temporary energy repositories that must be processed further to release their full potential.
The next step in energy production involves these carriers traveling to the inner mitochondrial membrane to participate in the Electron Transport Chain (ETC) and Oxidative Phosphorylation. Here, the \(\text{NADH}\) and \(\text{FADH}_2\) are oxidized, meaning they donate their high-energy electrons to a series of protein complexes. The movement of these electrons releases energy, which is used to pump hydrogen ions (protons) across the inner mitochondrial membrane.
This pumping action creates an electrochemical gradient in the intermembrane space, establishing a form of stored potential energy. This gradient is then harnessed by an enzyme called \(\text{ATP}\) synthase. As the protons flow back into the matrix through \(\text{ATP}\) synthase, the enzyme catalyzes the synthesis of large amounts of \(\text{ATP}\) from \(\text{ADP}\) and phosphate. This final step of cellular respiration, driven by the \(\text{NADH}\) and \(\text{FADH}_2\) from the Krebs Cycle, is responsible for producing over 95% of the cell’s total energy from aerobic metabolism.
Beyond Energy: The Cycle’s Anabolic Functions
Although the Krebs Cycle is primarily known for its role in energy production, it is classified as an amphibolic pathway, meaning it serves both catabolic (breakdown) and anabolic (synthesis) functions. The intermediates within the cycle are not locked into the energy-producing sequence; they can be siphoned off to create building blocks for other cellular components. This flexibility allows the cell to balance its energy needs with its growth and repair requirements.
For instance, the five-carbon intermediate \(\alpha\)-ketoglutarate can be removed from the cycle to serve as a precursor for synthesizing several amino acids, including glutamate. Similarly, the four-carbon compound oxaloacetate can be converted into aspartate or used to initiate gluconeogenesis, the process of synthesizing new glucose. Citrate, the first molecule formed in the cycle, can be transported out of the mitochondrion to the cytoplasm, where it is used as a precursor for the synthesis of fatty acids and cholesterol. These biosynthetic reactions maintain the cell’s structure and function, highlighting the cycle’s dual role in metabolism.