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Krebs cycle Knowledge-Based Study

Biology · Cellular Energetics · Biology · Cellular Respiration

Biology topic explanations on Krebs cycle.

Study notes

  1. Overview of the Krebs Cycle

    The Krebs cycle, also known as the citric acid cycle or the tricarboxylic acid (TCA) cycle, is the central metabolic pathway of aerobic cellular respiration. Following glycolysis and the transition step (pyruvate oxidation), the Krebs cycle completes the breakdown of glucose derivatives by harvesting high-energy electrons.

    Cellular Compartmentalization

    The reactions of the Krebs cycle occur in specific cellular environments depending on organism type:

    • Eukaryotes: The cycle occurs in the mitochondrial matrix, where all necessary enzymes are dissolved in solution, except for succinate dehydrogenase, which is embedded in the inner mitochondrial membrane.
    • Prokaryotes: Because prokaryotes lack membrane-bound organelles, the cycle takes place directly within the cytosol.

    The primary function of the cycle is not to produce large amounts of ATP directly, but rather to strip electrons from organic intermediates and transfer them to mobile electron carriers: NAD+ and FAD.

    Key Enzymatic Transformations

    The Krebs cycle is an eight-step cyclical pathway. Because it is a closed loop, the starting compound is regenerated at the end of each turn.

    1. Formation of Citrate

    The cycle begins when the two-carbon acetyl group of acetyl-CoA combines with a four-carbon molecule called oxaloacetate. This condensation reaction forms a six-carbon molecule called citrate (citric acid).

    2. Isomerization and Oxidative Decarboxylations

    Citrate is rearranged into its isomer, isocitrate, which then undergoes two successive rounds of oxidation and decarboxylation:

    • First Decarboxylation: Isocitrate (6C) is oxidized to α-ketoglutarate (5C). One molecule of carbon dioxide (CO2) is released, and NAD+ is reduced to NADH.
    • Second Decarboxylation: α-Ketoglutarate (5C) is oxidized and coupled to Coenzyme A to form succinyl-CoA (4C). Another molecule of CO2 is released, and a second NAD+ is reduced to NADH.

    3. Substrate-Level Phosphorylation

    The high-energy thioester bond of succinyl-CoA is cleaved to form succinate (4C). This exergonic reaction powers the phosphorylation of GDP to GTP (or ADP directly to ATP, depending on tissue type).

    4. Regeneration of Oxaloacetate

    Succinate is converted back to oxaloacetate through three sequential steps to accept the next acetyl group:

    • Oxidation: Succinate is oxidized to fumarate, transferring two electrons and two protons to reduce FAD to FADH2.
    • Hydration: Water is added across the double bond of fumarate to yield malate.
    • Final Oxidation: Malate is oxidized to regenerate oxaloacetate, reducing a third molecule of NAD+ to NADH.

    Net Yield and Stoichiometry

    To accurately account for the energy harvested during cellular respiration, outputs must be evaluated both per turn of the cycle and per molecule of entering glucose.

    Yield per Acetyl-CoA (Single Turn)

    • 2 molecules of CO2: Represents the complete oxidation of the two entering carbon atoms.
    • 3 molecules of NADH: Carrying high-energy electrons to the respiratory chain.
    • 1 molecule of FADH2: A second carrier supplying electrons at a lower free-energy level.
    • 1 molecule of ATP / GTP: Produced via substrate-level phosphorylation.

    Yield per Glucose Molecule

    Because each glucose molecule yields two molecules of pyruvate during glycolysis, two molecules of acetyl-CoA enter the cycle per glucose. Therefore, the cycle turns twice per original glucose molecule, yielding:

    • 4 CO2
    • 6 NADH
    • 2 FADH2
    • 2 ATP (or GTP)

    Combined with the outputs of glycolysis and pyruvate oxidation, all six carbons from the original glucose molecule have now been fully oxidized and released as metabolic waste in the form of CO2.

    Metabolic Integration

    The Krebs cycle does not operate in isolation; it is closely regulated according to cellular energy demands and functions as an amphibolic pathway.

    Regulatory Control Mechanisms

    The cycle is regulated primarily through allosteric feedback inhibition at key irreversible steps:

    • Inhibition: High concentrations of ATP and NADH indicate an abundant energy supply and inhibit key regulatory enzymes, such as isocitrate dehydrogenase and citrate synthase.
    • Activation: Elevated levels of ADP and NAD+ signal a depleted energy state and allosterically activate the cycle to accelerate fuel oxidation.

    The Amphibolic Role

    While the cycle is predominantly catabolic (breaking down carbon skeletons for energy), it also serves an anabolic function:

    • Intermediates such as oxaloacetate and α-ketoglutarate are regularly siphoned off as precursors for the synthesis of non-essential amino acids, purines, pyrimidines, and heme groups.
    • When intermediates are drawn off for biosynthesis, anaplerotic reactions replenish them to maintain continuous cyclic flow.