Citric Acid Cycle

Introduction to the Citric Acid Cycle (CAC)

  • The Citric Acid Cycle (CAC) is an essential metabolic pathway that plays a central role in cellular respiration.

Overview of Glycolysis Products

  • Glycolysis produces pyruvate, ATP, NADH, and small amounts of other metabolites, leading into the CAC.

The Citric Acid Cycle (CAC)

  • Often referred to as the "hub" of metabolism, the CAC is crucial for energy production.

  • Key substrates involved in the CAC include heme and chlorophyll.

Nutrient Conversion to Energy

  • Cells require nutrients to convert into usable energy:

    • Carbohydrates yield sugars.

    • Proteins yield amino acids.

    • Fats yield fatty acids and glycerol.

  • These nutrients can be oxidized, losing electrons to generate energy.

Entry of Fuels into CAC

  • Fuels enter the CAC primarily as acetyl-CoA.

  • For each pyruvate molecule:

    • 8 electrons are produced.

    • 6 electrons are captured by NAD+ forming 3 NADH.

    • 2 electrons are captured by FAD+ forming 1 FADH2.

Conversion of Pyruvate to Acetyl-CoA

  • Pyruvate, obtained from glycolysis, is converted as follows:

    • Enters the mitochondria.

    • Undergoes decarboxylation to form acetyl-CoA.

    • This process links glycolysis to the CAC.

Pyruvate Dehydrogenase Complex

  • Key components include:

    • PDH kinase (regulatory enzyme).

    • PDH phosphatase (regulatory enzyme).

  • These enzymes regulate the conversion of pyruvate to acetyl-CoA.

Key Steps in the Citric Acid Cycle

Citrate Synthase Step

  • Enzyme: Citrate Synthase

  • Reaction Characteristics:

    • Very negative ΔG°’ (favorable).

    • Combines acetyl-CoA (2 carbons) with oxaloacetate (4 carbons) to form citrate (6 carbons).

Aconitase Step

  • Enzyme: Aconitase

  • Function: Converts citrate into isocitrate (isomerization process).

Isocitrate Dehydrogenase Step

  • Enzyme: Isocitrate Dehydrogenase

  • Characteristics:

    • Rate-limiting step, inhibited by high ATP levels.

    • Produces NADH and CO2 for the electron transport chain (ETC).

Alpha-Ketoglutarate Dehydrogenase Step

  • Enzyme: α-Ketoglutarate Dehydrogenase

  • Produces NADH and CO2, feeds into the ETC.

Succinyl-CoA Synthetase Step

  • Enzyme: Succinyl-CoA Synthetase

  • Key Features:

    • Involves substrate-level phosphorylation.

    • Requires energy input.

Succinate Dehydrogenase Step

  • Enzyme: Succinate Dehydrogenase

  • Function:

    • Catalyzes oxidation-reduction reactions.

    • Only CAC enzyme located in the inner mitochondrial membrane (not in matrix).

Fumarase Step

  • Enzyme: Fumarase

  • Converts fumarate to malate.

Malate Dehydrogenase Step

  • Enzyme: Malate Dehydrogenase

  • Characteristics:

    • Fourth and final oxidation of the cycle.

    • Very positive ΔG°’, driven by the preceding citrate synthase reaction.

    • Produces NADH and regenerates oxaloacetate for the cycle.

Glyoxylate Cycle

  • Functions to skip CO2-generating steps, relevant for gluconeogenesis.

Key Enzymes in Glyoxylate Cycle

  • Isocitrate lyase:

    • Converts isocitrate into succinate and glyoxylate.

  • Malate synthase:

    • Converts acetyl-CoA and glyoxylate into malate.

Differences Between CAC and Glyoxylate Cycle

  • Glyoxylate Cycle:

    • Inputs 4 carbons (2 acetyl-CoA).

    • Releases no CO2.

    • Produces extra oxaloacetate per cycle.

    • Net synthesis of glucose from acetyl-CoA.

  • Citric Acid Cycle:

    • Inputs 2 carbons (1 acetyl-CoA).

    • Releases 2 CO2 molecules.

    • Produces 3 NADH, 1 FADH2, & 1 GTP per cycle.

    • No net synthesis of glucose from acetyl-CoA.

ATP Synthesis from Electrons in the CAC

  • Overview of ATP production:

    • Approximate yields per turn of CAC:

      • 2.5 ATP per NADH.

      • 1.5 ATP per FADH2.

  • Total ATP yield per glucose in aerobic conditions should be considered.