Topic 10 Study Notes on Acetyl-CoA and the Citric Acid Cycle

Topic 10: Acetyl-CoA Part 1: The Citric Acid Cycle

Readings

• Chapter 14, Section 15.2 (Mitochondrial Structure)

Overview of Glycolysis and Pyruvate Processing

• Glycolysis: Takes place in the cytoplasm and produces pyruvate. Under anaerobic conditions, pyruvate can be converted to:

  • Lactate

  • Ethanol

• Gluconeogenesis: Pyruvate can also be transformed back into glucose when necessary.

• Aerobic Conditions: Under these conditions, pyruvate is transported into mitochondria where it undergoes oxidation, resulting in the production of CO2.

Mitochondrial Structure

• The mitochondrion is characterized by two membranes:

  • Outer Membrane: Contains numerous pores and is permeable to most solutes of low molecular weight (up to approximately 5000 Da).

  • Inner Membrane: Impermeable to ions and charged molecules, which require specific paths (channels or transporters) to cross; it is folded into structures called cristae, which increase surface area significantly.

• Matrix: The space enclosed by the inner membrane containing soluble proteins, extrachromosomal DNA, and ribosomes.

• Mitochondrial Genome: Contains 37 genes that encode subunits of the complexes involved in oxidative phosphorylation, and RNA molecules needed for translating these subunits.

• Evolution of Mitochondria: Mitochondria are thought to have evolved from bacteria that developed a symbiotic relationship with primitive cells due to their independent DNA, two-membrane structures, and reproductive methods via division.

Mitochondrial Respiration

• Bioenergetic Reactions: The net result is the conversion of pyruvate and O2 into CO2 and H2O. This process is termed respiration, which is distinct from breathing.

• Physiological Respiration: The O2 inhaled is primarily used as the final electron acceptor during mitochondrial respiration.

Oxidation of Pyruvate to CO2

• Process Description: Occurs in two stages:

  1. Decarboxylation of Pyruvate: Addition of Coenzyme A forms acetyl-CoA.

  2. Citric Acid Cycle: The acetyl group from acetyl-CoA is oxidized through this cycle.

• Coenzyme A (CoA): Facilitates the transport of acyl groups within the cell, specifically transferring two carbons from pyruvate to the citric acid cycle via acetyl-CoA.

• Net Reaction for Acetyl-CoA Formation:

  • Reaction: pyruvate + NAD+ + CoA → acetyl-CoA + CO2 + NADH

  • Enzyme Involved: Pyruvate dehydrogenase complex.

Regulation of Pyruvate Dehydrogenase Complex

• Reaction Characteristics:

  • The reaction is irreversible and represents the exclusive pathway for acetyl-CoA production from carbohydrates in mammals.

  • The reaction rate is tightly regulated.

• Mammalian Limitations: Mammals lack pathways that convert acetyl groups from acetyl-CoA back into carbohydrates, indicating the inability to convert fats into carbohydrates.

• Enzyme Assembly: The pyruvate dehydrogenase complex is composed of three enzymes.

• Competitive Inhibition:

  • Acetyl-CoA and NADH inhibit the enzyme by competing with CoA and NAD+ at the active sites.

  • Acetyl-CoA and NADH promote phosphorylation of a serine residue on the enzyme complex, leading to its inactivation.

  • Conversely, pyruvate inhibits this phosphorylation and thus stimulates enzyme activity.

• Insulin's Role: Promotes dephosphorylation of the enzyme, enhancing its activity and stimulating the production of both glycogen and acetyl-CoA.

The Citric Acid Cycle

• Alternate Names: Known as the tricarboxylic acid (TCA) cycle or Krebs cycle (after Hans Krebs).

• Primary Function:

  • Transfers electrons from carbon atoms to electron carriers NAD+ and Q, producing NADH and QH2.

  • These carriers later feed electrons into the electron transport chain.

• Carbon Oxidation:

  • Two carbon atoms are oxidized to form two molecules of CO2; a total of four pairs of electrons are lost.

  • Three pairs are transferred to NAD+ (producing three NADH), while one pair transfers to Q, forming QH2.

• GTP Production:

  • Synthesis of one GTP from GDP and Pi, with GTP being energetically equivalent to ATP.

• Net Reaction of the Citric Acid Cycle:

  • Acetyl-CoA + 3NAD+ + Q + GDP + Pi → 2CO2 + CoA + 3NADH + QH2 + GTP

• Key Points Regarding the Cycle:

  1. Two carbons enter from acetyl-CoA and two carbons leave as CO2.

  2. Four reduced electron carriers are produced: three NADH and one QH2.

  3. One high-energy phosphoanhydride bond is generated in GTP.

  4. The cycle is unidirectional.

  5. The cycle absolutely requires oxygen.

Regulation of the Citric Acid Cycle

• Regulatory Factors:

  • 1) Availability of substrates

  • 2) Competitive inhibition by accumulated products

  • 3) Allosteric regulation, including activation by ADP

• The transfer of electrons to O2 via the electron transport chain is essential to regenerate NAD+ and Q required for the cycle.

Biosynthetic Pathways Related to Energy Metabolism

• Acetyl-CoA and intermediates from glycolysis and the citric acid cycle serve as raw materials to synthesize various biological molecules:

  • Cholesterol: All carbon atoms derived from acetyl-CoA.

  • Glycolytic intermediates: Involved in lipid, pyrimidine, and certain amino acid synthesis.

  • Citric acid cycle intermediates: Used for purine, pyrimidine, and amino acid synthesis as well as heme production.

• Implicating Energy Metabolism: Requires a diversion of acetyl-CoA and other molecules from energy metabolism, which contributes to the observation that ATP yield from glucose oxidation is typically lower than the theoretical maximum.

Catabolism of Amino Acids

• Amino acids can be degraded to generate pyruvate, acetyl-CoA, and citric acid cycle intermediates.

• Function of Proteins: Although proteins can act as energy storage molecules, their primary function is not energy provision.

• Nitrogen Discarding: During amino acid catabolism, nitrogen atoms are discarded as urea.

Topic 10 Review Questions

• WileyPLUS questions for Chapter 14:

  • Questions: 1, 9, 11, 13, 17, 25b, 55, 59, 61, 65, 77