2024-25 FFP1 Glycolysis TCA (1)

Importance of Glucose Metabolism

  • Glucose and related sugars are critical dietary components, primarily derived from the breakdown of carbohydrates.

  • Maintaining constant glucose levels is essential for bodily functions, especially for specific tissues like the brain and erythrocytes.

  • Diabetes reflects issues in glucose metabolism regulation.

  • Glycolysis converts glucose into pyruvate, which is significant for producing Acetyl-CoA.

Metabolic Pathways Overview

  • Glycolysis: Converts one molecule of glucose (6 carbons) into 2 pyruvate molecules (3 carbons) generating NADH and ATP.

  • TCA Cycle: 2 x Acetyl-CoA enters the TCA cycle, producing NADH, FADH2, CO2, and GTP through a series of enzymatic reactions.

Key Enzyme Functions

  • Enzymatic reactions in glycolysis and the TCA cycle involve:

    • Redox Reactions: Catalyzed by dehydrogenases, producing NADH and FADH2.

    • Phosphorylation: Substrate-level phosphorylation generating ATP and GTP.

Enzyme Regulation Mechanisms

  • Rate Limiting Steps: Certain steps in these pathways are rate-limited by key enzymes.

  • Feedback and Allosteric Regulation: E.g., ATP inhibits PFK1 while fructose-2,6-bisphosphate activates it.

  • Hormonal Regulation: Insulin affects GLUT4 transporters and influences glycolysis regulation.

  • Intermediate Availability: Levels of intermediates like oxaloacetate can regulate TCA cycle activity.

  • Oxygen Availability: Essential for oxidative phosphorylation; hypoxia affects ATP synthesis.

Glucose Entry into Cells

  • Facilitated Diffusion: Glucose enters cells via GLUT transporters and sodium-dependent co-transporters.

  • Hexokinase and Glucokinase:

    • Hexokinase: High affinity for glucose, operates in most tissues including the brain.

    • Glucokinase: Functions in the liver & pancreas, responsive to high glucose levels post-meal, prevents hypoglycemia during fasting.

Energy Yield from Glycolysis

  • Aerobic Glycolysis: Produces 2 ATP via substrate-level phosphorylation and 2 NADH.

  • Anaerobic Glycolysis: Produces 2 ATP and converts pyruvate to lactate, consuming NADH, leading to lactic acid accumulation.

Pyruvate Metabolism

  • Anaerobic Pathway: Converts pyruvate to lactate, generating 2 ATP per glucose but limited by lactic acid buildup.

  • Aerobic Pathway: Pyruvate is converted to Acetyl-CoA, entering the TCA cycle for further energy production (ATP, NADH, FADH2).

Pyruvate Dehydrogenase Complex (PDH)

  • Regulation: PDH activity is controlled by energy states: high ATP levels inhibit while low ATP activates it.

  • Clinical Relevance:

    • Deficiencies: PDH deficiency can lead to congenital lactic acidosis and neurological symptoms.

    • Vitamin Deficiencies: Impair coenzyme function affecting energy metabolism and leading to lethargy and organ dysfunction.

Energetics of the TCA Cycle

  • Produces NADH, FADH2, and GTP from acetyl-CoA.

  • Outputs: 2 carbon atoms enter and leave as CO2, contributing to electron transport and ATP synthesis.

  • Amphibolic Nature: The TCA cycle is involved in both catabolism (energy production) and anabolism (synthesis of macromolecules).

Summary of Post Lecture Tasks

  1. Identify Key Enzymes: Find enzymes involved in energy-generating reactions in the TCA cycle.

  2. Calculate Energy Yield: Assess the ATP yield from TCA cycle reactions considering NADH and FADH2 contributions.