2024-25 FFP1 Glycolysis TCA (1)

Importance of Glucose Metabolism

  • Glycolysis pathway:

    • Glycolysis converts glucose to pyruvate, precursor for Acetyl-CoA. Takes place in the cytosol

  • Diabetes:

    • Common disorder linked to dysregulation of glucose metabolism.

Metabolic Pathway 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 Reactions:

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

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

Regulation of Metabolic Pathways

  • Rate-Limiting Step: Controls pathway flow.

  • Feedback Regulation: NADH inhibits, NAD⁺ stimulates enzyme activity.

  • Hormonal Control: Insulin increases glucose uptake via GLUT4.

  • Enzyme Modification: Phosphorylation/dephosphorylation alters enzyme activity.

  • Intermediate Availability: Affects pathway rates (e.g., oxaloacetate in TCA cycle).

  • Oxygen Dependence: Oxygen is the final electron acceptor; hypoxia or anoxia disrupts oxidative phosphorylation.

Glucose Entry into Cells

  • Transport Mechanisms:

    • Facilitated diffusion through GLUT proteins (14 isoforms).

    • Sodium-dependent co-transport by SGLT proteins.

    • Once inside, glucose is phosphorylated to glucose-6-P by Hexokinase or Glucokinase (liver and pancreas)

Glycolysis and Energy Yield

  • Aerobic Glycolysis:

    • Total of 8 ATP produced from one glucose molecule through glycolysis and following reactions.

  • Anaerobic Glycolysis:

    • During oxygen deficit: glucose converts to lactate yielding only 2 ATP.

    • Accumulation of lactic acid can lead to lactic acidosis.

  • Feedback & Allosteric Inhibition:

    • PFK1 is inhibited by high levels of ATP, signaling sufficient energy.

    • Glucokinase is inhibited by PFK1’s substrate, Fructose-6-Phosphate (F6P).

  • Hormonal Regulation:

    • PFK1 is activated by Fructose-2,6-bisphosphate (F-2,6BP), produced by PFK2 from Fructose-6-Phosphate.

    • Insulin and glucagon regulate PFK2 activity, thus controlling F-2,6BP levels.

  • F-2,6BP Regulation:

    • F-2,6BP increases after a high-carbohydrate meal due to insulin, signaling high glucose levels.

    • This activates PFK1, speeding up glycolysis.

    • F-2,6BP also inhibits gluconeogenesis, preventing unnecessary glucose production, helping regulate blood glucose levels.

Metabolic Fates of Pyruvate

  • Pyruvate can enter multiple pathways based on energy needs and nutrient status:

    • Converted to acetyl CoA for TCA cycle or fatty acid synthesis based on excess caloric intake.

Pyruvate Dehydrogenase Complex (PDH)

  • Function and Regulation:

    • Key component in converting pyruvate to acetyl CoA (takes place in mitochondria).

    • Activity is strictly regulated via phosphorylation and substrate availability. (High ATP inhibits, low ATP activates)

  • Clinical Context:

    • Impaired Pyruvate Dehydrogenase (PDH) activity leads to lactic acidosis and energy deficit.

    • Genetic defects of PDH , arsenic poisoning, and vitamin deficiencies can adversely affect PDH function.

TCA Cycle Energetics

  • Energy Production:

    • Each cycle yields NADH, FADH2, GTP which enter the electron transport chain.

    • 2 carbon atoms enter and leave as 2 x CO2

    • Provides intermediates for biosynthesis (e.g., glucose, fatty acids).

    • The TCA cycle is both catabolic and anabolic (amphibolic).

Post-Lecture Learning Tasks

  1. Identify enzymes catalyzing energy reactions in TCA cycle.

  2. Calculate TCA cycle energy yield per glucose, equating GTP to ATP.