Wk 7&8 Lecture 2: Glycolysis

Introduction to Metabolism

• Metabolism is likened to a marathon, especially relevant for physically active students in sports.

• Understanding the use of glucose to generate ATP is vital for muscle contraction during physical activity.

Case Study: Sun Yee Swift

• Profile:

  • Age: 20 years

  • Weight: 105 pounds

  • Student at the University of Toronto

  • Marathon runner training for Canadian Olympic track team.

  • Training includes extended runs (>15 km), shorter runs (5-10 km), and essential rest days.

• Training Detail:

  • Morning run begins at 6 AM without eating since 8 PM the prior night.

• Muscle activity increases as she warms up, leading to ATP consumption in muscle contraction.

Muscle Contraction Mechanism

• Muscle fibers consist of thick and thin filaments.

• Contraction involves ATP breaking down to ADP and inorganic phosphate via ATPase.

• Creatine Phosphate Function:

  • Resting muscle has 25 millimolar of creatine phosphate.

  • Transfers phosphate to ADP for ATP regeneration in muscle.

Fuel Sources for ATP Production

• Glucose (alpha-D-glucopyranose) enters muscle via GLUT4 transporter in the membrane.

• With fasting since the previous evening, blood glucose is maintained around 3.5 millimolar.

Glycolysis Overview

• Pathway:

  • Glycolysis utilizes glucose to produce ATP, NADH, and pyruvate.

• Stages of Glycolysis:

  1. ATP Investment Phase:

     • Initial investment of 2 ATP to trap glucose in the cell as glucose-6-phosphate (G6P).

     • Enzyme: Hexokinase (first step, requires ATP).

  2. ATP Generation Phase:

     • Breakdown of glucose to produce 2 pyruvate and net gain of 2 ATP.

     • Enzymes involved include GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and PEP (phosphoenolpyruvate) producer (pyruvate kinase).

Key Enzymes in Glycolysis

• Hexokinase:

  • Phosphorylates glucose, trapping it in the cell. Requires magnesium.

• PFK-1 (Phosphofructokinase-1):

  • Second ATP investment site, forms fructose-1,6-bisphosphate from fructose-6-phosphate.

• GAPDH:

  • Forms NADH and one, three-bisphosphoglycerate (1,3-BPG) from glyceraldehyde-3-phosphate.

• Phosphoglycerate Kinase (PGK):

  • Produces ATP via substrate-level phosphorylation.

• Pyruvate Kinase:

  • Converts phosphoenolpyruvate to pyruvate, generating ATP.

Aerobic vs Anaerobic Glycolysis

• Aerobic Glycolysis:

  • Occurs with sufficient oxygen, yielding 2 ATP, 2 NADH, and pyruvate.

  • Pyruvate enters mitochondria for further ATP production.

• Anaerobic Glycolysis:

  • Occurs during limited oxygen; pyruvate converts to lactate via lactate dehydrogenase.

  • Results in 2 lactate, 2 ATP, and significant energy loss.

• Lactic Acidosis:

  • Accumulation of lactate during insufficient oxygen leading to muscle fatigue and pain.

Regulation of Glycolysis

• Key Regulatory Points:

  • Hexokinase: Inhibited by glucose-6-phosphate.

  • PFK-1: Main regulatory enzyme regulated by ATP/AMP ratio and pH levels due to lactate accumulation.

  • Pyruvate Kinase: Inhibited by ATP; regulation also influenced by liver's PKA in response to blood glucose levels.

Importance of Glycolysis

• Provides quick ATP sources where rapid energy is needed, essential for muscle activity during sprints or strenuous exercise.

• Produces intermediates (pyruvate) for mitochondrial metabolism and other biosynthetic pathways:

  • Leading to ATP production in aerobic conditions.

  • Contributing to gluconeogenesis in liver tissues.

Conclusion

• Glycolysis plays a crucial role in energy production for all cells, especially muscle cells during physical activity.

• Understanding these metabolic pathways is vital for optimizing performance, such as in Sun Yee's marathon training.