Chapter 8 (week 6) - Metabolism and Glycolysis Overview

Overview

This lecture reviews Chapter 8 of Lipincott's Biochemistry, providing an introduction to metabolism with a focus on glycolysis and its regulation.

Metabolism & Metabolic Pathways

• Metabolic pathways are sequences of chemical reactions converting substrates to products: catabolic (breakdown) and anabolic (synthesis).
• Catabolic pathways degrade large molecules into smaller ones, releasing energy stored as ATP; these are convergent processes.
• Anabolic pathways synthesize larger molecules from smaller precursors and require ATP; these are divergent processes.
• Metabolism is the sum of all chemical reactions occurring within a cell, tissue, or organism.

Regulation of Metabolism

• Metabolic regulation occurs through intracellular signals (substrate/product levels, enzyme activity) and intercellular signals (hormones, neurotransmitters).
• Hormonal signals often act via G protein-coupled receptors, activating secondary messengers (e.g., cAMP via adenylate cyclase).
• cAMP activates protein kinases, which phosphorylate proteins to regulate metabolism.

Glucose Uptake

• Glucose enters cells via GLUT transporters (facilitated diffusion) or SGLT (sodium-dependent active transport).
• GLUT1, 3, and 4 handle most glucose uptake; GLUT2 is found in liver and kidney, GLUT5 transports fructose.

Glycolysis: Steps and Regulation

• Glycolysis converts glucose to pyruvate, yielding a net of 2 ATP and 2 NADH per glucose molecule.
• Two phases: energy investment (uses 2 ATP) and energy payoff (produces 4 ATP and 2 NADH).
• Three irreversible steps:
  1. Glucose → Glucose-6-phosphate (hexokinase/glucokinase).
  2. Fructose-6-phosphate → Fructose-1,6-bisphosphate (phosphofructokinase-1, PFK-1, a key regulatory step).
  3. Phosphoenolpyruvate → Pyruvate (pyruvate kinase).
• PFK-1 is inhibited by ATP and citrate (high energy), activated by AMP/ADP and fructose-2,6-bisphosphate.
• Fructose-2,6-bisphosphate is regulated by PFK-2, which responds to insulin (activates glycolysis) and glucagon (activates gluconeogenesis).

Fate of Pyruvate

• With oxygen: Pyruvate enters mitochondria, is converted to acetyl-CoA, and enters the TCA cycle.
• Without oxygen: Pyruvate is converted to lactate, regenerating NAD+ for glycolysis (important in RBCs and hypoxic tissues).
• Excess lactate leads to lactic acidosis in severe hypoxia or intense exercise.

Glycolytic Disorders & Alternative Pyruvate Fates

• Pyruvate kinase deficiency impairs ATP production in RBCs, causing membrane damage and hemolytic anemia.
• Pyruvate can also be converted to oxaloacetate (for TCA cycle or gluconeogenesis) or ethanol (in yeast).

Key Terms & Definitions

• Catabolic Pathway — breaks down molecules, releasing energy.
• Anabolic Pathway — builds larger molecules, consuming energy.
• Glycolysis — pathway converting glucose to pyruvate with net ATP/NADH gain.
• PFK-1 (Phosphofructokinase-1) — main regulatory enzyme of glycolysis.
• Adenylate Cyclase — enzyme producing cAMP, a second messenger.
• GLUT Transporters — proteins facilitating glucose entry into cells.
• SGLT — sodium-dependent glucose transporter.
• Pyruvate kinase — enzyme catalyzing final irreversible step in glycolysis.

Action Items / Next Steps

• Review and memorize glycolysis steps, especially irreversible and regulatory reactions.
• Study the metabolic map and focus on the key pathways discussed.
• Complete chapter summary questions for self-assessment.