Metabolism I: Glycolysis

Roles of glucose

ATP production

• Oxidation through aerobic glycolysis yields pyruvate - efficient

• Fermentation by anaerobic glycolysis yields lactate - rapid, inefficient

Provision of building blocks for synthetic reactions

• Oxidation through pentose phosphate pathway → ribose-5-phosphate
• Precursor for nucleotide synthesis and DNA repair → growth

Glucose transport into cells

• Via Na+/glucose symporters

• Via passive facilitated diffusion glucose transporters – GLUTs (1-5)
• Different tissues have different GLUTs – different KM, regulated differently

Glycolysis

• The initial pathway for the conversion of glucose to pyruvate

• Per glucose there is a net gain of 2 ATP

1. Phosphorylation of glucose to give fructose-1,6-bisphospate – requires phosphofructokinase

2. Two interconvertible three-carbon molecules are formed

3. Generation of ATP through the oxidation of the 3C molecules

Control points

• Key enzyme that controls the rate of substrate movement in glycolysis (rate-limiting)

• Activated by AMP – increases glycolysis when energy is needed

• Inhibited by ATP – decreases glycolysis when energy is abundant

• Matches the rate of reaction to the rate of NADH regeneration

• Controls conversion of phosphoenolpyruvate to pyruvate (product exit)

• Decreases glycolysis if too much lactic acid is produced

• Lactic acid produced if there is a lack of oxygen – anaerobic metabolism

Anaerobic metabolism

1. In the absence of oxygen, pyruvate can act as a hydrogen acceptor, taking hydrogen ions from NADH

2. Pyruvate is converted into lactate and NAD is regenerated

The Warburg Effect

• Cancer cells produce energy by high rate of glucose metabolism to lactate - anaerobic glycolysis

• Cancer cells have low Km hexokinase
• Supports rapid cell growth - energy production, pathways for nucleotide synthesis
• Produces H+ and lactate as end products
• Inefficient ATP synthesis with high glucose demand

• Cancer can be treated by targeting glycolysis - patients given enzymes which act around control points