Glycolysis - Investment Phase

Summary

Glycolysis is a metabolic pathway that breaks down sugar molecules to produce high energy molecules, like ATP and NADH. It can be broken into two phases: an investment phase and a payout phase.

In the investment phase, energy is ‘invested’ in the form of ATP. In the first step, hexokinase catalyzes the transfer of a phosphate group from ATP to glucose. This step is an important point of regulation, as it’s an irreversible step that traps glucose in the cell.

Next, glucose-6-phosphate is isomerized to fructose-6-phosphate via phosphoglucoisomerase.

Next, PFK -- or phosphofructokinase -- catalyzes the transfer of another phosphate group from ATP molecule to produce fructose-1,6-bisphosphate. This step is irreversible and is often the most important point of regulation. 

Aldolase next splits fructose-1,6-bisphosphate into G3P and DHAP. G3P and DHAP are isomers that are interconverted by Triosephosphate Isomerase (TPI) because only G3P can proceed to the payout phase of Glycolysis.

Key Points

• Glycolysis Investment Phase
  • Etymology 
    • Glyco- = glucose = sugar
    • -lysis = to cut/split
  • Summary
    • Glycolysis is a metabolic pathway breaks down glucose to produce energy
      • Other carbohydrates are metabolized by the pathway as well
    • Occurs in the cytosol of the cell
      • part of anaerobic respiration
        • Can function with or without the presence of oxygen
      • Ancient pathway
        • highly conserved across different forms of life
        • Present in aerobic and anaerobic organisms
    • two phases
      • Investment phase
        • 2 ATP are ‘invested’ into glucose metabolism 
      • Payoff phase
        • 4 ATP and 2 NADH are produced
      • Net payoff: 2 ATP and 2 NADH (per glucose)
  • reaction steps (investment phase)
    • Glucose → [hexokinase] Glucose-6-phosphate
      • Kinases catalyze the transfer of a phosphate group
        • a phosphate group is transferred from ATP to Glucose
          • Phosphate transferred to #6 carbon in glucose
      • Commits glucose to the pathway
        • Glucose-6-phosphate cannot diffuse out of the cell
      • powered by 1 ATP
      • Irreversible (regulatory site)
    • Glucose-6-phosphate → [Phosphoglucoisomerase] fructose-6-phosphate
      • Isomerases catalyze conversions between isomers
        • Glucose-6-phosphate and fructose-6-phosphate are isomers
    • Fructose-6-phosphate [phosphofructokinase (PFK)] → Fructose-1,6-bisphosphate
      • Kinases catalyze the transfer of a phosphate group
        • a phosphate group is transferred from ATP to fructose-6-phosphate (F6P)
          • Phosphate transferred to #1 carbon in F6P
      • powered by 1 ATP
      • Irreversible rate-limiting step (main regulatory site)
        • PFK reaction is the first irreversible step in this pathway that is unique to glycolysis
          • Glucose-6-phosphate can be converted into glycogen or fed into the pentose phosphate pathway
    • Fructose-1,6-bisphosphate → [Aldolase] dihydroxyacetone phosphate (DHAP) + glyceraldehyde-3-phosphate (G3P)
      • Triosephosphate isomerase (TPI) catalyzes the interconversion between DHAP and G3P
        • Only G3P proceeds to the payoff phase
          • As G3P gets converted to the next intermediate, it decreases in concentration
          • This ‘pulls’ more DHAP to convert to G3P based on Le Chatlier’s principle
          • Eventually all DHAP will either be converted to G3P to enter the payoff phase
        • For every 1 molecule of glucose, 2 molecules of G3P enter payoff phase
  • Regulation
    • Regulation is based on energy need and blood glucose levels
      • Glycolysis speeds up when cells need to produce more energy and slows down when they don’t
      • Glycolysis speeds up when blood glucose levels are high and slows down when they are low
    • Regulatory steps
      • PFK reaction is the primary regulatory step
        • Regulation at other reversible steps as well
    • Glycolysis speeds up (activation)
      • High energy need
        • AMP
      • High blood glucose levels
        • Insulin
          • Insulin activates PFK-2, increasing Fructose-2,6-bisphosphate (F26BP) levels
            • Fructose-6-phosphate → [phosphofructokinase-2 (PFK-2)] Fructose-2,6-bisphosphate
            • F26BP activates PFK
              • Allows liver cells to override ATP inhibition
          • Insulin activates Glucokinase
            • Glucokinase is an alternative catalyst to hexokinase for the first reaction of glycolysis
            • Glucokinase is only found in the liver and in the pancreas.
    • Glycolysis slows down (inhibition)
      • Low energy need
        • ATP
        • Citrate
          • Citrate is a TCA intermediate, so high Citrate levels mean higher levels of energy production
        • Glucose-6-phosphate
          • Feedback inhibition on hexokinase
            • Glucose-6-phosphate builds up when the pathway is regulated at a later step
      • Low blood glucose levels
        • Glucagon
          • Inhibits PFK-2, decreasing Fructose-2,6-bisphosphate (F26BP) levels