Glycolysis

Summary

Glycolysis is a metabolic pathway that breaks down sugar to produce high energy molecules, like ATP and NADH. All of the reactions in glycolysis occur in the cytoplasm of cells.

The pathway begins with glucose, which is converted by either hexokinase or glucokinase to produce glucose-6-phosphate. This step consumes 1 molecule of ATP, and is an important irreversible and regulatory step that functions to trap glucose inside the cell. Notably, hexokinase is inhibited by its direct product, glucose-6-phosphate, while glucokinase is inhibited by an intermediate further downstream, fructose-6-phosphate.

In the next step, glucose-6-phosphate is converted to form fructose-6-phosphate.

Afterwards, PFK1 catalyzes the conversion of fructose-6-phosphate into fructose-1,6-bisphosphate.  This irreversible reaction consumes another molecule of ATP, and serves as the rate-limiting step of glycolysis. This reaction is therefore highly regulated: it is stimulated by AMP and fructose-2,6-bisphosphate, but is inhibited by ATP and citrate.

Next, aldolase acts on fructose-1,6-bisphosphate, creating one molecule of G3P and one DHAP intermediate. The DHAP is quickly converted into another molecule of G3P. This generates a total of 2 molecules of G3P.

Each molecule of G3P is then converted into 1,3-BPG, forming 1 molecule of NADH in the process. 

This 1,3-BPG is then converted by PG kinase to form 3-PG. This reaction produces 1 molecule of ATP.

The 3-PG is then converted into 2-PG.

Afterwards, enolase converts 2-PG to form PEP, which is an unstable, high-energy intermediate.

Finally, pyruvate kinase irreversibly converts PEP to pyruvate, forming another molecule of ATP in the process. This reaction is stimulated by Fructose-1,6-bisphosphate, and is inhibited by alanine, ATP, and glucagon.

At a higher level, all of the steps can be organized into two distinct phases: an initial investment phase and a later payoff phase. In the investment phase, 2 molecules of ATP are invested to break down each molecule of glucose into 2 molecules of G3P. In the later payoff phase, the 2 molecules of G3P are both turned into pyruvate, producing 4 molecules of ATP and 2 molecules of NADH. This means that glycolysis produces a net yield of two ATP, two NADH, and two pyruvate molecules.

Key Points

• Glycolysis
  • Summary
    • Metabolic pathway breaks down glucose to produce energy
      • Glyco- = glucose = sugar, -lysis = to cut/split
      • Part of anaerobic respiration
      • Produces 2 ATP per glucose molecule and 2 NADH
    • Steps occur in cytoplasm
  • Pathway
    • Glucose → Glucose-6-phosphate (G6P)
      • Via hexokinase/glucokinase (irreversible)
        • Glucose-6-phosphate inhibits hexokinase
        • Fructose-6-phosphate inhibits glucokinase
          • Glucokinase primarily found in liver and pancreas (high Vmax)
        • Consumes 1 ATP, making ADP
          • “Investment phase” of glycolysis
          • Irreversibility commits glucose to be used
    • → Fructose-6-phosphate (F6P)
      • Via phosphoglucoisomerase
    • → Fructose-1,6-bisphosphate
      • Via phosphofructokinase-1/PFK1 (irreversible)
        • Rate-limiting step of glycolysis
          • Everything above moves quickly
          • Main regulatory site of glycolysis via F-2,6-BP
          • First irreversible step in this pathway that is unique to glycolysis (vs. glycogenesis or pentose phosphate pathway)
        • Consumes 1 ATP, making ADP
          • “Investment phase” of glycolysis
      • Stimulated by
        • AMP
        • Fructose-2,6-bisphosphate
      • Inhibited by
        • ATP
          • Despite consuming ATP, the enzyme PFK is also allosterically regulated in having less affinity for F6P with too much ATP
        • Citrate
    • → Glyceraldehyde-3-phosphate (G3P)
      • Via aldolase
        • Aldolase B (in liver), aldolase A (in muscle)
      • 2 molecules of G3P made per glucose molecule
      • Technically 1 molecule of DHAP and 1 molecule of G3P is made, but triosephosphate isomerase converts DHAP into G3P
    • → 1,3-bisphosphoglycerate (1,3-BPG)
      • Via glyceraldehyde-3-phosphate dehydrogenase
      • Produces 1 NADH from NAD+
        • Technically 2 NADH are made per glucose molecule, since each glucose is turned into 2 molecules of G3P
      • May be shunted to form 2,3-bisphosphoglycerate (2,3-BPG), especially in red blood cells without mitochondria
    • → 3-phosphoglycerate (3-PG)
      • Via phosphoglycerate kinase
      • Produces 1 ATP from ADP
        • Technically 2 ATP are made per glucose molecule, since each glucose is turned into 2 molecules of G3P
    • → 2-phosphoglycerate (2-PG)
      • Catalyzed by mutase (isomerization reaction)
      • This isomerization reaction makes the molecule less stable (think higher energy)
    • → Phosphoenolpyruvate (PEP)
      • Catalyzed by enolase
    • → Pyruvate
      • Via pyruvate kinase (irreversible)
        • Inhibited in pyruvate kinase deficiency
      • Produces 1 ATP from ADP
        • But really 2 are made per glucose molecule, since each glucose is turned into 2 molecules of G3P
      • Stimulated by Fructose-1,6-bisphosphate
      • Inhibited by
        • ATP
        • Alanine
        • Glucagon