Glycolysis and gluconeogenesis

• The pentose phosphate pathway is not a metabolic pathway but assists in producing material for other pathways - e.g. NADPH and pentose sugars

  • NADP and NADPH reduction with enzyme allows the pathway to progress
  • Ribose 5-phosphate product is involved in nucleotides and DNA/RNA as a ribose sugar as well as in coenzymes
• Glycolysis

  • Substrate - glucose
  • Product - Pyruvate (in aerobic conditions) or Lactate (in anaerobic conditions)
  • Where in the cell? - Cytosol
  • What tissue? - Muscle
• Glycolysis overview

  • Catabolic process where bond between C3 and C4 of glucose is split to give 2 pyruvate molecules
  • occurs in the cytosol
  • increases the free energy in the form of ATP - not the main ATP source pathway though
  • provides substrates for the TCA cycle (pyruvate converts to acetyl-CoA
  • provides substrates for biosynthesis of fats and non essential fatty acids
  • In cells with no mitochondria (Red blood cells) it may be the only form of ATP
• Enzymes used in glycolysis

  1. Hexokinase
  2. Phosphoglucose isomerase
  3. Phosphofructokinase 1 (PFK 1)
  4. Aldolase
  5. Triosephosphate isomerase
  6. Glyceraldehyde 3-phosphate dehydrogenase
  7. Phosphoglycerate kinase
  8. Phosphoglyceromutase
  9. Enolase
  10. Pyruvate kinase

  Products

  • 2 ATP
  • 2 Pyruvate
  • 2 NADH
• Glycolysis in steps - first 5

  1. Glucose is phosphorylated (uses ATP giving ADP) - phosphate group is attached to carbon 6 using hexokinase - produces glucose 6-phosphate
  2. Glucose 6-phosphate is rearranged using phosphoglucose isomerase to convert it from an aldose to a ketose (fructose 6-phosphate)
  3. Fructose 6-phosphate is phosphorylated (uses ATP giving ADP) to fructose 1-6-phosphate by phosphofructokinase 1
  4. Fructose 1-6- phosphate is split in half by aldolase to make dihydroxyacetone phosphate and glyceraldehyde-3-phosphate
  5. (4.5) dihydroxyacetone phosphate is converted by triose phosphate isomerase to G-3-P
• Glycolysis in steps - last 5

  1. G-3-P is converted to 1, 3-bisphosphate (uses 2 NAD and 2 inorganic phosphates, makes 2 NADH) by glyceraldehyde-3-phosphate dehydrogenase
  2. 1, 3-bisphosphate is converted to 3-phosphogylcerate (uses ADP and makes ATP) using phosphoglycerate kinase
  3. 3-phosphoglycerate is rearranged into 2-phosphoglycerate by phosphoglycerate mutase
  4. 2-phosphoglycerate is converted to phophoenolpyruvate via a dehydration reaction catalysed by enolase
  5. phophoenolpyruvate is converted to pyruvate by pyruvate kinase (uses ADP and makes ATP and a H+)
• The body sees glucose 6-phosphate as a different molecule to glucose because its charged - creates concentration gradient to allow increased uptake of glucose from the blood into the cell/tissue

  • Glucose (without phosphorylation) moves from a high concentration outside of the cell, into the cell until equilibrium is reached where the concentration of glucose is the same inside as it is outside
  • Glucose (with phosphorylation) moves from a high concentration outside the cell into the cell. Glucose gets phosphorylated to give G6P which is not the same as free glucose (it's charged). SO the cell takes more glucose into the cell as no equilibrium is reached giving more glucose for glycolysis
• Hexokinase allosteric regulation

  Hexokinase is inhibited by G6P

  • A high concentration of glucose 6-phosphate signals that the cell doesn't need more glucose
  • When PFK is inactive, F6P concetration rises so does G6P
  • Inhibition of PFK, inhibits Hexokinase
• PFK - key regulator

  • The first irreversible step exclusive to glycolysis is the phosphofructokinase reaction - F6P to F16P - committed step
  • PFK reaction is only occurring in the glycolytic pathway - means it's the primary control step

  Activators of PFK

  • High AMP(low energy state) - means little ATP
  • F26BP (converts to F6P) activates PFK
  • High insulin - increases glycolysis to lower blood glucose) - stimulates F26BP synthesis

  Inhibitors

  • High ATP - means nothing else needs to be produced via pyruvate
  • High citrate in the TCA cycle - pathway is operating well, no need for more glycolysis
  • High glucagon - inhibits glycolysis so more glucose build up in the blood
• Pyruvate kinase allosteric regulator

  • F16BP activates Pyruvate kinase - product for PFK
  • ATP and alanine inhibit pyruvate kinase in the same way as PFK
  • Glucagon stimulates phosphorylation (slows down enzyme activity) via cAMP cascade - slows the glycolytic pathway in low blood glucose levels

  Activators

  • High F16BP - the previous glycolytic step
  • High insulin - increases glycolysis to lower blood glucose

  Inhibitors

  • High ATP - nothing else needs to be produced via pyruvate
  • High alanine - helps inhibit pyruvate kinase
  • High glucagon - inhibits glycolysis so more glucose build up in the blood