Gluconeogenesis and Other Pathway Reactions

Lecture Overview

  • Focus on Chapter 12 from "Biochemistry: Concepts and Connections".
  • Topics Discussed:
    • Glucose-6-phosphate dehydrogenase (G6PDH) deficiency.
    • Gluconeogenesis pathway with specific focus on three critical steps:
    • Conversion of pyruvate to phosphoenolpyruvate (PEP).
    • Conversion of fructose-1,6-bisphosphate (F1,6B) to fructose-6-phosphate (F6P).
    • Conversion of glucose-6-phosphate (G6P) to glucose.
    • Interconnections between glycolysis and gluconeogenesis.
    • Entry points of other biomolecules into glycolysis.
    • Glycogen metabolism: synthesis and breakdown.
    • Pentose phosphate pathway overview.

Disease of the Day: G6PDH Deficiency

  • G6PDH enzyme functions at lower efficiency, often asymptomatic in most individuals.
  • Importance of G6PDH:
    • It produces NADPH, essential for reducing glutathione (GSH), a key antioxidant in red blood cells.
Consequences of G6PDH Deficiency
  • Reduced availability of NADPH leads to impaired regeneration of GSH from its oxidized form (GSSG).
  • Chemical Reaction:
    GSSG+NADPH+H+<br/>ightarrow2GSH+NADP+GSSG + NADPH + H^+ <br /> ightarrow 2GSH + NADP^+
  • High levels of peroxide cause formation of "Heinz bodies" in erythrocytes, leading to hemolytic anemia.

Relationship to Malaria

  • Prevalence data showing correlation between G6PD deficiency and malaria protection.

Gluconeogenesis Overview

  • Gluconeogenesis resembles glycolysis but employs different enzymes for several reactions, especially where high energy is needed to reverse (steps require more energy).
  • Key Steps needing different enzymes:
    • Pyruvate to PEP: involves two enzymes.
    • F1,6B to F6P: requires Fructose-1,6-bisphosphatase instead of phosphofructokinase.
    • G6P to glucose: requires glucose-6-phosphatase instead of hexokinase.
  • Overall energy cost of gluconeogenesis:
    • 4 ATP, 2 GTP, 2 NADH.

Bypassing Steps in Gluconeogenesis

  • Bypass 1: Pyruvate to PEP

    • Enzymes involved:
    • Pyruvate carboxylase, converts pyruvate to oxaloacetate.
    • Phosphoenolpyruvate carboxykinase converts oxaloacetate to PEP.

  • Bypass 2 & 3: Removal of Phosphate Groups

    • Bypass involves hydrolytic reactions performed by:
    • Fructose-1,6-bisphosphatase: F1,6B to F6P.
    • Glucose-6-phosphatase: G6P to glucose.

Substrates for Gluconeogenesis

  • Gluconeogenesis does not solely convert pyruvate back to glucose, several substrates are utilized:
    1. Lactate: Primarily from anaerobic metabolism, utilized in the Cori cycle.
    2. Amino Acids: Most can be converted through gluconeogenic pathways, except leucine and lysine.
Cori Cycle
  • Lactate produced anaerobically is shunted to the liver, converted back to pyruvate and then glucose before returning to the bloodstream.
  • Important for energy recovery during intense exercise.

Regulation of Pathways

  • Reciprocal Regulation of Glycolysis and Gluconeogenesis:
    • Enzyme activities are regulated to maintain balance in energy production and utilization.
Glycolysis Control Points
  1. Hexokinase: Inhibited by high levels of G6P.
  2. Phosphofructokinase: Activated by AMP, inhibited by ATP and citrate.
  3. Pyruvate kinase: Activated by F1,6BP, inhibited by Acetyl-CoA and ATP.
Gluconeogenesis Control Points
  • Pyruvate to PEP: Increased by acetyl-CoA and glucagon, decreased by insulin.
  • F1,6B to F6P: Inhibited by AMP and fructose-2,6-bisphosphate.
  • G6P to glucose: Inhibited by high G6P levels.

Substrates Utilized in Glycolysis

  • Monosaccharides:

    • Galactose: From lactose, metabolized by galactokinase.
    • Fructose: From sucrose, metabolized by fructokinase.

  • Glycerol: Derived from fats, converted to dihydroxyacetone (DHAP).

Disaccharides and Polysaccharides
  • Disaccharides:
    • Maltose: Broken down to glucose by maltase.
    • Sucrose: Converted to glucose/fructose.
  • Polysaccharides:
    • Glycogen: Stored glucose, broken down by glycogen phosphorylase and debranching enzymes.

Glycogen Metabolism

  • Breakdown:

    • Glycogen phosphorylase breaks down 1-4 linkages.
    • 1-6 linkages require glucantransferase.

  • Synthesis:

    • UDP-glucose is the activated form needed for adding glucose units to glycogen.
Signaling for Glycogen Storage
  • Hormonal signals (glucagon, epinephrine) activate glycogen phosphorylase to promote glucose release during stress or energy-demanding states.

Pentose Phosphate Pathway Overview

  • Multipurpose pathway for producing:
    • NADPH for biosynthesis.
    • Ribose-5-phosphate for nucleotides.
    • Energy via glycolysis as needed.
Main Phases of the Pathway
  1. Oxidative Phase: G6P oxidized to ribulose-5-phosphate, resulting in NADPH production.
  2. Non-Oxidative Phase: Ribulose-5-phosphate converted to ribose-5-phosphate for nucleotide synthesis, along with recycling sugars for glycolytic pathways.

Summary and Next Classes

  • Next classes will include:
    • Citric acid cycle (Chapter 13).
    • Mitochondrial function and oxidative phosphorylation.