Lecture 17: Gluconeogenesis and Other Pathway Interactions

• Date: April 2, 2026
• Reading Material: Biochemistry: Concepts and Connections, Chapter 12, Pages 391-420

Lecture Overview

• Discussion Topics:
  • Glucose-6-phosphate dehydrogenase (G6PDH):
  • A disease linked to the pentose phosphate pathway.
  • Gluconeogenesis Pathway:
  • Focus on three steps that differ from glycolysis:
    • Conversion from 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.
  • Interactions between Glycolysis and Gluconeogenesis.
  • Entry Points of Other Ubiquitous Biological Molecules to Glycolysis.
  • Glycogen Metabolism:
  • How glycogen is synthesized (built up).
  • Pentose Phosphate Pathway:
  • A brief introduction to this pathway.

Glucose-6-Phosphate Dehydrogenase (G6PDH) Deficiency

• G6PDH is an enzyme involved in the pentose phosphate pathway that is typically present but may function at lower efficiency.
• Effects of G6PDH Deficiency:
  • Most individuals carrying this deficiency are asymptomatic.
  • G6PDH is crucial for the production of NADPH, essential for the reduction of glutathione (GSH), a critical antioxidant in red blood cells.

Mechanism of G6PDH Deficiency Damage

• When G6PDH is deficient:
  • NADPH production is impaired.
  • Limited NADPH leads to insufficient regeneration of GSH from its oxidized form, GSSG.
  • Reaction:
  • GSSG + NADPH + H^+
    ightarrow 2GSH + NADP^+
  • Accumulation of peroxide compounds leads to the formation of Heinz bodies, resulting in erythrocyte lysis and hemolytic anemia.

Connection to Malaria

• Prevalence:
  • WHO data indicates a correlation between G6PD deficiency and malaria prevalence in populations.
  • Categories of prevalence (%):
  • <0.5%
  • 0.5-2.9%
  • 3-6.9%
  • 7-9.9%
  • 10-11.9%
  • 15-26%

Overview of Gluconeogenesis

• Definition:
  • Gluconeogenesis is a pathway similar to glycolysis but uses different enzymes for various reactions.
• Key Differences:
  • There are three primary reactions that utilize different, more energetically favorable enzymes:
  • Pyruvate to phosphoenolpyruvate (PEP) involves pyruvate carboxylase and phosphoenolpyruvate carboxykinase.
  • Fructose-1,6-bisphosphate to fructose-6-phosphate involves fructose-1,6-bisphosphatase instead of phosphofructokinase.
  • Glucose-6-phosphate to glucose involves glucose-6-phosphatase instead of hexokinase.
• Energy Investment:
  • Requires 4 ATP, 2 GTP, and converts 2 NADH to 2 NAD+.

Bypass Mechanisms in Gluconeogenesis

• Bypass 1: Conversion of Pyruvate to PEP

  • Pyruvate is converted to oxaloacetate in the mitochondria by pyruvate carboxylase.
  • Oxaloacetate is subsequently converted to malate to cross the mitochondrial membrane, then back to oxaloacetate in the cytosol, where it is converted to PEP by phosphoenolpyruvate carboxykinase.

• Bypasses 2 and 3: Dephosphorylation Steps

  • Bypass 2:
  • Fructose-1,6-bisphosphate is hydrolyzed by fructose-1,6-bisphosphatase to form fructose-6-phosphate (F6P).
  • Bypass 3:
  • Glucose-6-phosphate is hydrolyzed by glucose-6-phosphatase to produce glucose.

Substrates for Gluconeogenesis

• Gluconeogenesis does not always revert directly from pyruvate to glucose; it often utilizes various substrates.
• Primary Substrates:
  1. Lactate:
  • Primarily reconverted via the Cori cycle.
  1. Amino Acids:
  • Most amino acids can be degraded to enter glycolysis or gluconeogenesis, with the exceptions of leucine and lysine.

Cori Cycle: Recovery of Lactate

• Lactate is produced in muscles under anaerobic conditions, when ATP needs are high.
• Lactate moves to the liver, where it is converted back into pyruvate and subsequently to glucose to be released into the bloodstream.

Amino Acids and Glycolysis

• Amino acids are metabolized through glycolysis and the citric acid cycle; most simple amino acids are processed via glycolysis while complex amino acids enter the citric acid cycle.
• Exceptions:
  • Leucine and lysine are not fully metabolized through glycolysis.
  • Portions of these amino acids are converted into ketone bodies.

Reciprocal Regulation of Glycolysis and Gluconeogenesis

• These pathways are reciprocally regulated to maintain homeostasis.
• Control points involve activation or inhibition of enzymes based on the needs of the cell.
• Glycolysis Control:
  1. Hexokinase:
  • Decreased activity with increased G6P levels (substrate-level control).
  1. Phosphofructokinase (PFK):
  • Increased by high AMP or ADP concentrations (allosteric activation).
  • Decreased by high ATP or citrate levels.
  1. Pyruvate Kinase:
  • Increased by fructose-1-bisphosphate.
  • Decreased by acetyl-CoA and ATP.

Pathway Controls in Gluconeogenesis

• Controls operate in reverse of glycolytic activators and inhibitors:
  • Conversion of pyruvate to PEP:
  • Increased by acetyl-CoA and glucagon; decreased by insulin.
  • Conversion of F1-6B to F6P:
  • Inhibited by AMP and fructose-2,6-bisphosphate.
  • Conversion of G6P to glucose:
  • High G6P concentrations promote the conversion back to glucose.

Other Substrates in Glycolytic Pathway

• Monosaccharides:
  • Galactose:
  • Derived from lactose breakdown; metabolized by galactokinase and requires ATP.
  • Fructose:
  • Derived from sucrose; metabolized by fructokinase.
• Glycerol:
  • Derived from fats; metabolized to dihydroxyacetone (DHAP).

Overview of Disaccharide Substrates in Human Metabolism

• Disaccharides mostly derived from glucose:
  • Maltose:
  • Broken down by maltase (two glucose molecules).
  • Lactose:
  • Composed of galactose and glucose; converted to galactose by lactase.
  • Sucrose:
  • Composed of glucose and fructose; fructose enters glycolysis as fructose-6-phosphate or fructose-1-phosphate.

Glycogen Synthesis

• UDP-Glucose Formation:
  • Gaining importance in the synthesis of glycogen, requires specific phosphate substrate for reactions to proceed efficiently.
• Process:
  • UDP-glucose acts as a more reactive form of glucose, allowing for efficient glycogen synthesis.

Glycogen Storage and Signaling

• Signal for Glycogen Use:
  • Hormonal signaling via glucagon or epinephrine binds to cell surface receptors, activating G-protein coupled receptors and increasing cyclic AMP levels.
  • This leads to activation of glycogen phosphorylase enzymes for rapid glucose release when needed.

Overview of the Pentose Phosphate Pathway

• The pentose phosphate pathway is an alternative method for glucose metabolism, less frequent than glycolysis.
• Functions of the Pathway:
  1. Produces NADPH (energy generation).
  2. Produces ribose-5-phosphate for nucleic acid synthesis.
  3. Generates energy via glycolysis when needed.
• Phases:
  1. Oxidative Phase:
     • G6P is oxidized to ribulose-5-phosphate; 2 NADPH produced per glucose-6-phosphate.
     • Loss of carbon through CO₂ byproduct.
  2. Reductive Phase:
     • Converts ribulose-5-phosphate to ribose-5-phosphate and rearranges 5-carbon sugars for further metabolism.

Main Steps of Pentose Phosphate Pathway

• Oxidation Step:
  • Three G6P are oxidized to yield three ribulose-5-phosphate and produce CO₂ as a byproduct.
  • Produces NADPH, crucial for aqueous cellular reactions.
• Reduction Step:
  • Production of ribose-5-phosphate for nucleotide formation.
  • Can rearrange sugars into forms useful for NADPH regeneration.

Nucleotide Formation

• Phases:
  • Oxidative Phase:
  • Produces NADPH from G6P.
  • Non-Oxidative Phase:
  • Forms necessary ribose-5-phosphate and can generate energy for cellular use.

Upcoming Lectures

• Next Classes:
  • Tuesday: Begin Chapter 13 - Citric Acid Cycle.
  • Thursday: Discuss Oxidative Phosphorylation.
• Summary of Lecture: Comprehensive discussion of gluconeogenesis, enzyme roles, and metabolic interactions with glycolysis and alternate pathways.