Study Notes from Lecture 17: Gluconeogenesis and Other Pathway Interactions

Lecture 17: Gluconeogenesis and Other Pathway Interactions

Date

  • April 2, 2026

Reading Material

  • Biochemistry: Concepts and Connections, Chapter 12, Pages 391 - 420

Lecture Overview

  • Topics Covered:

    • Glucose-6-phosphate dehydrogenase (G6PDH) and its deficiency as a disease of the pentose phosphate pathway

    • The gluconeogenesis pathway with focus on:

    • Three steps significantly different from glycolysis:

      • Conversion of pyruvate to phosphoenolpyruvate (PEP)

      • Fructose-1,6-bisphosphate (F1-6B) to fructose-6-phosphate (F6P)

      • Glucose-6-phosphate (G6P) to glucose

    • Interactions between glycolysis and gluconeogenesis

    • Entry points of other biological molecules to glycolysis

    • Glycogen metabolism and its synthesis

    • Introduction to the pentose phosphate pathway

Disease of the Day: Glucose-6-Phosphate Dehydrogenase (G6PDH) Deficiency

  • Characteristics:

    • The enzyme G6PDH is not absent, but functions at lower efficiency.

    • Most individuals with this deficiency are asymptomatic.

  • Importance:

    • G6PDH contributes to NADPH production which is crucial for reducing glutathione (GSH), an important antioxidant for red blood cells.

Mechanism of G6PDH Deficiency Damage

  • Lack of G6PDH leads to insufficient NADPH.

  • Implications of insufficient NADPH:

    • GSH cannot be regenerated from GSSG (oxidized glutathione), as NADPH is needed in the reaction:
      GSSG+NADPH+H+<br>ightarrow2GSH+NADP+GSSG + NADPH + H^+ <br>ightarrow 2GSH + NADP^+

  • Excess production of peroxide compounds causes the formation of Heinz bodies in erythrocytes.

  • Heinz bodies can lead to cell lysis and hemolytic anemia.

Connection to Malaria

  • Prevalence Data (WHO):

    • <0.5%

    • 0.5-2.9%

    • 3-6.9%

    • 7-9.9%

    • 10-11.9%

    • 15-26%

  • This data suggests a correlation between G6PD deficiency and malaria prevalence.

Overview of Gluconeogenesis

  • Gluconeogenesis is similar to glycolysis but utilizes different enzymes for some steps:

    • Certain reactions are energetically unfavorable in reverse and thus require distinct enzymes:

    • Notably, phosphates discouraged from reversal involve:

      • Steps 1 and 3 (phosphorylation steps)

    • The conversion from PEP to pyruvate also involves alternative enzymes.

Glycolysis and Gluconeogenesis: Key Differences

  • Significant differences in specific reactions:

    • Reaction 1: Glucose-6-phosphatase replaces hexokinase.

    • Reaction 3: Fructose-1,6-bisphosphatase replaces phosphofructokinase.

    • Reaction 10: Pyruvate carboxylase replaces pyruvate kinase.

  • Overall Energy Investment for Gluconeogenesis:

    • Requires:

    • 4 ATP

    • 2 GTP

    • 2 NADH which gets converted to 2 NAD+.

  • Additional transformations and bypasses will be discussed in the context of enzyme reactions.

Bypass Reactions in Gluconeogenesis

Bypass 1: Pyruvate to Phosphoenolpyruvate (PEP)

  • Pyruvate is converted back into phosphoenolpyruvate.

  • Involves two enzymes:

    1. Pyruvate Carboxylase:

    • Converts pyruvate to oxaloacetate in the mitochondria. Oxaloacetate must then be converted to malate before leaving mitochondria.

    1. Phosphoenolpyruvate Carboxykinase (PEPCK):

    • Converts malate (or oxaloacetate) to PEP.

Bypasses 2 & 3: Dephosphorylation Reactions

  • Removal of phosphate groups to return glucose:

    • Bypass 2: Transforming F1-6B to F6P via hydrolysis by Fructose-1,6-bisphosphatase.

    • Bypass 3: Transforming G6P to glucose via hydrolysis by Glucose-6-phosphatase.

Substrates for Gluconeogenesis

  • Gluconeogenesis does not always originate from pyruvate to glucose:

  • Other substrates contributing to the pathway include:

    1. Lactate - Primary substrate using the Cori cycle.

    2. Amino Acids - Degraded via glycolysis/gluconeogenesis, with all except leucine and lysine being metabolized in this manner.

Cori Cycle: Lactate Recovery

  • Pathway through which lactate is repurposed for energy:

    • Lactate forms under anaerobic conditions in muscles and is later transported to the liver.

    • In the liver, lactate is converted back into pyruvate, then glucose, and returned to the bloodstream.

Amino Acid Metabolism

  • Glycolysis and the citric acid cycle metabolize most amino acids:

    • Simpler ones metabolized through glycolysis; larger ones through the citric acid cycle.

    • Exception: Leucine and lysine progress through ketogenesis.

Reciprocal Regulation of Glycolysis and Gluconeogenesis

  • Both pathways are regulated to maintain homeostasis:

    • Regulation occurs at multiple control points using enzyme activation or inhibition,

    • Glycolysis and gluconeogenesis are reciprocally regulated at key steps.

Regulation in Glycolysis

  • Key regulatory enzymes include:

    1. Hexokinase:

      • Activity decreases with increased G6P concentrations (substrate level control).

    2. Phosphofructokinase:

      • Stimulated by increased AMP or ADP.

      • Inhibited by ATP or citrate, signaling a fully saturated citric acid cycle.

    3. Pyruvate Kinase:

      • Activated by fructose-1-bisphosphate; inhibited by Acetyl-CoA and ATP.

Regulation in Gluconeogenesis

  • Controls operate largely opposite to glycolysis:

    • Conversion of Pyruvate to PEP:

    • Stimulated by acetyl-CoA and glucagon, inhibited by insulin.

    • F1-6B to F6P:

    • Inhibited by AMP and fructose-2,6-bisphosphate.

    • G6P to Glucose:

    • High G6P concentrations stimulate conversion back to glucose.

Alternate Substrates in Glycolysis

  • Glycolysis does not exclusively utilize glucose:

Monosaccharides:

  • Galactose:

    • Derived from lactose; requires enzymes such as galactokinase and ATP.

  • Fructose:

    • Comes from sucrose breakdown; metabolized by fructokinase.

      • Glycerol:

  • Resulting from fat breakdown, converted to dihydroxyacetone phosphate (DHAP).

Disaccharides:

  • Major disaccharides includes:

    • Maltose (two glucose units) - Broken down by maltase.

    • Lactose (galactose + glucose) - Converted directly into galactose via lactase.

    • Sucrose (fructose + glucose) - Enters glycolysis via fructose-6-phosphate or fructose-1-phosphate pathway.

Glycogen Metabolism

Building Glycogen

  • Synthesis occurs through the formation of UDP-glucose (uridine diphosphate glucose).

  • Importance of UDP-glucose:

    • Acts as a substrate that requires priming for the reaction to build glycogen effectively.

Glycogen Storage Signalling

  • Quick release of glucose from glycogen is necessary during high-energy demands:

  • Signaling mechanisms include:

    • Hormonal: Glucagon or epinephrine activate glycogen phosphorylase enzymes through G-protein coupled receptors, resulting in amplified cyclic AMP signaling.

The Pentose Phosphate Pathway (PPP)

  • An alternative glucose breakdown method:

    • Functions in two phases:

    • Oxidative Phase:

      • Converts glucose-6-phosphate to ribulose-5-phosphate, producing 2 NADPH molecules and CO2.

    • Reductive Phase:

      • Converts products into ribose-5-phosphate for nucleic acid synthesis and rearranges sugars for further metabolic pathways.

Main Steps of the Pentose Phosphate Pathway

  1. Oxidation:

    • Three glucose-6-phosphate units oxidized into three ribulose-5-phosphate.

    • CO2 is released as byproduct, facilitating carbon removal from the cycle.

  2. Reduction:

    • Converts ribulose-5-phosphate into ribose-5-phosphate for nucleotides.

    • Can also alter three 5-carbon sugars into usable sugars for energy or citric acid cycle input.

Visual Overview of the Pathway Phases

  • Oxidative Phase: Produces NADPH and CO2 from G6P to ribulose-5-phosphate.

  • Nonoxidative Phase: Further utilizes ribulose-5-phosphate in nucleotide synthesis and other metabolic pathways.

Lecture Summary and Next Classes

  • Upcoming Topics:

    • Chapter 13: Citric Acid Cycle (Tuesday)

    • Oxidative Phosphorylation (Thursday)

  • Closing Remarks: See you next class!