Week 2

Glycolytic Pathway Reactions

• The glycolytic pathway consists of a series of reactions that convert glucose into fructose 1,6-bisphosphate (Frc-1,6-bisP).

  • Key Points:

  • Most living eukaryotic and prokaryotic cells depend on this pathway.

  • Structural changes in glucose and glycolytic intermediates are shown in linear forms for clarity.

Initial Steps in Glycolysis

• The conversion of glucose to Frc-1,6-bisP occurs in three main steps for most cells:

  1. Phosphorylation (Reaction #1)

  2. Isomerization (Reaction #2)

  3. Another Phosphorylation (Reaction #7)

• Certain cell types may utilize an alternate route from glucose to Frc-1,6-bisP via sorbitol and fructose.

• The initial reactions trap glucose inside the cell and form Frc-1,6-bisP, which can readily cleave into glyceraldehyde 3-phosphate (Gl-3-P) and dihydroxyacetone phosphate (DHAP).

Entry of Galactose into Glycolysis

• Galactose Metabolism:

  • Galactose, obtained from dietary sources, is converted to glucose 1-phosphate (Glc-1-P) in the liver via a series of reactions before entering glycolysis as glucose 6-phosphate (Glc-6-P).

  • The liver's ability to metabolize galactose is useful for the galactose tolerance test, assessing hepatic function.

  • Galactose is also synthesized in the body for lactose formation in mammary glands, as well as for glycolipids (e.g., cerebrosides) and glycoproteins.

Conversion Steps

1. Glucose to Glc-6-P

   • This process is part of metabolic pathways for galactose.

Enzymatic Reactions in Glycolysis

• Enzyme: Phosphohexose Isomerase (Reaction #2)

  • Converts Glc-6-P to fructose 6-phosphate (Frc-6-P) in a readily reversible reaction, changing from aldopyranose (glucose) to ketofuranose (fructose).

Regulation of Enzymatic Activity

• The regulation of phosphorylation and metabolism of fructose involves several enzymes:

  • Hexokinase: Converts glucose to Glc-6-P. The same enzyme also facilitates the conversion of fructose to fructose 6-phosphate.

  • Fructokinase (Reaction #4): A liver enzyme that converts fructose to fructose 1-phosphate (Frc-1-P), specific to fructose and does not phosphorylate glucose.

Impact on Diabetic Patients

• Fructose Metabolism in Diabetes:

  • Fructose is quickly metabolized in the liver, hence, fructose administration alone has limited effectiveness in replenishing carbohydrate stores.

  • Fructose and sorbitol accumulation in eye lenses raises concerns about the formation of diabetic cataracts due to osmotic damage.

  • Polyol Pathway: Converts glucose to fructose through sorbitol, increasing in diabetic conditions and influencing cataract formation.

Key Regulatory Enzyme: Phosphofructokinase (PFK)

• PFK catalyzes the conversion of Frc-6-P to Frc-1,6-bisP (Reaction #7) and serves as a critical regulatory step in glycolysis.

  • Cofactors: Mg++ and K+.

  • Inhibitors:

  • ATP

  • Citrate

  • Glucagon (liver)

  • High [H+]

  • Stimulators:

  • ADP

  • AMP

  • Frc-6-P

  • Inorganic phosphate (Pi)

  • Ammonium ion (NH4+)

  • Epinephrine (muscle)

Energy Status Regulation

• PFK activity is finely tuned by the intracellular concentration of ATP and AMP, allowing the cell to properly allocate energy resources.

  • Energy Buffering:

  • Phosphocreatine provides a buffering for ATP in muscles, maintaining energy levels during increased demand.

  • The reaction:
    $ADP + ext{Phosphocreatine} <br>ightleftharpoons ATP + ext{Creatine}$

  • This reaction pathway and modulation of energy levels are vital during exercise, impacting PFK activity accordingly.

Summary of Initial Reactions

• Initial glycolytic reactions capitalize on substrates such as galactose, fructose, glycogen, and glucose.

• The regulation of PFK is central to controlling the rate of glycolysis, influenced by various factors such as ATP/ADP ratios, pH, and the presence of different metabolites and hormones.

Objectives and Questions

Objectives

• Describe the steps in converting glucose to Frc-1,6-bisP, including intermediates and ATP consumption.

• Outline pathways for fructose to Gl-3-P conversion.

• Explain how galactose is incorporated into hepatic EMP and its dietary significance.

• Discuss the role of the Polyol Pathway in diabetes and the implications of galactosemia.

• Identify tissue specificities in aldose reductase and sorbitol dehydrogenase activities.

• Explain the regulation of fructose metabolism by factors such as glucagon and insulin.

Questions

1. Which enzyme converts glucose to sorbitol in nerve cells and the lens of the eye?

   • a. Sorbitol dehydrogenase

   • b. Fructokinase

   • c. Hexokinase

   • d. Phosphofructokinase

   • e. Aldose reductase

2. Which enzyme is notably liver-specific in large animals?

   • a. Hexokinase

   • b. Aldose reductase

   • c. Phosphofructokinase

   • d. Sorbitol dehydrogenase

   • e. Glucosephosphate isomerase

3. Which compound stimulates phosphofructokinase activity in muscle cells?

   • a. ATP

   • b. Citrate

   • c. Ammonium ion

   • d. Glucagon

   • e. Phosphocreatine

4. Which is required in the conversion of glucose to sorbitol?

   • a. Pi

   • b. NADPH

   • c. NAD+

   • d. NADH

   • e. NADP+

5. Which compound cannot convert to glycolytic intermediates in the lens?

   • a. Glucose

   • b. Sorbitol

   • c. Fructose

   • d. Galactitol

   • e. Fructose 1-phosphate

Answers

1. e

2. d

3. c

4. b

5. d