Week 8 - Pyruvate Fate and Gluconeogenesis

Week 8 - Synchronous Lecture: The Fate of Pyruvate and Gluconeogenesis

• Kimchi is a fermented food made by microorganisms through anaerobic glycolysis
• Lactate is a byproduct of this process and acts as a preservative

Metabolism of other Hexoses

• Glucose, galactose, and fructose are metabolized differently
• Fructose metabolism varies in the liver and muscles.

Metabolism of other Hexoses (detail from next page)

• Galactose is converted to glucose-6-phosphate through the "Leloir pathway"
• Fructose is converted to fructose-1-phosphate
• Both pathways lead to the production of pyruvate.

Fructose and Obesity

• Consumption of high-fructose corn syrup has risen significantly in the US.
• Studies link high-fructose corn syrup consumption to obesity and abnormal increases in body fat and triglycerides.
• Fructose is metabolized into fat within the body, unlike glucose which is processed for energy or stored as glycogen.

Glycogen Metabolism

• Glucose is initially transformed into glucose-6-phosphate.
• This glucose-6-phosphate is metabolized through glycolysis and gluconeogenesis.
• Glycogenolysis involves the breakdown of glycogen into glucose, while glycogen synthesis involves building glycogen from glucose.
• Blood glucose levels typically range from 80-110 mg/dL.

Gluconeogenesis

• Brain and red blood cells depend solely on glucose for fuel.
• Gluconeogenesis occurs primarily in the liver and partially in the kidneys.
• Gluconeogenesis uses non-carbohydrate precursors to generate glucose when necessary.
• The pathways of glycolysis and gluconeogenesis do not simply reverse each other, different reactions are required.

Gluconeogenesis (location)

• Enzymes for glycolysis and gluconeogenesis are both present in the cytosol, requiring similar cellular location.

Gluconeogenesis (problem)

• Some reactions in glycolysis are irreversible.
• Gluconeogenesis involves different reactions to overcome these irreversible steps.

Gluconeogenesis (new enzymes)

• Four new enzymes help bypass these irreversible reactions during gluconeogenesis.
• These new enzymes include pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose bisphosphatase, and glucose-6-phosphatase.

Glucose-6-phosphatase and Fructose bisphosphatase

• These enzymes are vital for gluconeogenesis as they bypass the irreversible reactions in glycolysis.
• They remove phosphate groups through hydrolysis.

Conversion of pyruvate to phosphoenolpyruvate

• Pyruvate can be produced from lactate through homolactic fermentation.
• Amino acid breakdown produces oxaloacetate which plays a key role in converting pyruvate to phosphoenolpyruvate.
• This conversion requires an expenditure of 2 ATP.

Glycolysis and Gluconeogenesis (net reaction)

• Glycolysis generates ATP from glucose.
• Gluconeogenesis consumes ATP to create glucose from other sources.
• Net ATP consumption occurs if glycolysis and gluconeogenesis occur simultaneously.

Glycolysis Regulation (Fructose-2,6-bisphosphate)

• Fructose-2,6-bisphosphate regulates glycolysis.
• It activates phosphofructokinase and inhibits fructose bisphosphatase.
• This control system ensures a reciprocal relationship between glycolysis and gluconeogenesis.

PDC Control (product inhibition)

• Products of the pyruvate dehydrogenase complex (PDC) can regulate its activity.

PDC Control (phosphorylation)

• The E1 enzyme of the PDC is regulated by phosphorylation.
• Phosphorylation inactivates the enzyme, while dephosphorylation reactivates it.

Activity W8L-1 (Question 1)

• Metformin decreases phosphoenolpyruvate carboxykinase activity, which in turn likely leads to a decrease in blood sugar levels.

Activity W8L-2 (Question 1)

• Increased acetyl-CoA levels activate the PDC.

Activity W8L-3 (Question 1)

• Pyruvate dehydrogenase is least likely to decrease levels of cytosolic acetyl-CoA.

Explore the complex processes of pyruvate metabolism and gluconeogenesis in this Week 8 synchronous lecture. Learn about the distinct metabolic pathways for hexoses like glucose, galactose, and fructose, including their implications for health and obesity. Delve into how diet influences these metabolic processes and affects overall health.