Biochemistry Week 8: Pyruvate & Hexose Metabolism

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

• Kimchi is a fermented food produced by microorganisms via anaerobic glycolysis. Lactate is a byproduct and acts as a preservative.

Metabolism of Other Hexoses

• Glucose, galactose, and fructose are metabolized differently, but all eventually lead to pyruvate.
• Specific enzymes are involved in processing each sugar; examples include hexokinase, galactokinase, fructokinase, and others.
• Different pathways exist for metabolism within muscle vs. liver cells.

Metabolism of Other Hexoses (More Detail)

• Galactose is converted to G6P through galactokinase then to Glucose-1-P.
• Fructose (muscle) uses hexokinase,
• Fructose (liver) uses fructokinase for breakdown.

Fructose and Obesity

• High-fructose corn syrup consumption has significantly increased in the U.S. in recent years.
• Research suggests a link between high fructose consumption and obesity.
• High-fructose corn syrup is prevalent in many processed foods.
• Fructose is metabolized differently than glucose and is more likely to be stored as fat.
• Bypassing PFK leads to glycerol-3-phosphate (liver) formation, a precursor to triglycerides.

Glycogen Metabolism

• Glycolysis converts glucose into pyruvate, releasing ATP.
• Gluconeogenesis produces glucose from non-carbohydrate sources when glucose levels are low.
• Glycogen is a storage form of glucose.
• Glycogenolysis is the breakdown of glycogen into glucose.
• Glycogenesis is the production of glycogen from glucose.
• Normal blood glucose levels are 80-110 mg/dL.

Gluconeogenesis

• Brain and red blood cells need glucose for fuel.
• Gluconeogenesis occurs primarily in the liver and to a lesser extent in the kidneys during fasting.
• It makes glucose from non-carbohydrate precursors.
• Gluconeogenesis does not simply reverse glycolysis, it requires alternative reactions.

Gluconeogenesis (Location)

• Enzymes for glycolysis and gluconeogenesis are located in the cytosol.

Gluconeogenesis (Problem)

• Some reactions of glycolysis are irreversible.
• Gluconeogenesis needs different reactions to bypass these irreversible steps.

Gluconeogenesis (Enzymes)

• Key enzymes important in gluconeogenesis include pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose bisphosphatase, and glucose-6-phosphatase. These enzymes catalyze reactions to circumvent the irreversible steps.

Glucose-6-Phosphatase and Fructose Bisphosphatase

• These are crucial enzymes in gluconeogenesis. Removal of phosphate groups is needed.
• They use hydrolysis to bypass irreversible steps in glycolysis.

Pyruvate to Phosphoenolpyruvate

• Pyruvate is converted to phosphoenolpyruvate through pyruvate carboxylase and phosphoenolpyruvate carboxykinase, a process requiring energy.
• Pyruvate can be made from lactate (homolactic fermentation) and breakdown of amino acids.

Glycolysis vs. Gluconeogenesis

• Glycolysis and gluconeogenesis are opposing processes.
• Simultaneous operation would be wasteful. Regulation is required to ensure pathways operate in a complementary fashion, rather than futile cycles.
• Glycolysis "ON" during sufficient glucose levels, gluconeogenesis would be "OFF." The Opposite is also true.

PDC (Pyruvate Dehydrogenase Complex) Control

• PDC activity is regulated in different ways. Product inhibition is one mechanism.
• Covalent modification, specifically phosphorylation, is another key regulatory step to control E1.

PDC Cofactors/Prosthetic Groups

• Several cofactors, such as thiamine pyrophosphate (TPP), lipoic acid, coenzyme A (CoA), FAD, and NAD+, are necessary for the PDC to function.

PDC Reactions

• The PDC catalyzes a series of reactions that convert pyruvate to acetyl-CoA, a preparatory step for the citric acid cycle; this produces CO2.

Lipoamide and Acetyl-CoA

• Lipoamide is a crucial cofactor in the PDC and it carries the acetyl group to Coenzyme A in the reaction

PDC Control (Summary)

• Levels of reaction products (like acetyl-CoA) and changes in the activity of individual enzymes within the complex control PDC activity.
• In the other hand, phosphorylation, and dephosphorylation of the E1 enzyme acts as a major switch to regulate the PDC.

Activity W8L1 & W8L2 Questions

• Metformin reduces phosphoenolpyruvate carboxykinase expression and thus likely decreases blood sugar levels.
• An increase in acetyl-CoA levels would increase PDC activity. An increase in calcium levels would lead to increased PDC activity.

Activity W8L3 Question

• Decreased activity of pyruvate carboxylase is least likely to decrease levels of cytosolic acetyl-CoA, because pyruvate carboxylase is required to make oxaloacetate from Pyruvate, which is required later during gluconeogenesis.