Metabolism - lecture 3

Glycogen and Glucose Utilization

  • The human body contains approximately 190 grams of glucose reserves.

  • The glucose concentration in blood fluids is around 20 grams.

  • Muscles utilize glycogen stores, which may lead to misconceptions about glycogen quantity during exercise.

  • During prolonged fasting or intense exercise, glucose levels become depleted, necessitating glucose synthesis from other sources.

Gluconeogenesis Explained

  • Gluconeogenesis: The process of producing new glucose from non-carbohydrate sources.

    • Commonly initiated during high-protein diets or intermittent fasting, facilitating fat usage and potential weight loss.

    • Prolonged periods without sufficient glucose can lead to the breakdown of musculoskeletal protein, impacting muscle mass.

    • The body's priority for glucose allocation: 1st from glucose supply, 2nd from glycogen, 3rd from fat, and finally from protein.

Energy Sources for Gluconeogenesis

  • Initial energy source for the brain is glucose.

  • If glucose and glycogen stores are low, the body will mobilize fat for energy, leading to weight loss.

  • Fat breakdown can eventually lead to muscle protein degradation, producing ammonia as a metabolic waste product.

Substrates for Gluconeogenesis

  • Major substrates include:

    • Pyruvate and Lactate: One-third of precursors for gluconeogenesis come from lactate produced by muscles and red blood cells.

    • Alanine: Derived from protein breakdown in muscles, transported to the liver for conversion back to glucose.

    • Glycerol: Released from adipose tissue when fatty acids are metabolized for energy, also used in gluconeogenesis.

    • Amino Acids: All except leucine and lysine can contribute to glucose production through gluconeogenesis.

    • Propionyl CoA: A byproduct from odd-numbered fatty acid breakdown, can also serve as a substrate for gluconeogenesis.

Mechanism of Gluconeogenesis

  • Gluconeogenesis primarily occurs in the liver with contributions from the kidneys.

  • Key steps involve bypassing three irreversible glycolytic reactions (steps 1, 3, and 10):

  1. Bypassing Reaction 1: Pyruvate is converted to oxaloacetate by pyruvate carboxylase in the mitochondrial matrix.

    • Requires ATP; the resulting oxaloacetate exits the mitochondria after conversion to malate, which can cross the mitochondrial membrane.

  2. Bypassing Reaction 3: Conversion of oxaloacetate to phosphoenolpyruvate (PEP) by phosphoenolpyruvate carboxykinase (PEPCK).

    • This reaction occurs in the cytoplasm and does not involve a direct carboxyl group removal.

  3. Bypassing Reaction 10: Involves multiple steps with different enzymes to facilitate glucose formation from PEP.

Important Enzymes and Steps in Gluconeogenesis

  • Pyruvate Carboxylase: Catalyzes the carboxylation of pyruvate to oxaloacetate, crucial for TCA cycle replenishment.

  • Malate Dehydrogenase: Converts oxaloacetate to malate for transport across the mitochondrial membrane.

  • Phosphoenolpyruvate Carboxykinase (PEPCK): Catalyzes the conversion of oxaloacetate to PEP using GTP, initiating gluconeogenesis in the cytoplasm.

Summary of the Glycogen to Glucose Pathway

  • Gluconeogenesis operates as a reversal of glycolysis but with specific enzymatic changes to bypass irregular reactions.

  • The liver acts as the primary organ for glucose production, ensuring glucose availability for bodily functions during fasting or strenuous activities.

  • This metabolic process is vital for maintaining blood glucose levels and supporting energy demands, particularly for the brain and muscles.