BIOL2771 WK4 P4

Definition and Importance
- Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate substrates.
- It is energetically very expensive but essential for the formation of new glucose when cells lack energy.
Energy Requirements
- For each molecule of glucose formed from pyruvate:
- Six high energy phosphate groups are required.
- Specifically, four ATP and two GTP are utilized in this process.
- Two molecules of NADH are converted to NAD+; this conversion is required for the process of gluconeogenesis, specifically for the conversion of two molecules of 1,3-bisphosphoglycerate in the pathway.
Free Energy Changes
- Free energy change for gluconeogenesis:
- ext{ΔG} = -16 ext{ kJ/mol}
- Free energy change for glycolysis (conversion of glucose to pyruvate):
- ext{ΔG} = -63 ext{ kJ/mol}
- The two processes are not simply reverses of each other; differences in energy changes reflect their distinct physical and chemical processes.
Irreversibility of Gluconeogenesis
- The high energy cost of gluconeogenesis ensures that this process is irreversible.
- The three bypass steps in gluconeogenesis correspond to the irreversible steps in glycolysis.
- If gluconeogenesis did not require this investment of energy, pyruvate produced could be excreted, resulting in a loss of a high-energy substrate that could be converted to ATP through aerobic oxidation.

Conversion Limitations
- Mammalian cells cannot convert fatty acids directly into glucose.
- Unlike mammals, microbes and plants can convert fatty acids into glucose.
Metabolic Byproducts of Fatty Acids
- Fatty acids are primarily metabolized into acetyl coenzyme A (acetyl-CoA).
- There is no direct pathway in mammals to convert acetyl-CoA into pyruvate, which is a substrate for gluconeogenesis.
- Fatty acids can be broken down into glycerol, which is derived from triacylglycerols.
- However, the amount of glycerol available for gluconeogenesis is minimal.
Alternative Pathways in Other Organisms
- Certain organisms, like plants, yeast, and some bacteria, possess the glyoxylate cycle.
- This cycle allows the conversion of acetyl-CoA to oxaloacetate, enabling these organisms to use fatty acids as precursors for gluconeogenesis.
- This pathway is crucial in plants during the germination phase, providing energy and carbohydrates before photosynthesis begins:
- Seedlings rely on stored oils for energy production and for biosynthesis of the cell wall as they develop.

Sources of Glucose in Gluconeogenesis
- Glucose can be synthesized from various precursors including lactate, pyruvate, and oxaloacetate.
- Any compound that is an intermediate in the citric acid cycle (also known as the Krebs cycle) can also be converted to glucose.
Relationship to Glycolysis
- Seven steps of gluconeogenesis are the exact reversal of glycolytic pathway reactions.
- Three specific steps differ and must bypass glycolytic reactions through exergonic reactions:
- First Bypass:
  - Conversion of pyruvate to phosphoenolpyruvate (PEP) via oxaloacetate; requires ATP and GTP.
- Second Bypass:
  - Fructose-1,6-bisphosphate is converted to fructose-6-phosphate by the enzyme fructose bisphosphatase-1, which dephosphorylates the intermediate.
- Third Bypass:
  - Glucose-6-phosphate is converted to glucose by the enzyme glucose-6-phosphatase, removing the phosphate group and releasing glucose.
Tissue Importance
- Major sites of gluconeogenesis in mammals include the liver, kidneys, and small intestine.
- These processes are crucial during times of stress when energy demands are high, especially for the brain, muscles, and erythrocytes.

Energy Cost Problem:
- A question is presented regarding the energy cost in ATP equivalents when transforming glucose to pyruvate via glycolysis and then back to glucose via gluconeogenesis.
- Students are encouraged to analyze both processes to determine how many ATP are consumed and generated in these reactions, leading to a deeper understanding of the energy dynamics involved in metabolic pathways.