Glycolysis and Gluconeogenesis Overview

Glycolysis:

• Definition: Glycolysis is the breakdown of glucose to extract energy.

• Key Product: Produces pyruvate, essential for cellular energy production (ATP) and can feed into other metabolic pathways.

• Location: Glycolysis occurs in the cytosol of cells, making it accessible for rapid energy production without the need for organelle involvement.

Gluconeogenesis:

• Definition: Gluconeogenesis is the synthesis of glucose from non-carbohydrate sources, ensuring blood sugar levels can be maintained during fasting or strenuous exercise.

• Location: Primarily takes place in the liver, and to a lesser extent in the kidneys.

• Energy Requirement: This process is energetically costly, requiring 6 ATP equivalents (4 ATP and 2 GTP) for the synthesis of one glucose molecule from pyruvate.

Glycolysis Process:

Comprised of 10 Steps, Divided into 3 Stages:

Stage 1: Preparatory Phase

1. Activation Steps:

   • Step 1: Phosphorylation of Glucose

     • Enzyme: Hexokinase

     • Action: Glucose is phosphorylated to glucose 6-phosphate using ATP. This is an irreversible step that traps glucose within the cell and prepares it for further metabolism.

   • Step 2: Rearrangement

     • Action: Glucose 6-phosphate is converted to fructose 6-phosphate (isomerization), retaining the phosphate group, allowing for the subsequent phosphorylation in the next step.

   • Step 3: Second Phosphorylation

     • Enzyme: Phosphofructokinase-1 (PFK-1)

     • Action: Fructose 6-phosphate is phosphorylated to fructose 1,6-bisphosphate. This is a key regulatory step and also consumes another ATP, creating a more unstable fructose 1,6-bisphosphate molecule due to the presence of two negatively charged phosphate groups.

Stage 2: Cleavage Phase

• Conversion of Fructose 1,6-bisphosphate:

  • Action: The molecule is cleaved into two three-carbon sugars: dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (G3P).

  • Enzymes:

    • Aldolase: Cleaves fructose 1,6-bisphosphate into DHAP and G3P.

    • Triose Phosphate Isomerase: Facilitates the interconversion of DHAP and G3P.

  • Summary: This stage results in two molecules of G3P from one fructose 1,6-bisphosphate.

Stage 3: Energy Yielding Phase

• Production of ATP and NADH:

  1. Step 1: Oxidation of G3P

     • Action: G3P is oxidized in the presence of inorganic phosphate, producing 1,3-bisphosphoglycerate (BPG) and NADH from NAD+. This step is crucial as it captures energy in the form of NADH.

  2. Step 2: ATP Generation

     • Action: BPG is converted to 3-phosphoglycerate (3-PG), generating ATP through substrate-level phosphorylation, which is essential in producing energy without oxygen.

  3. Steps 3-5: Isomerization and Dehydration

     • Action: 3-PG is converted to 2-phosphoglycerate (2-PG), followed by dehydration to produce phosphoenolpyruvate (PEP). This steps rearranges and activates the molecules further for the next conversion.

  4. Final Step: Conversion of PEP to pyruvate generates more ATP, achieving a net yield of 2 ATP and 2 NADH per glucose molecule.

Use of Pyruvate:

• Anaerobic Respiration: In the absence of oxygen, pyruvate can be converted to lactate in muscle cells, regenerating NAD+ necessary for glycolysis to continue and enable ATP production in low-oxygen environments.

• Gluconeogenesis: Pyruvate can be converted back to glucose via the gluconeogenic pathway in liver cells, allowing for glucose maintenance during fasting.

• TCA Cycle: Pyruvate may enter the tricarboxylic acid cycle (TCA) for additional energy extraction, feeding into further oxidation to generate more ATP.

Cori Cycle:

• Lactate to Glucose Process: Lactate produced in muscle during anaerobic conditions is transported to the liver.

  • Action: Lactate is converted back to pyruvate by lactate dehydrogenase, then this pyruvate can ultimately be phosphorylated back to glucose.

  • Energy Cost: Significant ATP consumption is required as it supports gluconeogenesis in the liver.

Gluconeogenesis Specifics:

• Key Enzyme: Pyruvate Carboxylase: Converts pyruvate to oxaloacetate in mitochondria, relies on ATP and CO2.

• Exporting Intermediates: Oxaloacetate must be converted back to phosphoenolpyruvate before progressing to fructose 1,6-bisphosphate, thereby requiring additional ATP.

• Significance: While energetically costly, gluconeogenesis can utilize pyruvate from lipid degradation when glucose levels are low, ensuring a continuous supply of glucose is available for cellular metabolism.

Final Considerations:

• Fate of Synthesized Glucose: Once glucose is synthesized, it can be utilized for various metabolic pathways, such as glycogenesis for energy storage or can be released into the bloodstream to maintain blood sugar levels for other tissues.