Krebs

Overview of ATP Hydrolysis and Glycolysis

  • Polling Question on ATP:

    • Importance of ATP hydrolysis for energy.

    • Hydrolysis of terminal phosphate groups in ATP is more exergonic than AMP.

    • ATP is a key energy molecule, central to metabolic processes.

  • Energetic Comparison of Phosphorylated Compounds:

    • ATP is in the middle of a table comparing phosphorylated compounds. Compounds above ATP can phosphorylate it, while those below can be phosphorylated by ATP hydrolysis.

    • Focus on two high-energy intermediates in glycolysis for ATP synthesis, rather than memorizing standard free energy changes.

  • Key Terms Defined:

    • Substrate Level Phosphorylation: Engaged in ATP generation through direct enzymatic transfer of phosphate from a substrate:

    • Enzymatically transfers phosphate to ADP.

    • Fermentation: Involves glycolysis and additional steps for NAD regeneration, essential for glycolysis to continue.

Key Reactions in Glycolysis and Gluconeogenesis

  • Definitions:

    • Glycolysis: Breakdown of glucose to pyruvate.

    • Gluconeogenesis: Synthesis of glucose from pyruvate.

  • ATP/GTP Reactions:

    • Glycolysis: Requires ATP in reactions 1 & 3.

    • Gluconeogenesis: Requires ATP/GTP in 3 reactions.

    • ATP/GTP are considered energetically equivalent.

    • ATP is produced in two reactions during glycolysis.

  • NAD+ and NADH:

    • NADH is produced in glycolysis during the 6th reaction catalyzed by glyceraldehyde 3-phosphate dehydrogenase (GAPDH).

    • In gluconeogenesis, NADH is needed to reverse this step.

  • Irreversible Reactions:

    • Glycolysis: Reactions 1, 3, and 10 are irreversible.

    • Bypassing these reactions in gluconeogenesis requires different enzymes (examples given).

  • Enzyme Regulation:

    • Key regulated enzymes:

    • Glycolysis: Hexokinase (inhibited by glucose 6-phosphate), phosphofructokinase-1 (PFK-1), and pyruvate kinase.

    • Gluconeogenesis: Pyruvate carboxylase and fructose 1,6-bisphosphatase.

Regulation of Glycolysis vs Gluconeogenesis

  • Fructose 2,6-bisphosphate:

    • Main regulator; increases phosphofructokinase activity (promotes glycolysis) and inhibits fructose 1,6-bisphosphatase (inhibits gluconeogenesis).

  • Hormonal Control:

    • Glucagon and epinephrine activate signaling pathways to lower fructose 2,6-bisphosphate and promote gluconeogenesis.

  • Enzyme Activity States:

    • Phosphofructokinase-2 (PFK-2): Dual-function; becomes phosphorylated under low fructose 2,6-bisphosphate levels, favoring gluconeogenesis.

Aerobic vs Anaerobic Metabolism

  • Glycolysis Requires:

    • Does not require oxygen; happens in cytoplasm.

    • Can occur in aerobic (oxygen-present) or anaerobic (oxygen-absent) conditions.

  • Role of ATP Production:

    • Glycolysis results in a net profit of 2 ATP.

    • Total inputs for gluconeogenesis can equate to 6 ATP equivalent used.

Pyruvate Processing and Citric Acid Cycle

  • Pathway Summary:

    • Pyruvate enters down the mitochondria via the mitochondrial pyruvate carrier, relying on proton gradients for transport.

    • Converted into acetyl coenzyme A in the mitochondrial matrix.

  • Citric Acid Cycle Overview:

    • Acetyl CoA enters the cycle, producing NADH and FADH2, reducing potential energy while releasing CO2.

    • Regeneration of oxaloacetate is crucial as it restarts the cycle.

    • Enzymatic Steps:

    • 1. Citrate Synthase: Joins acetyl CoA with oxaloacetate to form citrate.

    • 2. Aconitase: Converts citrate to isocitrate.

    • 3. Isocitrate Dehydrogenase: Converts isocitrate into alpha-ketoglutarate, reducing NAD+ to NADH while decarboxylating.

    • 4. Alpha-Ketoglutarate Dehydrogenase: Converts alpha-ketoglutarate to succinyl CoA, also generating NADH and CO2.

    • 5. Succinyl CoA Synthetase: Converts succinyl CoA to succinate, yielding GTP or ATP.

Important Notes and Conclusions

  • Memorization Required:

    • Students are advised to study further on subsequent reactions and enzymes involved in the citric acid cycle, ensuring clarity on metabolic pathways.

  • Integration of Knowledge:

    • Understanding the implications of ATP production and the importance of regulated enzymatic reactions will dictate energy balance in cells like hepatocytes and muscle cells.

  • Active Study Recommended:

    • Review additional materials related to these pathways, specifically contrasting glycolysis and gluconeogenesis to solidify these critical metabolic processes.