24.1 Krebs Cycle/Citric Acid Cycle/Tricarboxylic Acid Cycle

Krebs Cycle/Citric Acid Cycle/Tricarboxylic Acid Cycle

• The Krebs cycle, also known as the citric acid cycle or tricarboxylic acid (TCA) cycle, metabolizes pyruvate molecules generated during glycolysis.

• Pyruvate molecules are transported across the mitochondrial membrane into the inner mitochondrial matrix.

• The Krebs cycle produces high-energy molecules: ATP, NADH, and FADH2.

• NADH and FADH2 pass electrons through the electron transport chain in mitochondria to generate additional ATP molecules.

• Each pyruvate is converted into a two-carbon acetyl-CoA molecule during this cycle.

Pyruvate Conversion and Entry into the Krebs Cycle

• The three-carbon pyruvate from glycolysis is converted into two-carbon acetyl-CoA by the enzyme pyruvate dehydrogenase in a reaction known as oxidative decarboxylation.

  • This reaction releases carbon dioxide (CO2) and generates NADH from NAD+.

• Acetyl-CoA then enters the Krebs cycle by combining with oxaloacetate (a four-carbon molecule) to form citrate (a six-carbon molecule), releasing coenzyme A (CoA).

Steps of the Krebs Cycle

• Citrate is systematically converted back to oxaloacetate (starting material for the cycle) via multiple steps:

  • Enzyme aconitase converts citrate into isocitrate.

  • Isocitrate is then oxidized and decarboxylated to form a five-carbon α-ketoglutarate, producing NADH and releasing CO2.

  • α-Ketoglutarate is further converted into four-carbon succinyl-CoA by α-ketoglutarate dehydrogenase, generating another NADH and CO2 in the process.

  • Succinyl-CoA is converted into succinate by succinyl-CoA dehydrogenase, producing GTP, which can phosphorylate ADP to generate ATP.

  • Succinate is converted to fumarate by succinate dehydrogenase, generating FADH2.

  • Fumarate is converted to malate.

  • Finally, malate is converted back to oxaloacetate by malate dehydrogenase, reducing NAD+ to NADH.

• Total yield per cycle:

  • 3 NADH

  • 1 ATP (via GTP)

  • 1 FADH2

Key Implications of the Krebs Cycle

• Each carbon of pyruvate is converted into CO2, which is released as a byproduct of oxidative (aerobic) respiration.

• The cycle also provides starting materials to process and break down proteins and fats.

Oxidative Phosphorylation and the Electron Transport Chain

• The electron transport chain (ETC) utilizes NADH and FADH2 produced by the Krebs cycle to generate ATP.

• The ETC includes four enzyme complexes (Complex I - Complex IV) and two coenzymes (ubiquinone and cytochrome c), acting as electron carriers and proton pumps.

• Electrons are transferred through these complexes, with the final electron acceptor being molecular oxygen (O2), forming water (H2O).

• Proton pumping creates a proton gradient across the inner mitochondrial membrane, essential for ATP production via ATP synthase.

• ATP synthase rotates as H+ ions flow down their concentration gradient, merging ADP and inorganic phosphate (Pi) to form ATP.

ATP Production from Aerobic Respiration

• Two ATP are produced through glycolysis. However, the net production is zero due to the use of two ATP for transporting NADH into mitochondria.

• For every glucose molecule:

  • ATP/NADH/FADH2 counts are doubled because each glucose produces two pyruvate molecules.

  • Approximately three ATP are produced per oxidized NADH and about two ATP per oxidized FADH2, leading to a net production of 36 ATP per glucose molecule.

Gluconeogenesis

• Gluconeogenesis is the synthesis of new glucose molecules from non-carbohydrate sources like pyruvate, lactate, glycerol, or amino acids (e.g., alanine and glutamine).

• Primarily occurring in the liver during fasting, starvation, or low-carbohydrate diets, gluconeogenesis is essential for maintaining blood glucose levels, especially for organs like the brain that require glucose as an energy source.

Pathway of Gluconeogenesis

• The process is not a simple reversal of glycolysis:

  • Pyruvate is first converted to oxaloacetate.

  • Oxaloacetate is transformed into phosphoenolpyruvate (PEP) using the enzyme phosphoenolpyruvate carboxykinase (PEPCK).

  • PEP is then converted back into glycolytic intermediates until glucose is generated:

  • 2-phosphoglycerate to 3-phosphoglycerate

  • 3-phosphoglycerate to 1,3 bisphosphoglycerate

  • 1,3 bisphosphoglycerate to glyceraldehyde-3-phosphate

  • Two molecules of glyceraldehyde-3-phosphate produce fructose-1,6-bisphosphate, which is subsequently converted to fructose-6-phosphate and glucose-6-phosphate, leading to glucose production.

• Key nucleotide enzymatic substitutions in gluconeogenesis include:

  • Glucose-6-phosphatase replaces hexokinase.

  • Fructose-1,6-bisphosphatase replaces phosphofructokinase-1.

Role of Glycerol in Gluconeogenesis

• Glycerol, derived from fats, can be phosphorylated to dihydroxyacetone phosphate (DHAP).

  • DHAP can either enter the glycolytic pathway or be used in gluconeogenesis.

Body's Metabolic Rate

• The human body’s metabolic rate decreases approximately 2% per decade after the age of 30.

• Reduced lean muscle mass largely contributes to this decline, particularly between ages 50 and 70, where muscle loss equates to decreased strength and physical activity.

• A positive-feedback system often ensues, where reduced activity leads to further muscle loss and a decrease in metabolism.

Strategies to Maintain Metabolism

• Suggested methods to counteract metabolic decline include:

  • Eating breakfast and frequent small meals.

  • Consuming adequate lean protein.

  • Staying hydrated with water.

  • Regular exercise, including strength training.

  • Ensuring adequate sleep.

  • Avoiding excess sugar to prevent fat storage. - Consumption of spicy foods and green tea may be beneficial. - Stress avoidance and relaxation techniques help regulate cortisol, which can slow metabolism.