Cellular Respiration: Glycolysis, Krebs Cycle, and More

Posted on Jan 6, 2025 in Biochemistry

Glycolysis

Glycolysis (ATP Expenditure)

  1. Phosphorylation: Glucose + ATP – (Hexokinase) -> ADP + Glucose-6-Phosphate
  2. Glucose-6-Phosphate <- (Phosphohexose Isomerase) -> Fructose-6-Phosphate
  3. Phosphorylation: Fructose-6-Phosphate + ATP – (Phosphofructokinase-1) -> Fructose-1,6-Bisphosphate + ADP
  4. Fructose-1,6-Bisphosphate <- (Aldolase) -> Glyceraldehyde-3-Phosphate + Dihydroxyacetone Phosphate
  5. Dihydroxyacetone Phosphate <- (Triose Phosphate Isomerase) -> Glyceraldehyde-3-Phosphate

Energy Yield

  1. Glyceraldehyde-3-Phosphate + NAD+ + Pi – (Glyceraldehyde-3-Phosphate Dehydrogenase) -> 1,3-Bisphosphoglycerate + NADH + H+
  2. Dephosphorylation: 1,3-Bisphosphoglycerate + ADP <- (Phosphoglycerate Kinase) -> 3-Phosphoglycerate + ATP
  3. Isomerization: 3-Phosphoglycerate <- (Phosphoglycerate Mutase) -> 2-Phosphoglycerate
  4. 2-Phosphoglycerate <- (Enolase) -> Phosphoenolpyruvate + H2O
  5. Dephosphorylation: Phosphoenolpyruvate + ADP – (Pyruvate Kinase) -> Pyruvate + ATP

Net Yield:

  • 2 NADH
  • 2 ATP (which can yield 3 ATP each through the electron transport chain)

Pyruvate undergoes oxidative decarboxylation, losing CO2 and electrons that reduce NAD+ to NADH + H+. It then combines with Coenzyme A (CoA-SH) to form Acetyl-CoA, catalyzed by the Pyruvate Dehydrogenase complex. Acetyl-CoA then enters the Krebs cycle.

Glycolysis Regulation

  • Steps 1, 3, and 10 are highly regulated.
  • Hexokinase is inhibited by Glucose-6-Phosphate in muscle.
  • Phosphofructokinase-1 (PFK1) is inhibited by high concentrations of ATP and citrate. It is activated by high concentrations of AMP and ADP, as well as Fructose-2,6-Bisphosphate.
  • Pyruvate Kinase is inhibited by ATP and Acetyl-CoA.

Gluconeogenesis

Gluconeogenesis maintains blood glucose levels by converting non-carbohydrate molecules (lactate, amino acids, alanine, propionate, glycerol) into glucose. It primarily occurs in the liver (90%) and kidneys (10%).

2 Pyruvate + 2 NADH + 4 ATP + 2 GTP + 6 H2O -> Glucose + 2 NAD+ + 4 ADP + 2 GDP + 6 Pi

Glycogenolysis

Glycogenolysis is the breakdown of glycogen (a polymer of 12-18 glucose units) to obtain glucose. Glycogen Phosphorylase removes glucose units until 4 remain on a branch. Glucan Transferase then moves 3 glucose units to the main branch. Finally, the debranching enzyme removes the remaining glucose unit.

Glycogenolysis Regulation

  • Glycogen Synthase exists in two forms: Synthase I (active, dephosphorylated) and Synthase D (less active, phosphorylated).
  • Glycogen Phosphorylase also exists in two forms: Phosphorylase a (active, phosphorylated) and Phosphorylase b (less active, dephosphorylated).
  • Epinephrine and glucagon activate Glycogen Phosphorylase and inhibit Glycogen Synthase.
  • Insulin inhibits Glycogen Phosphorylase and activates Glycogen Synthase.

Krebs Cycle (Citric Acid Cycle)

  • The process begins with the oxidation of pyruvate, producing Acetyl-CoA and CO2.
  • Acetyl-CoA reacts with a molecule of Oxaloacetate (4 carbons) to form Citrate (6 carbons) through a condensation reaction.
  • Through a series of reactions, Citrate is converted back into Oxaloacetate. One cycle consumes 1 Acetyl-CoA and produces 2 CO2. It also consumes 3 NAD+ and 1 FAD, producing 3 NADH, 3 H+, and 1 FADH2.
  • The net yield per molecule of pyruvate is: 1 GTP, 3 NADH, 1 FADH2, 2 CO2.
  • Each glucose molecule produces two pyruvate molecules, which in turn produce two Acetyl-CoA molecules. Therefore, for each glucose molecule, the Krebs cycle yields: 2 GTP, 6 NADH, 2 FADH2, 4 CO2.

Krebs Cycle Regulation

Citrate Synthase, Isocitrate Dehydrogenase, and alpha-Ketoglutarate Dehydrogenase are inhibited by high concentrations of ATP.

Converging Pathways

Carbohydrates

In the second stage of catabolism, glycolysis produces 2 Pyruvate molecules, which enter the mitochondrial matrix and are converted to Acetyl-CoA, subsequently entering the Krebs cycle.

Proteins

Peptide bonds are degraded in the digestive tract by proteases. Amino acids enter cells for protein synthesis or energy production via the Krebs cycle. To enter the cycle, amino groups are removed by aminotransferases and deaminases.

Lipids

Hydrolysis of triglycerides yields glycerol and fatty acids. Glycerol can be converted into glucose via Dihydroxyacetone Phosphate and Glyceraldehyde-3-Phosphate through gluconeogenesis. Fatty acids are degraded in the mitochondrial matrix through successive rounds of beta-oxidation, releasing Acetyl-CoA, which can enter the Krebs cycle. Sometimes, the Krebs cycle can yield Propionyl-CoA (3 carbons), which can be used for glucose synthesis in hepatic gluconeogenesis.

Final ATP Yield:

  • 32 ATP with malate-aspartate shuttle
  • 30 ATP with glycerol-3-phosphate shuttle