Glucose breakdown and energy production are vital cellular processes. Glycolysis splits glucose into pyruvate, while the Krebs cycle further breaks down pyruvate. These steps generate ATP and electron carriers for the electron transport chain.

The electron transport chain uses electron carriers to create a proton gradient. This gradient powers ATP synthase, producing most of the cell's ATP. Gluconeogenesis reverses this process, making glucose from non-carbohydrate sources when needed.

Glycolysis and the Krebs Cycle

Steps and outcomes of glycolysis

• Glycolysis breaks down glucose into two pyruvate molecules through a 10-step process
  • ATP phosphorylates glucose forming glucose-6-phosphate (catalyzed by hexokinase)
  • ATP phosphorylates fructose-6-phosphate creating fructose-1,6-bisphosphate (catalyzed by phosphofructokinase)
  • Fructose-1,6-bisphosphate splits into glyceraldehyde-3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP), two 3-carbon molecules
  • Oxidation and phosphorylation of G3P yields 1,3-bisphosphoglycerate
  • Conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate generates 2 ATP
  • 3-phosphoglycerate converts to 2-phosphoglycerate
  • 2-phosphoglycerate converts to phosphoenolpyruvate (PEP)
  • PEP converts to pyruvate generating 2 ATP
• Glycolysis yields a net energy outcome of 2 ATP and 2 NADH per glucose molecule (glucose to 2 pyruvate)

Pyruvate in the Krebs cycle

• Pyruvate converts to acetyl-CoA releasing CO2 and generating 1 NADH (catalyzed by pyruvate dehydrogenase complex)
• Acetyl-CoA combines with oxaloacetate forming citrate
• Citrate converts to isocitrate
• Oxidation of isocitrate to α-ketoglutarate releases CO2 and generates 1 NADH
• Oxidation of α-ketoglutarate to succinyl-CoA releases CO2 and generates 1 NADH
• Conversion of succinyl-CoA to succinate generates 1 GTP (or ATP)
• Oxidation of succinate to fumarate generates 1 FADH2
• Fumarate undergoes hydration to malate
• Oxidation of malate to oxaloacetate generates 1 NADH
• Each pyruvate molecule yields 3 NADH, 1 FADH2, 1 GTP (or ATP), and 2 CO2 in the Krebs cycle (citric acid cycle)

Electron Transport Chain and ATP Synthesis

Electron flow in cellular respiration

• The electron transport chain (ETC) consists of protein complexes in the inner mitochondrial membrane
• NADH and FADH2 from glycolysis and the Krebs cycle donate electrons to the ETC
  • Complex I receives electrons from NADH
  • Complex II receives electrons from FADH2
• Electrons undergo redox reactions as they pass through ETC complexes (I, III, and IV)
• Protons (H+) are pumped from the mitochondrial matrix into the intermembrane space during electron flow
• The ETC-generated proton gradient drives ATP synthesis via oxidative phosphorylation
• Oxygen acts as the final electron acceptor combining with protons to form water (cellular respiration)

Mechanism of oxidative phosphorylation

• ATP synthase, an enzyme complex in the inner mitochondrial membrane, synthesizes ATP
• The ETC-generated proton gradient drives protons back into the mitochondrial matrix through ATP synthase
• Proton flow through ATP synthase causes conformational changes that catalyze ADP phosphorylation to ATP
• Chemiosmotic coupling links the proton gradient's chemical energy to ATP synthesis
• The number of ATP molecules generated per NADH and FADH2 depends on the specific ETC complexes involved
  • NADH typically yields 2.5-3 ATP
  • FADH2 typically yields 1.5-2 ATP

Gluconeogenesis

Glucose production via gluconeogenesis

• Gluconeogenesis synthesizes new glucose molecules from non-carbohydrate precursors
• Main gluconeogenic substrates include:
  • Amino acids (from protein catabolism)
  • Glycerol (from triglyceride breakdown)
  • Lactate (from anaerobic glycolysis in skeletal muscle)
• The liver is the primary site of gluconeogenesis with minor contributions from the kidneys
• Key gluconeogenic steps:
  1. Pyruvate carboxylase carboxylates pyruvate to oxaloacetate
  2. PEP carboxykinase decarboxylates and phosphorylates oxaloacetate forming phosphoenolpyruvate (PEP)
  3. Fructose-1,6-bisphosphatase converts fructose-1,6-bisphosphate to fructose-6-phosphate
  4. Glucose-6-phosphatase removes the phosphate from glucose-6-phosphate yielding free glucose
• Hormones like glucagon and cortisol regulate gluconeogenesis promoting the process during fasting or stress (low blood glucose)

Additional Carbohydrate Metabolism Pathways

Glycogen metabolism

• Glycogenesis: synthesis of glycogen from glucose for storage
• Glycogenolysis: breakdown of glycogen to glucose-1-phosphate for energy production

Alternative glucose metabolism

• Pentose phosphate pathway: generates NADPH and ribose-5-phosphate for biosynthetic processes

Metabolic regulation

• Allosteric regulation of key enzymes (e.g., phosphofructokinase) controls flux through metabolic pathways
• Hormonal control (e.g., insulin, glucagon) coordinates carbohydrate metabolism with whole-body energy needs