reciprocal control of metabolic pathway

• Metabolism


  Comprises hundreds of metabolites and thousands of reactions
• Regulation Needs


  • Pathways must occur at the right time
  • Overlapping activities require both independence and interdependence
• Reciprocal Regulation


  Corresponding pathways that perform opposing functions (e.g., glycolysis vs. gluconeogenesis) must be tightly regulated to prevent futile cycles
• Elements Regulating Enzyme Activity

  • Regulation of Enzyme Quantity (gene expression)
  • Regulators of Enzyme Activity (allosteric regulation and covalent modifications)
• Glycolysis


  1. Breakdown of glucose to pyruvate, generating ATP

  2. Occurs in the cytoplasm

  3. Key Enzymes: Hexokinase, Phosphofructokinase-1 (PFK-1), Pyruvate Kinase

  4. Activated by: AMP, ADP, fructose-2,6-bisphosphate (F2,6BP)

  5. Inhibited by: ATP, citrate

  6. Allosteric Modulation: PFK-1 is activated by AMP and inhibited by ATP and citrate

  7. Covalent Modification: Pyruvate kinase is regulated by phosphorylation in response to hormonal signals (inactivated by glucagon)
• Gluconeogenesis


  1. Synthesis of glucose from non-carbohydrate precursors

  2. Mainly occurs in the liver and kidney cortex

  3. Key Enzymes: Pyruvate Carboxylase, PEP Carboxykinase, Fructose-1,6-bisphosphatase (FBPase-1), Glucose-6-phosphatase

  4. Inhibited by: AMP, F2,6BP

  5. Activated by: Citrate

  6. Allosteric Modulation: FBPase-1 is inhibited by AMP and F2,6BP

  7. Gene Expression: PEP carboxykinase and glucose-6-phosphatase are upregulated by glucagon and downregulated by insulin
• Glycogen Synthesis (Glycogenesis)


  1. Converts glucose to glycogen for storage

  2. Occurs in the liver and muscle

  3. Key Enzymes: Glycogen Synthase, Branching Enzyme

  4. Activated by: Insulin, dephosphorylation (PP1)

  5. Inhibited by: Phosphorylation (GSK3, PKA)

  6. Hormonal Regulation: Insulin promotes dephosphorylation and activation of glycogen synthase
• Glycogen Degradation (Glycogenolysis)


  1. Breaks down glycogen to release glucose

  2. Occurs in the liver and muscle

  3. Key Enzymes: Glycogen Phosphorylase, Debranching Enzyme

  4. Activated by: Glucagon (liver), adrenaline (muscle), phosphorylation (phosphorylase kinase)

  5. Inhibited by: Insulin, dephosphorylation (PP1)

  6. Allosteric Modulation: Glycogen phosphorylase is activated by AMP and inhibited by ATP, G6P, and glucose
• Fatty Acid Synthesis


  1. Synthesis of fatty acids from acetyl-CoA

  2. Occurs in the cytoplasm

  3. Key Enzymes: Acetyl-CoA Carboxylase (ACC), Fatty Acid Synthase (FAS)

  4. Activated by: Citrate, insulin

  5. Inhibited by: Palmitoyl-CoA, glucagon, AMPK

  6. Covalent Modification: ACC is activated by dephosphorylation (insulin) and inhibited by phosphorylation (glucagon, AMPK)

  7. Allosteric Regulation: Citrate activates ACC; palmitoyl-CoA inhibits ACC
• Fatty Acid Oxidation


  1. Breakdown of fatty acids to acetyl-CoA

  2. Occurs in the mitochondrial matrix

  3. Key Enzymes: Acyl-CoA Dehydrogenase, Enoyl-CoA Hydratase, β-Hydroxyacyl-CoA Dehydrogenase, Thiolase

  4. Inhibited by: Malonyl-CoA, which prevents fatty acid entry into mitochondria

  5. Hormonal Regulation: Glucagon and adrenaline promote fatty acid oxidation by activating PKA, which phosphorylates and inactivates ACC, reducing malonyl-CoA levels
• Insulin


  • Promotes glycogen synthesis, glycolysis, and fatty acid biosynthesis
  • Activates dephosphorylation enzymes (PP1) and promotes enzyme synthesis
  • Increases the expression of glycolytic and lipogenic enzymes (e.g., hexokinase, PFK-1, pyruvate kinase, acetyl-CoA carboxylase, fatty acid synthase)
• Glucagon and Adrenaline


  • Promote glycogenolysis, gluconeogenesis, and fatty acid oxidation
  • Activate phosphorylation enzymes (PKA) and inhibit biosynthetic enzymes
  • Increase the expression of gluconeogenic enzymes (e.g., PEP carboxykinase, glucose-6-phosphatase)
• Allosteric Regulation


  • Glycogen Phosphorylase: Activated by AMP (muscle), Inhibited by ATP, G6P, glucose (liver)
  • Glycogen Synthase: Activated by G6P
  • PFK-1: Activated by AMP, ADP, F2,6BP, Inhibited by ATP, citrate
  • FBPase-1: Inhibited by AMP, F2,6BP
• Gene Regulation


  • PEP Carboxykinase: Activated by cAMP (glucagon), inhibited by insulin
  • Glucose-6-Phosphatase: Decreased expression by insulin
  • Fatty Acid Synthase Complex: Increased expression by insulin
  • Acetyl-CoA Carboxylase: Increased expression by insulin
• Compartmentalization of Pathways


  • Fatty Acid Biosynthesis: Occurs in the cytoplasm, enzymes are part of the fatty acid synthase complex, separated from β-oxidation to prevent futile cycling
  • Fatty Acid Oxidation: Occurs in the mitochondrial matrix, enzymes are separate and distinct from those in fatty acid biosynthesis
• Key Concepts


  • Reciprocal Regulation: Opposing pathways are regulated to prevent futile cycles, ensures efficient use of resources
  • Allosteric Modulation: Enzyme activity is regulated by molecules that bind to sites other than the active site, allows rapid response to changes in metabolite levels
  • Covalent Modification: Phosphorylation and dephosphorylation regulate enzyme activity, provides a rapid and reversible means of regulation
  • Gene Expression: Hormonal signals can increase or decrease the synthesis of enzymes, long-term regulation through changes in protein levels
• Metabolic pathways are interconnected and reciprocally regulated
• Enzyme regulation involves allosteric control, covalent modification, and gene expression
• Hormones like insulin, glucagon, and adrenaline play key roles in regulating these pathways