BCH 413: THE INTEGRATION OF METABOLISM

Metabolism Consists of Highly Interconnected Pathways

  • The basic strategy of catabolic metabolism:

    • Objective: To form ATP, reducing power, and building blocks for biosynthesis.
    • ATP is the universal currency of energy.
    • High phosphoryl transfer potential of ATP provides energy for:
      • Muscle contraction
      • Active transport
      • Signal amplification
      • Biosyntheses
    • Hydrolysis of ATP changes the equilibrium ratio of products to reactants in a coupled reaction by a factor of approximately 10810^8.
    • Allows thermodynamically unfavorable reactions to proceed by coupling them to ATP hydrolysis.

  • ATP generation details:

    • Oxidation of fuel molecules (e.g., glucose, fatty acids, amino acids).
    • Common intermediate: Acetyl CoA.
    • Carbon atoms of the acetyl unit are oxidized to CO2CO_2 via the citric acid cycle.
    • Yields NADH and FADH2, which transfer high-potential electrons to the respiratory chain.
    • Proton gradient across the mitochondrial membrane is utilized to synthesize ATP.
    • Glycolysis generates ATP, though significantly less than oxidative phosphorylation.
    • Oxidation of glucose to pyruvate yields only 2 ATP, while complete oxidation to CO2CO_2 yields 30 ATP.

  • NADPH role:

    • Major electron donor in reductive biosyntheses.
    • Needed for reactions where products are more reduced than precursors.
    • Usually provided by NADPH; mainly supplied through the pentose phosphate pathway.

  • Building blocks for biomolecules:

    • Diverse biological molecules synthesized from a limited set of precursors.
    • Central metabolic pathways generate not only energy but also essential building blocks (e.g., acetyl CoA for fatty acids).
    • Central pathways have both anabolic and catabolic roles.

  • Distinction of biosynthetic and degradative pathways:

    • Biosynthetic pathways (e.g., fatty acid synthesis) are separate from degradative pathways to ensure thermodynamic favorability.
    • Coupling biosynthetic pathways to ATP hydrolysis makes them exergonic.

Recurring Motifs in Metabolic Regulation

  • Coordination required between anabolism and catabolism.
  • Metabolic networks sense and respond to their component pathways.

  1. Allosteric interactions:

    • Determined by enzyme activities rather than substrate amounts.
    • Irreversible reactions (committed steps) are control sites, e.g., phosphofructokinase in glycolysis.
    • Allosteric regulation allows rapid detection of diverse signals.

  2. Covalent modification:

    • Some enzymes controlled by covalent modifications in addition to allosteric interactions.
      • Example: Glycogen phosphorylase (enhanced by phosphorylation) vs. glycogen synthase (inhibited by phosphorylation).
    • Allows rapid pathway switching via low concentrations of triggering signals.
    • Lasts longer than reversible allosteric interactions.

  3. Enzyme levels:

    • The rates of synthesis and degradation of enzymes regulated by hormones.

  4. Compartmentation:

    • Eukaryotic cell compartments influence metabolic patterns.
    • Molecular fates determined by cellular location (cytosol vs. mitochondria).

  5. Metabolic organ specialization:

    • Different organs display metabolic specializations due to differential gene expression.

Major Metabolic Pathways and Control Sites

  1. Glycolysis:

    • Converts glucose to pyruvate, generating 2 ATP and 2 NADH.
    • Cellular conditions affect NAD+ regeneration:
      • Anaerobic: Reduction of pyruvate to lactate.
      • Aerobic: Electron transfer from NADH to O2 via the electron-transport chain.
    • Primarily serves: ATP generation and carbon skeletons for biosynthetic needs.
    • Regulation:
      • Phosphofructokinase: Key control site, decreased by high ATP, increased by AMP and fructose 2,6-bisphosphate, especially in the liver.

  2. Citric acid cycle and oxidative phosphorylation:

    • Oxidizes fuel molecules inside mitochondria; most enter as acetyl CoA.
    • Generates:
      • One GTP
      • Four pairs of electrons as 3 NADH and 1 FADH2.
    • Electrons transferred to O2 for ATP generation.
    • Tight coupling via respiratory control links the cycle's rate with the need for ATP.
    • Anabolic roles provide biosynthetic intermediates (e.g., succinyl CoA for porphyrins).

  3. Pentose phosphate pathway:

    • Consists of two stages:
      • Oxidative decarboxylation of glucose 6-phosphate.
      • Produces NADPH for reductive biosynthesis and ribose 5-phosphate for nucleotide synthesis.
      • Committed step controlled by NADP+ levels.

  4. Gluconeogenesis:

    • Synthesizes glucose from non-carbohydrate precursors (lactate, glycerol, amino acids).
    • Major entry point: Pyruvate converted to oxaloacetate in mitochondria.
    • Reciprocal regulation with glycolysis, ensuring mutual exclusivity of activity.
      • Example: Fructose 1,6-bisphosphatase in gluconeogenesis inhibited by AMP and activated by citrate.

  5. Glycogen synthesis and degradation:

    • Glycogen is a branched glucose polymer.
    • Degeneration via phosphorylase yields glucose 1-phosphate, converted to glucose 6-phosphate.
    • Synthesis dependent on UDP-glucose.
    • Hormonal regulation ensures coordinated control between synthesis and degradation.

  6. Fatty acid synthesis and degradation:

    • Synthesis occurs in the cytosol with malonyl CoA serving as the activated intermediate.
    • Acetyl CoA transported from mitochondria to cytosol as citrate.
    • Regulation by the availability of ATP and abundance of citrate.
    • Beta-oxidation of fatty acids occurs in mitochondria, generating acetyl CoA and electron carriers.

Key Junctions in Metabolic Flow: Glucose 6-Phosphate, Pyruvate, and Acetyl CoA

  1. Glucose 6-Phosphate:

    • Converts to:
      • Glycogen (when ATP abundant)
      • Pyruvate (when ATP or carbon skeletons are needed)
      • Ribose 5-phosphate (via pentose phosphate pathway).
    • Synthesis from glycogen mobilization or gluconeogenesis from pyruvate and glucogenic amino acids.

  2. Pyruvate:

    • Derived from glucose 6-phosphate, alanine, and lactate.
    • Functions include:
      • Conversion to lactate to regenerate NAD+ under anaerobic conditions.
      • Transamination to form alanine, linking amino acid and carbohydrate metabolism.
      • Carboxylation to oxaloacetate (gluconeogenesis) and oxidative decarboxylation to acetyl CoA (commitment to oxidation or lipid synthesis).

  3. Acetyl CoA:

    • Major sources: Oxidative decarboxylation of pyruvate and beta-oxidation of fatty acids.
    • Fates include full oxidation via the citric acid cycle, formation of ketone bodies, or transport to the cytosol for fatty acid synthesis.

Unique Metabolic Profiles of Different Organs

  1. Brain:

    • Primarily uses glucose as fuel; continuous supply needed due to lack of fuel stores.
    • Consumes ≈ 120 g of glucose daily (≈ 60% of body’s glucose utilization).
    • High energy demands for maintaining Na+-K+ membrane potential and neurotransmitter synthesis.
    • Glucose transport mainly by GLUT3, ensuring constant supply.

  2. Muscle:

    • Major fuels: glucose, fatty acids, ketone bodies.
    • Maintains large glycogen stores (≈ 1200 kcal) for bursts of activity.
    • Glycolytic activity during high-intensity contractions, utilizing lactate cycling with the liver.

  3. Adipose Tissue:

    • Stores triacylglycerols as a metabolic fuel reservoir (15 kg ≈ 135,000 kcal).
    • Triacylglycerols hydrolyzed and reesterified; glucose required for triacylglycerol synthesis.

  4. Kidney:

    • Produces urine to excrete metabolic wastes and maintain osmolarity.
    • High energy demands for reabsorption processes; significant glucose reabsorption via sodium-glucose cotransporters.
    • Important site for gluconeogenesis during starvation.

  5. Liver:

    • Central node for fuel metabolism, interacting with other organs to regulate blood metabolites.
    • Processes glucose and converts it to glycogen; contributes to gluconeogenesis from lactate, glycerol, and amino acids.
    • Regulates lipid metabolism, synthesizing fatty acids and ketone bodies as needed.

Metabolic Changes in Response to Food Intake and Starvation

  1. Well-fed/Postabsorptive State:

    • Triggered by food intake—insulin secretion increases, signifying the fed state.
    • Insulin stimulates:
      • Glycogen synthesis
      • Protein synthesis
      • Suppression of gluconeogenesis.
    • High glucose levels in blood lead to rapid glycogen synthesis in the liver.

  2. Early Fasting State:

    • Blood-glucose levels drop, insulin decreases, and glucagon levels rise—mobilizing glycogen.
    • Glucagon stimulates glycogen breakdown and gluconeogenesis, conserving blood glucose and shifting muscle utilization from glucose to fatty acids.

  3. Refeeding State:

    • Liver initially does not absorb glucose but replenishes glycogen stores; excess glucose shifts towards fatty acid synthesis.

Prolonged Starvation Metabolic Adaptations to Conserve Protein

  • Goals:
    Maintain glucose (for brain) and minimize protein degradation.
  • Initial shifts toward fatty acid and ketone utilization occur to reduce reliance on glucose production from protein breakdown.
  • Ketone bodies become primary brain fuel after several days of starvation, conserving muscle mass and protein stores.

Metabolic Derangements in Diabetes

  • Diabetes Mellitus: Characterized by abnormal glucose metabolism:
    • Type I: Insulin deficiency due to autoimmune destruction of pancreatic beta cells.
    • Type II: Insulin resistance despite normal or elevated insulin levels.
  • High glucagon to insulin ratio leads to excess glucose production and lipid mobilization, causing diabetic symptoms.

Caloric Homeostasis: Regulation of Body Weight

  • Obesity is mainly caused by excessive caloric intake relative to expenditure.
  • Hormonal signals:
    • Insulin and leptin regulate appetite and energy balance.
  • Leptin signaling has shown to impact obesity.

Fuel Choice During Exercise

  • Fuel selection varies.
    • Anaerobic exercise fueled by ATP, creatine phosphate, and glycogen (leading to lactate).
    • Aerobic exercise shifts reliance to glycogen and fatty acids (requires muscles, liver, adipose coordination).
  • Rate of ATP generation and duration of exercise influence fuel selection.

Alcohol and Metabolism

  • Ethanol metabolism in the liver leads to:
    • Accumulation of NADH, inhibiting gluconeogenesis and fatty acid oxidation.
    • Spillage over to fat accumulation resulting in fatty liver.
  • Chronic ethanol use leads to progressive liver damage: fatty liver, alcoholic hepatitis, cirrhosis.