Metabolism — Comprehensive Study Notes

Introduction of Metabolism

  • Chemical energy in biological systems is primarily stored or released via:
    • Fats
    • Carbohydrates
    • Other biomolecules (e.g. proteins, nucleic acids)
  • Universal cellular energy currency: ATP (Adenosine Triphosphate\text{Adenosine Triphosphate})
  • End–products (chemical “waste”) of most energy-releasing pathways:
    • CO2\text{CO}_{2} (carbon dioxide)
    • H2O\text{H}_{2}\text{O} (water)
  • Metabolism = the sum total of every chemical reaction in a cell or whole organism.

Catabolism vs. Anabolism

  • Catabolism
    • Definition: pathways that release energy by breaking complex molecules → simpler ones.
    • Key example: cellular respiration—complete oxidation of glucose in the presence of O2\text{O}_{2}.
    • Typical reaction type: hydrolysis (water is added, bonds are cleaved).
  • Anabolism
    • Definition: pathways that consume energy to synthesize complex molecules from simpler precursors.
    • Key example: protein synthesis from amino acids.
    • Typical reaction type: dehydration (condensation) (water is removed, bonds are formed).
  • Energetic interplay: energy liberated by catabolism (mostly captured as ATP\text{ATP}, NADH\text{NADH}, FADH2\text{FADH}_{2}) fuels anabolic work.

Energetic Relationship (Catabolism ↔ Anabolism)

  • Catabolic Reactions
    • Convert complex polymers (glycogen, proteins, triglycerides) → simple monomers (glucose, amino acids, fatty acids, glycerol).
    • Energy transfer: complex molecule → ATP\text{ATP} (plus heat release).
    • Net equation (conceptual):
      Complex Mol.+ADP+Pi→Simpler Mol.+ATP+Heat\text{Complex Mol.} + \text{ADP} + P_{i} \rightarrow \text{Simpler Mol.} + \text{ATP} + \text{Heat}
  • Anabolic Reactions
    • Use ATP\text{ATP} hydrolysis to drive formation of new bonds, regenerating complex molecules.
    • Conceptual equation:
      Simpler Mol.+ATP→Complex Mol.+ADP+Pi+Heat\text{Simpler Mol.} + \text{ATP} \rightarrow \text{Complex Mol.} + \text{ADP} + P_{i} + \text{Heat}
  • Overall, heat is lost at each transfer, underscoring metabolic inefficiency and the second law of thermodynamics.

Citric Acid Cycle (Tricarboxylic Acid Cycle / Krebs Cycle)

  • Entry: Acetyl–CoA\text{Acetyl–CoA} (2C) condenses with oxaloacetate (4C) → citrate (6C).
  • Step-by-step highlights (each catalyst and purpose):
    • 1. Citrate Synthase – Condensation
    • Acetyl–CoA+Oxaloacetate+H2O→Citrate+CoA–SH\text{Acetyl–CoA} + \text{Oxaloacetate} + \text{H}_{2}\text{O} \rightarrow \text{Citrate} + \text{CoA–SH}
    • Converts acetate’s methyl → methylene, establishing a 6-C backbone.
    • 2. Aconitase – Dehydration/Rehydration (Isomerization)
    • Citrate ⇌ cis-Aconitate ⇌ Isocitrate
    • Shifts the –OH to a more oxidizable position, priming for decarboxylation.
    • 3. Isocitrate Dehydrogenase – Oxidative Decarboxylation
    • Isocitrate+NAD+→α-Ketoglutarate+CO2+NADH\text{Isocitrate} + \text{NAD}^{+} \rightarrow \alpha\text{-Ketoglutarate} + \text{CO}_{2} + \text{NADH}
    • 4. α-Ketoglutarate Dehydrogenase Complex – Oxidative Decarboxylation
    • Mechanistically analogous to pyruvate dehydrogenase.
    • Produces succinyl-CoA, CO2\text{CO}_{2}, and NADH\text{NADH}.
    • 5. Succinyl-CoA Synthetase – Substrate-level Phosphorylation
    • Conserves thioester energy as \text{GTP (\approx ATP)}.
    • Succinyl–CoA+GDP+Pi→Succinate+CoA–SH+GTP\text{Succinyl–CoA} + \text{GDP} + P_{i} \rightarrow \text{Succinate} + \text{CoA–SH} + \text{GTP}
    • 6. Succinate Dehydrogenase – Dehydrogenation
    • Introduces C=C producing fumarate + FADH2\text{FADH}_{2}.
    • 7. Fumarase – Hydration
    • Adds H2O\text{H}_{2}\text{O} across the double bond → malate.
    • 8. Malate Dehydrogenase – Dehydrogenation
    • Malate+NAD+→Oxaloacetate+NADH\text{Malate} + \text{NAD}^{+} \rightarrow \text{Oxaloacetate} + \text{NADH}
  • Products per cycle (per acetyl unit): 3 NADH3\,\text{NADH}, 1 FADH<em>21\,\text{FADH}<em>{2}, 1 GTP(→ATP)1\,\text{GTP} (\rightarrow ATP), 2 CO</em>22\,\text{CO}</em>{2}.
  • Functional importance: completes oxidation of carbon skeletons; regenerates oxaloacetate for continuity.

Fatty-Acid Oxidation (General)

  • Definition: enzymatic degradation of fatty acids → capture of chemical energy (primarily as NADH\text{NADH}, FADH2\text{FADH}_{2}, and acetyl-CoA).
  • Three mechanistic routes:
    1. β-oxidation (major)
    2. α-oxidation (specialized/minor)
    3. ω-oxidation (microsomal “overflow” when β is impaired)
β-Oxidation
  • Location: mitochondrial matrix (also peroxisomes for very-long chains).
  • Substrate: acyl-CoA (fatty acid activated by CoA + ATP).
  • Repetitive sequence: oxidation → hydration → oxidation → thiolysis; each spiral removes a 2-C acetyl-CoA.
  • Feeds acetyl-CoA to the citric acid cycle and reduced cofactors to the electron-transport chain.
α-Oxidation
  • Location: brain & liver.
  • Removes one carbon from the carboxyl end (useful for branched-chain fatty acids—e.g. phytanic acid).
  • Necessary because β-oxidation is sterically hindered by a β-methyl branch.
ω-Oxidation
  • Location: endoplasmic reticulum (ER).
  • Attacks the terminal (ω) methyl group → converts it to a dicarboxylic acid.
  • Normally minor but up-regulated when β-oxidation is defective (e.g. carnitine deficiency, MCAD deficiency).

Urea Cycle (Disposal of Ammonia)

  • Purpose: detoxify ammonium by converting it into urea (water-soluble, excreted by kidneys).
  • Key intermediates & enzymes:
    1. Carbamoyl Phosphate Synthetase I (CPS-I)
    • NH<em>3+CO</em>2+2 ATP→Carbamoyl Phosphate+2 ADP+Pi\text{NH}<em>{3} + \text{CO}</em>{2} + 2\,\text{ATP} \rightarrow \text{Carbamoyl Phosphate} + 2\,\text{ADP} + P_{i}
    1. Ornithine Transcarbamoylase (OTC)
    • Carbamoyl-P + L-ornithine → citrulline.
    1. Argininosuccinate Synthase
    • Citrulline + L-aspartate + ATP → argininosuccinate + AMP + PPi.
    1. Argininosuccinate Lyase
    • Argininosuccinate → L-arginine + fumarate.
    1. Arginase
    • L-arginine + H2O\text{H}_{2}\text{O} → urea + L-ornithine (cycle restarts).
  • Connection to TCA: generated fumarate re-enters mitochondria, can replenish TCA intermediates (called the Krebs–Henseleit bicycle).

Integrative & Practical Notes

  • ATP as central node: catabolic production (glycolysis, β-oxidation, TCA) vs. anabolic consumption (protein, nucleotide, lipid synthesis).
  • Heat generation at each metabolic transfer = basis of thermoregulation in endotherms.
  • Pathology links
    • Defects in β-oxidation → accumulation of fatty acids, reliance on ω-oxidation → elevated dicarboxylic acids in urine.
    • Urea-cycle enzyme deficiencies → hyperammonemia; neurological symptoms due to ammonia toxicity.
  • Regulation themes
    • Compartmentalization (cytosol vs. mitochondria vs. ER).
    • Allosteric control (e.g. acetyl-CoA activates CPS-I via N-acetylglutamate).
    • Energy charge (ratio [ATP][ADP]+[AMP]\frac{[ATP]}{[ADP]+[AMP]}) governs anabolic vs. catabolic flux.

Quick Reference Equations & Numbers

  • Net ATP\text{ATP} yield from complete oxidation of one glucose ≈ 30–32 ATP30\text{–}32\,ATP.
  • Energy equivalence: GTP≈ATP\text{GTP} \approx \text{ATP} (readily exchanged by nucleoside-diphosphate kinase).
  • β-oxidation of palmitate (16C):
    • 7 cycles → 8 acetyl-CoA + 7 NADH + 7 FADH2.
    • Total ATP after ETC & TCA ≈ 106 ATP106\,ATP (after subtracting activation cost).
  • Stoichiometry of urea cycle: NH<em>3+CO</em>2+Aspartate+3 ATP+2 H<em>2O→Urea+2 ADP+2 P</em>i+AMP+PPi+Fumarate\text{NH}<em>{3} + \text{CO}</em>{2} + \text{Aspartate} + 3\,ATP + 2\,H<em>{2}O \rightarrow \text{Urea} + 2\,ADP + 2\,P</em>{i} + AMP + PP_i + \text{Fumarate}.

Key Terms Glossary

  • Hydrolysis: cleavage with H2O\text{H}_{2}O.
  • Dehydration/Condensation: bond formation producing H2O\text{H}_{2}O.
  • Dehydrogenation: removal of H₂, commonly forms C=C or C=O, transfers electrons to NAD⁺/FAD.
  • Decarboxylation: loss of CO2\text{CO}_{2} from carboxyl group.
  • Thiolysis: cleavage by CoA–SH (in β-oxidation).