Heme Metabolism Notes

Objectives of Heme Metabolism Study

  • Identify amphibolic intermediates of heme synthesis.
  • Recognize key regulated enzymes in hepatic heme biosynthesis.
  • Describe color differences between porphyrins and porphyrinogens.
  • Differentiate mitochondrial and cytosolic enzymes in heme biosynthesis.
  • Understand heme conversion to bilirubin: mitochondrial vs cytosolic reactions.
  • Comprehend porphyrias and their clinical manifestations.
  • Define direct and indirect bilirubin, including causes of jaundice.

Porphyrins

  • Definition: Cyclic compounds consisting of four modified pyrrole subunits interconnected via methenyl bridges.
  • Metalloporphyrin: Porphyrins that bind metal ions, primarily iron in human heme.
  • Function of Heme: Prosthetic group of hemoglobin, myoglobin, cytochromes, catalase, and tryptophan pyrrolase.
    • Structure: Iron (Fe2+) at the center of a protoporphyrin IX ring.

Structure of Porphyrins

  • Formation: Four pyrrole rings linked by methenyl bridges.
  • Substituents: Side chains replace hydrogen atoms in the molecule, with positions numbered from 1 to 8.

Heme Biosynthesis Locations

  • Liver: Major site for synthesis of heme proteins (e.g., cytochromes).
  • Bone Marrow: Erythrocyte-producing cells involved in hemoglobin synthesis.
  • Mitochondria vs. Cytosol: Initial and final heme synthesis steps occur in mitochondria; intermediates are synthesized in cytosol.

Heme Biosynthesis Pathway Overview

  1. Formation of 8-Aminolevulinic acid (ALA) from glycine and succinyl-CoA by ALA synthase (rate-limiting step).
  2. Porphobilinogen (PBG) formation: condensation of ALA by ALA dehydratase.
  3. Uroporphyrinogen III synthesis: linear tetrapyrrole is cyclized by uroporphyrinogen III synthase.
  4. Coproporphyrinogen III: Decarboxylation of uroporphyrinogen III (cytosolic).
  5. Formation of Protoporphyrinogen IX from coproporphyrinogen III in mitochondria.
  6. Conversion to Protoporphyrin IX via oxidation.
  7. Introduction of iron (Fe2+) into protoporphyrin IX by ferrochelatase.

Porphyrias

  • Definition: Rare inherited defects in heme synthesis causing accumulation of porphyrin precursors, leading to clinical symptoms.
  • Types: Erythropoietic (bone marrow) and Hepatic porphyrias.
  • Symptoms: Abdominal pain, neuropsychiatric signs, skin photosensitivity.

Jaundice

  • Definition: Yellowing of the skin and eyes due to bilirubin deposition in tissues; a symptom rather than a disease.
  • Types of Jaundice:
  • Hemolytic: Excessive breakdown of red blood cells increases unconjugated bilirubin.
  • Hepatocellular: Damage to liver cells affects bilirubin conjugation, leading to increased unconjugated bilirubin.
  • Obstructive: Bile duct obstruction leads to accumulation of conjugated bilirubin in the blood.

Bilirubin Metabolism

  1. Formation: Heme degradation through the action of heme oxygenase results in biliverdin and then bilirubin.
  2. Uptake by Liver: Bilirubin transported to the liver via albumin.
  3. Conjugation: Bilirubin diglucuronide (conjugated bilirubin) formed for excretion.
  4. Excretion: Active transport into bile canaliculi.
  5. Intestinal Conversion: Bacteria convert bilirubin to stercobilin (feces coloring) and urobilin (urine coloring).

Laboratory Tests for Bilirubin

  • Jendrassik-Grof Test: Measures total bilirubin by forming a colored complex with diazo reagent. - Direct Spectrophotometric: Measures bilirubin concentration using absorbance at specific wavelengths.
  • Normal Ranges:
  • Adults: Total bilirubin: 0.2-1.2 mg/dL, Direct bilirubin: 0.0-0.2 mg/dL, Indirect: 0.2-0.8 mg/dL.
  • Infants: Total bilirubin: 2-6 mg/dL (0-1 day).

Conclusion

  • Understanding heme metabolism is crucial for diagnosing and managing conditions related to bilirubin and porphyrins.
  • A sound grasp of the biochemical pathways involved helps in clinical settings, especially pertaining to jaundice and porphyrias.