Harvey's Garden

Heme synthesis

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Mitochondria are necessary for the first and the final 3 steps.

A useful mnemonic for the intermediates: “Great Students Always Produce Highly Useful Content Pertaining to Pathways & Heme.” (Glycine/Succinyl-CoA → ALA → Porphobilinogen → Hydroxymethylbilane → Uroporphyrinogen → Coproporphyrinogen → Protoporphyrinogen → Protoporphyrin → Heme)

The pathway starts and ends in the mitochondria, with intermediate steps in the cytoplasm.

1. Glycine + Succinyl-CoA → δ-Aminolevulinic acid (ALA)

  • Enzyme: ALA synthase (Rate-limiting step)
  • Location: Mitochondria
  • Cofactor: Vitamin B6 (pyridoxine)
  • Regulation: Inhibited by heme and glucose.
  • Deficiency: X-linked Sideroblastic Anemia
    • Presents as microcytic anemia with iron accumulation in mitochondria.
    • Dx: Ringed sideroblasts in bone marrow (Prussian blue stain).

2. ALA → Porphobilinogen (PBG)

  • Enzyme: ALA dehydratase
  • Location: Cytoplasm
  • Inhibited by: Lead

3. Porphobilinogen (PBG) → Hydroxymethylbilane

  • Enzyme: Porphobilinogen (PBG) deaminase
  • Location: Cytoplasm
  • Deficiency: Acute Intermittent Porphyria (AIP) (Autosomal Dominant)
    • Accumulates: PBG, ALA.
    • Presentation (The 5 P’s):
      • Painful abdomen
      • Port-wine colored urine (darkens on standing)
      • Polyneuropathy
      • Psychological disturbances
      • Precipitated by triggers (e.g., CYP450 inducers, alcohol, starvation).
    • Tx: Glucose and heme (inhibit ALA synthase).

4. Uroporphyrinogen III → Coproporphyrinogen III

  • Enzyme: Uroporphyrinogen decarboxylase
  • Location: Cytoplasm
  • Deficiency: Porphyria Cutanea Tarda (PCT) (Most common porphyria)
    • Accumulates: Uroporphyrin (tea-colored urine).
    • Presentation: Blistering cutaneous photosensitivity and hyperpigmentation.
    • Associations: Hepatitis C, alcohol use, hemochromatosis.

5. Protoporphyrin IX + Fe²⁺ → Heme

  • Enzyme: Ferrochelatase
  • Location: Mitochondria
  • Inhibited by: Lead

Lead Poisoning

  • Mechanism: Inhibits ALA dehydratase and Ferrochelatase.
  • Accumulates: Protoporphyrin, ALA in blood.
  • Presentation:
    • Lead lines on gingivae (Burton lines) & on long bone metaphyses.
    • Encephalopathy & Erythrocyte basophilic stippling.
    • Abdominal colic & sideroblastic Anemia.
    • Drops (wrist and foot drop).
  • Dx: ↑ blood lead level, basophilic stippling on peripheral smear.
  • Tx: Chelation therapy (e.g., EDTA, Dimercaprol, Succimer for kids).

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