Heme Synthesis Lecture Notes

Introduction

• Heme Synthesis Pathway
  • An important biochemistry pathway
  • Mnemonic to remember steps: "Some Great Doctors Palpate Heart Under Cover and Produce Pure Heme"

Sites of Heme Synthesis

• Erythroid Precursor Cells: ~80% of heme synthesis
• Liver: Remaining synthesis
• Occurs in both mitochondria and cytosol
  • ALA Synthase: Mitochondrial enzyme
  • Coproporphyrinogen oxidase, Protoporphyrinogen oxidase, and Ferrochelatase: Mitochondrial enzymes

Steps in Heme Synthesis

Step 1: Synthesis of Delta-Aminolevulinic Acid (ALA)

• Reactants: Succinyl Coenzyme A + Glycine
• Enzyme: ALA Synthase (PLP dependent)
• Intermediate: Alpha-amino-beta-keto adipate
• Process: Removal of CoA and decarboxylation

Step 2: Formation of Porphobilinogen

• Reactants: Two molecules of Delta-Aminolevulinic Acid
• Enzyme: ALA Dehydratase (zinc-containing, inhibited by lead)
• Product: Porphobilinogen (monopyrrole)
• Process: Dehydration (removal of 2 H2O molecules)

Step 3: Formation of Hydroxymethylbilane

• Reactants: Four molecules of Porphobilinogen
• Enzyme: Uroporphyrinogen I Synthase (PBG Deaminase or HMB Synthase)
• Product: Hydroxymethylbilane (Linear tetrapyrrole)

Step 4: Formation of Uroporphyrinogen III

• Enzyme: Uroporphyrinogen III Cosynthase
• Process: Cyclization
• Deficiency: Leads to Congenital Erythropoietic Porphyria

Step 5: Conversion to Coproporphyrinogen III

• Enzyme: Uroporphyrinogen Decarboxylase
• Process: Decarboxylation (removal of 4 CO2)
• Deficiency: Leads to Porphyria Cutanea Tarda (photosensitivity)

Step 6: Formation of Protoporphyrinogen IX

• Enzyme: Coproporphyrinogen Oxidase (mitochondrial)
• Process: Oxidation

Step 7: Formation of Protoporphyrin

• Enzyme: Protoporphyrinogen Oxidase

Step 8: Formation of Heme

• Enzyme: Ferrochelatase (Heme Synthase)
• Process: Incorporation of iron

Important Enzyme Details

• ALA Synthase
  • Two types: ALA Synthase 1 (erythroid cells) & ALA Synthase 2
  • Regulated by feedback inhibition
• Other Key Enzymes: U1, U3, UD, Coproporphyrinogen Oxidase, Protoporphyrinogen Oxidase, Ferrochelatase

Associated Disorders (Porphyrias)

• Acute Intermittent Porphyria: Uroporphyrinogen I Synthase deficiency
• Congenital Erythropoietic Porphyria: Uroporphyrinogen III Cosynthase deficiency
• Porphyria Cutanea Tarda: Uroporphyrinogen Decarboxylase deficiency
• Hereditary Coproporphyria: Coproporphyrinogen Oxidase deficiency
• Variegate Porphyria: Protoporphyrinogen Oxidase deficiency
• Protoporphyria: Ferrochelatase deficiency

Summary

• Mnemonic: Sum Great Doctors Palpate Heart Under Cover and Produce Pure Heme
• Pathway Review: Succinyl CoA + Glycine → ALA → Porphobilinogen → Hydroxymethylbilane → Uroporphyrinogen III → Coproporphyrinogen III → Protoporphyrinogen IX → Protoporphyrin → Heme

Conclusion

• Next Steps: Discussion on porphyrias in upcoming lectures
• Reminder: Review pathway and mnemonics for better understanding

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