Lecture Notes: Heme Synthesis Pathway

Introduction

• Heme is a prosthetic group, specifically a protoporphyrin 9 with an iron moiety.
  • Consists of four pyrrole rings with iron in the center.

Importance of Heme

• Hemoglobin Synthesis: Essential for oxygen transport in red blood cells.
  • Hemoglobin has four heme groups.
  • Myoglobin, another oxygen transport protein, contains one heme group.
• Erythropoietic System: Produces heme mainly in long bones (85%) for hemoglobin.
• Cytochrome Synthesis: Vital for the cytochrome P450 system in the liver, crucial for detoxification.
  • Hepatic System: Produces heme for the liver’s detoxification processes.

Heme Synthesis Pathway

1. Start: Glycine and succinyl-CoA combine.

2. ALA Synthase

   • Enzyme: Amino levulinic acid (ALA) synthase.
   • Location: Mitochondria.
   • Regulation:
     • Inhibited by hemin (hepatic system).
     • Upregulated by reduced hepatic heme.
     • Upregulated by iron and erythropoietin (erythropoietic system).
   • Rate-limiting Step

3. ALA Dehydratase

   • Location: Cytosol.
   • Converts ALA to porphobilinogen.
   • Requires zinc, inhibited by lead.

4. Uroporphyrinogen Synthesis

   • Uroporphyrinogen I Synthase: Converts porphobilinogen to uroporphyrinogen I.
   • Uroporphyrinogen III Co-synthase: Converts to uroporphyrinogen III in the cytosol.

5. Coproporphyrinogen Formation

   • Uroporphyrinogen Decarboxylase: Converts uroporphyrinogen III to coproporphyrinogen III.

6. Protoporphyrinogen Conversion

   • Coproporphyrinogen Oxidase: Converts to protoporphyrinogen IX.
   • Protoporphyrinogen Oxidase: Converts to protoporphyrin IX.

7. Ferrochelatase

   • Location: Mitochondria.
   • Adds iron to protoporphyrin IX to form heme.
   • Inhibited by lead.

Key Enzymes to Remember

1. ALA Synthase - Rate-limiting enzyme.
2. ALA Dehydratase - Inhibited by lead.
3. Ferrochelatase - Inhibited by lead.

Mnemonic for Steps

• APOCPP
  • A: Aminolevulinic acid
  • P: Porphobilinogen
  • U1: Uroporphyrinogen I
  • U3: Uroporphyrinogen III
  • C: Coproporphyrinogen III
  • P9: Protoporphyrinogen IX
  • P: Protoporphyrin
  • Final Product: Heme

Conclusion

• Review these steps and enzymes to grasp the heme synthesis pathway.
• Understanding the pathway assists in recognizing how lead poisoning causes anemia.