Tetrapyrrole Synthesis: Heme Synthesis, Porphyrias, and Catabolism

Blood and Grass: Structural Chemistry

• Structure of Heme

  • Comprised of a porphyrin ring with iron at its center.

• Structure of Chlorophyll

  • Similar structural framework as heme, but includes a magnesium atom instead of iron.

Global Visibility of Chlorophyll

• Chlorophyll can be detected from space and plays a central role in photosynthesis.

Modified Tetrapyrroles

• Significance

  • Haem and analogous molecules are integral to fundamental metabolic processes.

• Structural Similarities

  • All modified tetrapyrroles follow a branched biosynthetic pathway, leading to compounds like B12, chlorophyll, and heme.

Key Pathways in Modified Tetrapyrrole Synthesis

• Branched Biosynthetic Pathway

  • Focus primarily on heme synthesis, being the only tetrapyrrole produced by humans.

Stages of Heme Synthesis

1. Construction of the Macrocycle

• Initial formation of the porphyrin structure.

2. Modification of the Macrocycle

• Final chemical modifications to create functional heme.

Heme Synthesis Overview

• Two Stages of Synthesis

  1. Create the macrocycle in an unsymmetrical fashion.

  2. Enhance hydrophobicity and aromaticity of the structure.

Enzymatic Steps in Heme Synthesis

• (i) Making the Macrocycle

  • Involves 7 key enzymatic steps:

    • Formation of 5-Aminolevulinic acid

    • Conversion into Porphobilinogen

    • Formation of Hydroxymethylbilane and Uroporphyrinogen III as macrocyclic intermediates.

• (ii) Modification of the Macrocycle

  • Converts Uroporphyrinogen III into more complex forms like Heme through stages involving decarboxylation (6 total) and iron incorporation.

Sources of 5-Aminolevulinic Acid (5-ALA)

• Origin

  • 5-ALA is synthesized via the TCA cycle, revealed through David Shemin's experiments with 15N-glycine, demonstrating its incorporation into heme over its half-life correlating to red blood cells.

Iron Incorporation in Heme Synthesis

• Mechanisms for Fe Uptake

  • Cells utilize specialized mechanisms to uptake iron, which is stored as ferritin and delivered to ferrochelatase.

• Coordinated Delivery

  • The delivery of iron is synchronized with heme synthesis processes.

Compartmentalization of Heme Synthesis

• Location

  • Heme synthesis occurs primarily in mitochondria, with the first and final three steps localized there.

Summary of Enzymatic Steps in Heme Synthesis

• Complete Workflow of Heme Production

  • Steps include:

    1. Formation of 5-Aminolevulinic Acid (5-ALA)

       ALA dehydratase or PBG synthase

    2. Generation of Porphobilinogen (PBG)

       PBG deaminase or HMB synthase

    3. Creation of Hydroxymethylbilane (HMB)

       Uro’gen synthase

    4. Synthesis of Uroporphyrinogen III

       Uro’gen decarboxylase

    5. Transition to Coproporphyrinogen III

       Copro’gen oxidase

    6. Protoporphyrinogen IX

       Proto’gen oxidase

    7. Protoporphyrin IX

       Ferrochelatase

    8. Heme

• Key enzymes include:

  • ALA dehydratase, PBG synthase, HMB synthase, Uro'gen synthase, Uro'gen decarboxylase, Copro'gen oxidase, Proto'gen oxidase, and Ferrochelatase.