Tetrapyrrole-heme biosynthesis and its disorders. Heme incorporation into apoproteins and its function.

Introduction

Heme is an iron-containing tetrapyrrole that serves as a critical prosthetic group in hemoproteins such as hemoglobin, myoglobin, cytochromes, and catalase. Its biosynthesis is tightly regulated and occurs through a multistep pathway distributed between the mitochondria and cytosol. Deficiencies or disruptions in this pathway can lead to a group of disorders known as porphyrias. Heme's incorporation into apoproteins is essential for their structural integrity and function.

Main Biochemical Mechanisms

Heme Biosynthesis Pathway

The heme biosynthetic pathway consists of eight enzymatic steps:

1. δ-Aminolevulinic acid (ALA) synthesis– In mitochondria, glycine and succinyl-CoA condense to form ALA, catalyzed by ALA synthase (rate-limiting step).

2. Porphobilinogen (PBG) formation – Two ALA molecules condense in the cytosol via ALA dehydratase.

3. Hydroxymethylbilane synthesis – Four PBGs are polymerized by PBG deaminase.

heme

4. Uroporphyrinogen III synthesis – Cyclization by uroporphyrinogen III synthase.

5. Coproporphyrinogen III formation – Decarboxylation of uroporphyrinogen III by uroporphyrinogen decarboxylase.

6. Protoporphyrinogen IX formation – Coproporphyrinogen III enters mitochondria and is oxidized.

7. Protoporphyrin IX synthesis – Further oxidation yields protoporphyrin IX.

8. Heme formation – Insertion of Fe²⁺ into protoporphyrin IX by ferrochelatase completes heme synthesis.

Heme Incorporation into Apoproteins

After synthesis, free heme is inserted into apoproteins to form functional hemoproteins. This process is protein-specific and often assisted by chaperones. In hemoglobin and myoglobin, heme binds in a hydrophobic pocket to allow reversible oxygen binding. In cytochromes, heme participates in electron transfer via reversible oxidation-reduction.

Clinical Relevance and Disorders

Defects in heme biosynthesis enzymes cause porphyrias, which are classified based on the tissue of enzyme deficiency and the step affected:

- **Acute intermittent porphyria** (PBG deaminase deficiency): abdominal pain, neuropsychiatric symptoms.

- **Porphyria cutanea tarda** (uroporphyrinogen decarboxylase deficiency): photosensitivity, blistering skin lesions.

- **Erythropoietic protoporphyria** (ferrochelatase deficiency): photosensitivity, liver dysfunction.

Lead poisoning can also impair heme synthesis by inhibiting ALA dehydratase and ferrochelatase.

Disrupted heme incorporation may lead to accumulation of toxic free heme or impaired oxygen transport and redox activity.

Conclusion

Heme biosynthesis is a vital and highly regulated pathway crucial for the formation of hemoproteins. Disorders in this pathway can result in metabolic diseases with neurological, cutaneous, or hematological manifestations. Proper incorporation of heme ensures the function of essential proteins in respiration, detoxification, and oxidative metabolism.

References

1. Lehninger Principles of Biochemistry, 7th Edition

2. Lippincott Illustrated Reviews: Biochemistry, 7th Edition

3. Guyton and Hall Textbook of Medical Physiology, 14th Edition