Makindo Medical Notes

Heme is an essential component of haemoglobin, myoglobin, and various cytochromes, playing a crucial role in oxygen transport, storage, and electron transport in cells. Understanding heme synthesis, its biochemistry, and physiological roles is vital for comprehending many biological processes and disorders.

Heme Synthesis

• Location:
  • Occurs in the mitochondria and cytoplasm of erythroid cells (precursors to red blood cells) and hepatocytes (liver cells).
• Steps of Heme Synthesis:
  • Aminolevulinic Acid (ALA) Synthesis:
    • Condensation of glycine and succinyl-CoA catalyzed by ALA synthase (ALAS), the rate-limiting enzyme.
    • Occurs in the mitochondria.
  • Porphobilinogen (PBG) Formation:
    • Two molecules of ALA are converted into porphobilinogen by ALA dehydratase (ALAD).
    • Occurs in the cytoplasm.
  • Hydroxymethylbilane Formation:
    • Four molecules of PBG are condensed to form hydroxymethylbilane by hydroxymethylbilane synthase (HMBS).
  • Uroporphyrinogen III Synthesis:
    • Hydroxymethylbilane is cyclized to form uroporphyrinogen III by uroporphyrinogen III synthase (UROS).
  • Coproporphyrinogen III Synthesis:
    • Uroporphyrinogen III is decarboxylated to coproporphyrinogen III by uroporphyrinogen decarboxylase (UROD).
  • Protoporphyrinogen IX Formation:
    • Coproporphyrinogen III is transported back into the mitochondria and oxidized to protoporphyrinogen IX by coproporphyrinogen oxidase (CPOX).
  • Protoporphyrin IX Formation:
    • Protoporphyrinogen IX is oxidized to protoporphyrin IX by protoporphyrinogen oxidase (PPOX).
  • Heme Formation:
    • Insertion of iron (Fe²⁺) into protoporphyrin IX catalyzed by ferrochelatase, forming heme.

Regulation of Heme Synthesis

• Primarily regulated at the level of ALA synthase (ALAS):
  • Feedback Inhibition: Heme itself inhibits ALAS to prevent overproduction.
  • Gene Expression: Various factors, including iron availability, control the expression of ALAS genes.
  • Hormonal Regulation: Erythropoietin and other hormones can increase ALAS activity to meet increased demands for heme.

Biochemistry of Heme

• Heme is a prosthetic group consisting of an iron ion held in a heterocyclic ring, known as a porphyrin.
  • Iron can exist in ferrous (Fe²⁺) or ferric (Fe³⁺) states.
  • In its functional form in haemoglobin and myoglobin, iron is in the ferrous state.
• Heme is essential for the function of various haemoproteins:
  • Haemoglobin: Carries oxygen in red blood cells.
  • Myoglobin: Stores oxygen in muscle cells.
  • Cytochromes: Involved in electron transport and energy production in mitochondria.
  • Peroxidases and Monooxygenases: Catalyze reactions involving hydrogen peroxide and oxygen, respectively.

Physiology of Heme

• Oxygen Transport and Storage:
  • Heme in haemoglobin binds to oxygen in the lungs and releases it in tissues, facilitating cellular respiration.
  • Myoglobin in muscle cells stores oxygen, providing a reserve during periods of high demand.
• Electron Transport:
  • Heme-containing cytochromes are essential components of the electron transport chain in mitochondria, crucial for ATP production.
• Detoxification:
  • Heme proteins such as cytochrome P450 enzymes play a key role in the metabolism and detoxification of various xenobiotics and drugs.

Clinical Relevance

• Porphyrias:
  • A group of genetic disorders resulting from defects in heme synthesis enzymes, leading to the accumulation of porphyrins or their precursors.
  • Symptoms vary but can include photosensitivity, abdominal pain, and neurological complications.
  • Examples include acute intermittent porphyria (AIP) and porphyria cutanea tarda (PCT).
• Anaemias:
  • Iron deficiency anaemia results from inadequate heme synthesis due to a lack of iron.
  • Sideroblastic anaemia involves defective incorporation of iron into heme, leading to iron accumulation in mitochondria.
• Lead Poisoning:
  • Lead inhibits ALAD and ferrochelatase, enzymes involved in heme synthesis, resulting in anaemia and neurological effects.

Summary

Heme is a crucial molecule involved in oxygen transport, electron transport, and detoxification processes. Its synthesis involves a series of enzymatic steps regulated at multiple levels to ensure proper function. Disorders in heme synthesis can lead to various clinical conditions, emphasizing the importance of understanding heme biochemistry and physiology.