Hemoglobin Synthesis and Catabolism: Comprehensive Notes

Hemoglobin Structure

• Hemoglobin (Hb) is a large protein composed of two major components: heme (3%) and globin proteins.

• Heme contains an iron pigment.

• Heme is an iron ($Fe^{2+}$ ferrous form) protoporphyrin IX complex.

• Globin is made up of four polypeptide chains.

• In normal adult hemoglobin (HbA), globin consists of two alpha ($extbf{\alpha}$) chains (141 amino acids) and two beta ($extbf{\beta}$) chains (146 amino acids).

• Four units of heme attach to one unit of globin.

Heme Synthesis

• Site: Occurs in most body cells, but most abundantly in erythroid precursors (immature red blood cells), primarily in the mitochondria and cytosol.

• First Step: Formation of Porphobilinogen (PBG) from Succinyl-CoA and Glycine.

  • Heme synthesis begins with the condensation of glycine and succinyl-CoA to form $\delta$-aminolevulinic acid (ALA).

  • $\delta$-Aminolevulinate Synthase (ALA Synthase) catalyzes this committed step of the heme synthesis pathway.

    • It is usually the rate-limiting enzyme for the overall pathway.

    • Heme functions as a feedback inhibitor.

  • PBG Synthase (Porphobilinogen Synthase), also known as ALA Dehydratase, catalyzes the condensation of two molecules of $extbf{\delta}$-aminolevulinic acid (ALA) to form porphobilinogen (PBG).

• Second Step: Formation of Heme from the Protoporphyrin Ring + Iron.

  • The protoporphyrin ring is formed by the condensation of four molecules of porphobilinogen.

  • Iron is inserted into protoporphyrin by the enzyme ferrochelatase to form heme.

• Enzyme Deficiencies and Associated Diseases in Heme Synthesis Pathway:

  • ALA Synthase deficiency: Can lead to Sideroblastic anemia.

  • PBG Synthase (ALA Dehydratase) or Ferrochelatase inhibition by lead: Leads to Lead poisoning.

  • Ferrochelatase deficiency: Causes Erythropoietic Protoporphyria.

  • Hydroxymethylbilane synthase (or Porphobilinogen deaminase or Uroporphyrinogen I synthase) deficiency: Causes Acute Intermittent Porphyria.

  • Uroporphyrinogen decarboxylase deficiency: Causes Porphyria Cutanea Tarda (PCT).

Porphyrias

• Definition: Rare, inherited (or sometimes acquired) defects in heme synthesis, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors.

• Classification:

  • Erythropoietic: Enzyme deficiency occurs in erythropoietic cells of the bone marrow.

  • Hepatic: Enzyme deficiency occurs in the liver.

• Clinical Manifestations - General Patterns:

  • Enzyme defects prior to tetrapyrrole synthesis typically manifest with abdominal and neuropsychiatric signs.

  • Enzyme defects leading to the accumulation of tetrapyrrole intermediates often cause photosensitivity (skin itching and burning when exposed to sunlight).

• Specific Porphyrias:

  • $\delta$-ALA Dehydratase Porphyria ($extbf{\delta}$-aminolevulinic acid dehydratase deficiency):

    • Accumulation of porphyrin precursor $\delta$-aminolevulinic acid (ALA).

  • Acute Intermittent Porphyria (AIP) (Uroporphyrinogen I synthase or porphobilinogen deaminase deficiency):

    • Accumulation of porphobilinogen and $\delta$-aminolevulinic acid (ALA) in the urine.

    • Patients are NOT photosensitive.

    • Symptoms: Acute abdominal pain, dark red