MBBCh BMS 202: Hemoglobin Structure

Learning Outcomes

• Understand the structure of heme.
• Identify the primary locations of heme biosynthesis.
• Describe the heme synthetic pathway and its regulation.
• Recognize porphyrias as enzymatic defects affecting heme synthesis.

Red Blood Cells (RBCs)

• Shape: Biconcave discs, enhancing surface area for gas exchange.
• Diameter: Approximately 7 microns.
• Life span: 120 days in peripheral circulation.
• Synthesized in the bone marrow.
• Mature RBCs lack a nucleus and mitochondria and mainly function to transport oxygen (O2) and carbon dioxide (CO2) via hemoglobin.

Hemoglobin

• A respiratory pigment made of heme and globin, synthesized in immature RBCs.
• Normal hemoglobin concentration:
  • Adult males: 13.5 – 16.5 gm/dl.
  • Adult females: 12.0 – 14.8 gm/dl.
• Types of hemoglobin:
  • Normal: HbA (97%), HbA2 (2%), HbF (1%), HbA1c (glycosylated).
  • Abnormal: Carboxyhemoglobin, Methemoglobin, Sulfhemoglobin.

Structure of Hemoglobin

• Composed of 4 heme groups and 4 globin chains (2 alpha and 2 beta).
• Alpha chain: 141 amino acids; Beta chain: 146 amino acids.

Structure of Heme

• Heme is an iron porphyrin, a cyclic compound formed by four linked pyrrole rings.
• Iron complexes with nitrogen atoms in the porphyrin structure.

Importance of Heme

• Essential component of various hemoproteins:
  • Hemoglobin
  • Myoglobin
  • Cytochromes (C & P450)
  • Catalase
  • Peroxidase

Sites of Heme Synthesis

• Predominantly occurs in:
  • Bone marrow for hemoglobin synthesis.
  • Liver for cytochrome P450 synthesis.
• Cellular locations:
  • Mitochondria (first and last reactions).
  • Cytosol (intermediate steps).

Pathway of Heme Synthesis

• Synthesis begins in mitochondria with the production of delta-aminolevulinic acid (ALA).
• Transition to cytosol includes steps like the synthesis of porphobilinogen, uroporphyrinogen III, and coproporphyrinogen III.
• Final reactions return to mitochondria for the production of heme.

Key Steps in Heme Synthesis

• First step: Synthesis of ALA from succinyl CoA and glycine, catalyzed by ALA synthase (key regulatory step).
• Last step: Formation of heme by combining iron with protoporphyrin IX, catalyzed by ferrochelatase.

Lead Poisoning and Heme Synthesis

• Lead poisoning inhibits ALA dehydratase and ferrochelatase, leading to the accumulation of porphyrins and ALA in blood and urine.

Regulation of Heme Synthesis

• The regulatory step is controlled by heme and other factors such as glucose and steroids.
• ALA synthase activity is inhibited by hemin and stimulated by iron availability, hypoxia, and erythropoietin.

Disorders of Heme Synthesis (Porphyrias)

• Characterized by increased blood porphyrins and urinary excretion.
• Caused by enzyme deficiencies in the heme synthesis pathway.
• Manifestations include dark urine, photosensitivity, skin rash, neuropathy, hypertension, and abdominal pain.
• Classification:
  • Inherited and acquired (e.g., lead poisoning, alcoholic liver disease).

Diagnosis of Porphyrias

• Measurements of porphobilinogen (PBG) in urine and heme synthesis intermediates in various biological samples.

Case Discussion on Lead Poisoning

• Symptoms include abdominal pain, mental status changes, and fatigue.
• Lead interferes primarily with ALA dehydratase enzyme.

Take Home Messages

• Heme biosynthesis predominantly occurs in bone marrow and liver.
• Glycine and succinyl CoA are starting materials for porphyrin synthesis.
• ALA synthesis, catalyzed by ALA synthase, is the committed step.
• Porphyrias result from defects in the heme synthesis pathway, leading to porphyrin accumulation.

Explore the intricate details of hemoglobin structure and the synthesis of heme in this MBBCh BMS 202 module. Understand key concepts and outcomes associated with the locomotor system and integument module. Prepare to deepen your knowledge in medical biochemistry under the guidance of Dr. Ghada Helal.