Block 9

• The basic structure of porphyrins is the pyrrole
• Heme is the major porphyrin in humans
• 70% of heme is made in the bone marrow and goes into hemoglobin
• 15% of heme is made for liver cytochrome p450 enzymes
• Hemoproteins

  Myoglobin

  Hemoglobin

  Cytochromes of the ER (P450, b5)

  Cytochromes of the mitochondria (P450, a, a3, b, c1, c)

  Catalase
• The key regulatory step in heme synthesis is the condensation of succinyl CoA with glycine which is catalyzed by ALA synthase
• ALA synthase requires PLP (pyridoxal phosphate) derived from Vitamin B6
• Hemin and heme repress and allosterically inhibit ALA synthase
• For porphyrin synthesis, succinyl CoA can be produced via anaplerotic reactions.
• For each molecule of heme synthesized, 8 molecules of succinyl CoA are required
• ALA dehydrogenase converts ALA to porphobilinogen
• Lead is an inhibitor of ALA dehydrase because it replaces zinc and is inactive
• Zinc deficiency will also impair ALA dehydrase
• Porphobilinogen is converted to Hydroxymethylbilane or Polypyrryl Methane by Porphobilinogen deaminase
• Porphobilinogen deaminase produces ammonia
• Hydroxymethylbilane is converted to Uroporphyrinogen III by Uroporphyrinogen III synthase
• Uroporphyrinogen III is converted to Coproporphyrinogen III by Uroporphyrinogen decarboxylase
• Coproporphyrinogen III is converted to Protoporphyrin IX
• Protoporphyrin IX is converted to Heme by Ferrochelatase which inserts a ferrous iron molecule
• ALA is synthesized in the mitochondria before being transported to the cytoplasm
• Coroporphyrinogen III is transported back into the mitochondrion for completion of heme synthesis
• Lead exposure often occurs via pipes and paints
• Lead poisoning in children may manifest as anemia and encephalopathic crisis
• Lead poisoning in adults may manifest as fatigue, abdominal pain and/or arthralgia
• Lead inactivates ferrochelatase indirectly by resulting in the formation of zinc protoporphyrin
• Lead poisoning leads to microcytic anemia and basophilic stippling
• Acute intermittent porphyria is caused by partial deficiency of porphobilinogen deaminase
• In AIP, ALA and porphobilinogen accumulate and have neurotoxic effects
• 5 Ps of AIP

  Painful abdomen

  Port wine-colored urine

  Polyneuropathy

  Psychological disturbances

  Precipitated by drugs
• Drugs worsen AIP because heme is required for cytochrome P450 enzyme function
• Treatment for AIP

  Withdraw offending drugs, Administer hematin, carbohydrate-rich diet
• Congenital erythropoietic porphyria is caused by a genetic defect in uroporphyrinogen III synthase that allows for the spontaneous formation of uroporphyrinogen I
• In CEP, uroporphyrinogen I and its metabolites accumulate and create free radicals when they react with light
• Congenital Erythropoietic Porphyria

  Hypersensitivity to sunlight

  Hemolytic anemia and spleen enlargement

  Red wine-colored urine
• With porphyria cutanea tarda there is a deficiency of uroporphyrinogen decarboxylase which causes an accumulation of uroporphyrinogen III
• The two most common forms of porphyria cutanea tarda are familial (20%) and sporadic (80%)
• Porphyria cutanea tarda is the most common subtype of porphyrias
• Porphyria cutanea tarda can be aggravated by alcohol and is associated with hepatitis C and hypersensitivity to sunlight
• Heme is catabolized by reticuloendothelial cells of the spleen, liver and bone marrow
• During catabolism, heme is first converted to biliverdin