Bio lec 1

• Porphyrins


  Cyclic compounds formed by the linkage of four pyrrole rings through methenyl bridges (-CH=)
• Porphyrins


  • They are able to complex with metal ions through the nitrogen atom of the pyrrole rings to form metalloporphyrins
  • Porphyrins are metabolically active only as metalloporphyrins
• Biosynthesis of porphyrins


  1. Stage I: Synthesis of δ-Amino Laevulinic acid (δ-ALA), which occurs in mitochondria

  2. Stage II: Synthesis of coproporphyrinogen III (major series) and coproporphyrinogen I (minor series) which occurs in cytosol

  3. Stage III: Synthesis of protoporphyrin IX, which occurs in mitochondria again
• δ-Amino Laevulinic acid (δ-ALA)

  The product of the first stage of heme synthesis which occurs in mitochondria
• ALA synthase


  The enzyme that catalyses the first reaction in heme synthesis
• Substrates for the first reaction in heme synthesis

  Succinyl COA and Glycine
• Porphobilinogen


  The product of the condensation of two molecules of ALA
• ALA dehydratase (porphobilinogen synthase)


  The enzyme that catalyses the formation of porphobilinogen
• Ferrochelatase (haem synthetase)


  The enzyme that catalyses the insertion of an atom of Fe++ into the central position of protoporphyrin
• Hemeproteins

  • Hemoglobin
  • Myoglobin
  • Cytochrome C
  • Cytochrome P450
  • Catalase
  • Tryptophan pyrrolase
• ALA synthase


  The key regulatory enzyme of heme biosynthesis
• ALAS1


  The ALA synthase isoform found in all tissues (hepatic)
• ALAS2


  The ALA synthase isoform found in erythroid cells of bone marrow
• Heme


  Acts as a negative regulator of ALAS1 by repressing synthesis of the enzyme and directly inhibiting the existing enzyme
• Drugs (barbiturates, griseofulvin)


  Decrease intracellular heme concentration, derepressing (inducing) ALAS1, leading to increased heme synthesis
• Hemin


  The oxidised form of heme, with Fe3+ instead of Fe2+
• Hemin


  • Decreases the amount and activity of ALAS1 by repressing transcription of its gene, increasing degradation of its mRNA, and decreasing import of the enzyme into mitochondria
• Porphyrins


  • They are soluble if they have polar side chains
  • They absorb light maximally at 400 nm and in the visible region
  • They show fluorescence in organic solvents when exposed to UV light
  • They are colored compounds
• Porphyrins reacting with molecular oxygen at 400 nm


  Form oxygen radicals that injure lysosomes and other organelles, releasing degradative enzymes
• Photochemotherapy


  A combination therapy involving the use of a light-sensitive porphyrin-containing drug and laser light, which destroys tumour cells
• Porphyrias


  Diseases of heme biosynthesis characterized by increased excretion of porphyrins or porphyrin precursors in urine and feces, and accumulation in plasma and tissues
• Types of porphyrias


  • Erythropoietic porphyrias
  • Hepatic porphyrias
• Lead poisoning


  Causes inhibition of ferrochelatase and ALA dehydratase, displacing Zn2+ at the enzyme active sites
• Effects of lead poisoning


  • In children: developmental defects, drop in IQ, hyperactivity, insomnia, many other health problems
  • In adults: severe abdominal pain, mental confusion, many other symptoms
• Treatment of porphyrias

  1. Symptomatic

  2. Avoid drugs that induce cytochrome P450

  3. Glucose loading and hematin administration (both inhibit ALA synthase enzyme)

  4. β carotene (decreases photosensitivity)

  5. Sunscreens that filter out visible light