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Summary Haem Biosynthesis, Catabolism

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Haem Biosynthesis, Catabolism

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Friday, February 26, 2016

Haem Biosynthesis, Catabolism and Iron Metabolism

Haem
- Structure: porphyrin ring - made up of pyrrole rings that come together
• Tightly bound prosthetic group
• Complex of protoporphyrin IX and ferrous iron
- Iron held in center of haem molecule by binds to four N of porphyrin ring
- Fe2+ can also form two other bonds - one on each side of planar porphyrin ring
• One coordinated to side chain of globin histidine, one available for oxygen
• Multiple methyne bridges
• At eight points, may be bound to: acetyl, methyl, propenyl, vinyl (side chains)
• Also in chlorophyll - binds to magnesium
- Found in:
• RBCs - Bind to haemoglobin
• Cytochrome C - ETC
• Catalase
- Synthesized in
• 75-85% in bone marrow
• ~15% in liver
• Both in cytoplasm and in mitochondria - RBCs cannot b/c no mitochondria

Haem Synthesis
- Glycine + Succinyl CoA —Aminolevulivic acid synthase ALAS) + pyridoxal
phosphate (Vitamin B6 - cleans e- sink)—> aminolevulinic acid

• Rate limiting step - in mitochondria
• ALAS can have end-product inhibition


1

, Friday, February 26, 2016
- ALAS-1 in liver - haem synthesis is variable - mediated by amount of haem
present - end-product inhibition
- ALAS-1 also affected by certain drugs that activate cytochrome P450 (haem
used up here, cannot inhibit ALAS-1

• ALAS-2 present in bone marrow - not inhibited by haem
- Affected by rate of synthesis of globin - production of both are linked —> allows
production of hemoglobin
- B6 deficiency - lower haem productions, free iron present
• Small, pale RBCs - hypochromic, microcytic
- 2 aminolevulinic acid—aminolevulinic acid dehydrogenase/porphobilinogen
synthase (zinc & sulphur-hydrate group containing enzyme - inhibited by lead)—>
porphobilinogen

• Lead poisoning - less haem production - anemia, weakness
• Cytosol
- Eventually, structure cylclicises and forms the porphyrin ring - mitochondria
- Final step, ferrochelatase adds iron to complete the harm structure - mitochondria
- Problems with haem synthesis: porphyria - photosensitivity

Haem Catabolism
- 100-200 million RBCs broken down in a day, 70kg person ~6g haem turnover
- Porphyrin ring has to be broken down and expelled, otherwise toxic
• Spleen, liver, bone marrow
• Haem —Haem oxygenase—> biliverdin —Biliverdin reductase—>bilirubin
- Haem oxygenase makes haem linear by breaking it down into biliverdin by
breaking the first methyne bridge

• Iron put back into iron pool
• Globin recycled
- Biliverdin reductase makes insoluble bilirubin

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