Haem Synthesis and the Porphyrias

Key points

• • Haem synthesis begins in mitochondria, where glycine and succinyl-CoA combine to form delta-aminolaevulinic acid; ALA synthase (aminolaevulinate synthase) is the rate-limiting enzyme.
• • The pathway then shuttles between mitochondria and cytoplasm and finishes when ferrochelatase inserts iron into protoporphyrin IX.
• • The porphyrias are disorders of haem synthesis, mostly inherited but sometimes acquired, in which the intermediates formed before the blocked step accumulate.
• • Acute intermittent porphyria blocks porphobilinogen deaminase (also called hydroxymethylbilane synthase) and causes attacks of abdominal pain and neurological signs, with urine that darkens on standing and no skin rash.
• • Some porphyrias cause photosensitive skin blistering, as in the commonly acquired porphyria cutanea tarda, because porphyrins in the skin absorb light; others are predominantly neurovisceral, so the picture varies by type.
• • Lead poisoning mimics porphyria by inhibiting ALA dehydratase and ferrochelatase, raising ALA and giving similar features.