Haem Synthesis
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Direct answer
Haem — the ferrous iron complex of protoporphyrin IX found in haemoglobin, myoglobin and cytochromes — is built in eight steps that begin and end in the mitochondrion, with the intermediate steps in the cytosol. The rate-limiting enzyme is delta-aminolaevulinic acid (ALA) synthase, which condenses glycine with succinyl-CoA and requires pyridoxal phosphate. Haem, the end product, feeds back to repress ALA synthase, and porphyrias result when individual enzymes of the pathway fail.
What you must remember
- ALA synthase (a hepatic ALAS1 and an erythroid ALAS2 form) is rate-limiting, requires vitamin B6 as pyridoxal phosphate, and is repressed by haem; erythroid synthesis is additionally geared to iron availability.
- Pathway map: ALA dehydratase (a zinc enzyme, cytosolic) joins two ALA molecules into porphobilinogen; hydroxymethylbilane synthase (porphobilinogen deaminase), uroporphyrinogen decarboxylase, coproporphyrinogen oxidase and protoporphyrinogen oxidase follow; ferrochelatase inserts ferrous iron into protoporphyrin IX in the mitochondrion.
- Only the type III isomer is physiologically useful; uroporphyrinogen III synthase deficiency causes congenital erythropoietic porphyria with severe photosensitivity.
- Acute intermittent porphyria (hydroxymethylbilane synthase deficiency) causes recurrent abdominal pain, neuropsychiatric features and tachycardia; urine darkens on standing, ALA and porphobilinogen are raised, and there is no photosensitivity.
- Porphyria cutanea tarda, from uroporphyrinogen decarboxylase deficiency, is the commonest porphyria — photosensitive bullous lesions on sun-exposed skin with tea-coloured urine, triggered by alcohol, oestrogens, iron excess and hepatitis C.
- Lead inhibits ALA dehydratase and ferrochelatase, producing abdominal colic, basophilic stippling and a sideroblastic anaemia with raised ALA and coproporphyrin.
- Haem degradation occurs in macrophages: haem oxygenase opens the ring to biliverdin, reduced to bilirubin, which travels on albumin to the liver for conjugation.
Common confusion
Acute (neurovisceral) and cutaneous porphyrias are frequently conflated. The acute hepatic porphyrias present with abdominal pain and neuropsychiatric episodes and are diagnosed by raised ALA and porphobilinogen; the erythropoietic and cutaneous porphyrias present with photosensitivity because photosensitising porphyrins accumulate. Variegate porphyria and hereditary coproporphyria can show both features, which examiners use as trick options.
Exam-focused takeaway
Theory answers should trace the pathway with its mitochondrial-cytosolic-mitochondrial location switches, the rate-limiting enzyme with its regulation, and the enzyme-defect map of porphyrias plus lead poisoning. In the viva, expect why pyridoxine deficiency causes sideroblastic anaemia and which porphyria is the commonest. MCQs match enzyme to disease — ALA synthase regulation, ALA dehydratase and lead, hydroxymethylbilane synthase and acute intermittent porphyria, uroporphyrinogen decarboxylase and porphyria cutanea tarda.
Frequently asked questions
Which enzyme is rate-limiting in haem synthesis and how is it regulated?
ALA synthase; it needs pyridoxal phosphate, is repressed by haem through feedback, and its erythroid form is induced when iron is available for haemoglobin production.
Why does urine darken in acute intermittent porphyria?
Excess porphobilinogen oxidises on exposure to light and air into reddish-brown pigments, colouring urine left standing.
Which is the commonest porphyria?
Porphyria cutanea tarda, due to uroporphyrinogen decarboxylase deficiency, presenting with photosensitive bullous eruptions.
How does lead poisoning affect haem synthesis?
Lead inhibits ALA dehydratase and ferrochelatase, blocking porphyrin synthesis and iron insertion, causing anaemia with basophilic stippling and raised ALA levels.
Where does haem degradation occur and what does it produce?
In reticuloendothelial macrophages, mainly of the spleen; haem oxygenase converts haem to biliverdin and carbon monoxide, and biliverdin is reduced to bilirubin for hepatic conjugation.