# Haem Synthesis

> Haem synthesis notes for MBBS Biochemistry — enzymes, regulation, porphyrias and lead poisoning effects explained for exam revision.

- Canonical URL: https://prepelephant.com/topics/mbbs/biochemistry/haem-synthesis
- Exam / course: MBBS · Subject: Biochemistry
- Publisher: PrepElephant (https://prepelephant.com) — Prepared and reviewed by the PrepElephant Academic Review Team
- First published: 2026-10-02
- Last updated: 2026-10-02
- How to cite: "Haem Synthesis", PrepElephant, https://prepelephant.com/topics/mbbs/biochemistry/haem-synthesis

## 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.