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[Biochemistry](https://durgical.com/en/biochemistry/) · Metabolic pathway

# Heme synthesis

Eight enzymes turn glycine and succinyl-CoA into heme, the iron ring of hemoglobin; when one of them fails, a porphyria appears.

Updated 2026-11-01

## Interactive map

**Balance:** CO₂ +14 nh3 +4

## Key facts

- It starts and ends in the mitochondrion: step 1 and steps 6–8 are mitochondrial; steps 2–5 take place in the cytosol.
- The rate-limiting step is ALA synthase, which needs pyridoxal phosphate (vitamin B6); heme represses the liver isoform (ALAS1).
- Each heme uses 8 glycines and 8 succinyl-CoA; 8 CO₂ leave at step 1, 4 NH₃ at step 3 and 6 more CO₂ at steps 5 and 6 (the balance is per heme).
- About 85 % of heme is made in bone marrow erythroid precursors and nearly all the rest in the liver (cytochromes P450).
- Lead inhibits ALA dehydratase and ferrochelatase: urine ALA rises, and so does zinc protoporphyrin in red cells.

**Also called**
Porphyrin biosynthesis

## Regulation

- Heme represses ALAS1 synthesis and blocks its import into the mitochondrion: end-product negative feedback.
- Drugs that induce cytochromes P450 (barbiturates, some anticonvulsants), fasting, alcohol and progesterone raise ALAS1 and trigger acute porphyria attacks.
- Glucose and intravenous heme lower ALAS1: that is why they are used in an acute attack.
- In the erythroblast iron is in charge: ALAS2 mRNA carries an iron-responsive element (IRE) and is translated only when iron is available.

## The steps, one by one

- **Step 1 · [ALA synthase (ALAS1 liver, ALAS2 erythroid)](https://durgical.com/en/biochemistry/enzymes/ala-synthase/)** irreversible Glycine + succinyl-CoA → [δ-Aminolevulinic acid](https://durgical.com/en/biochemistry/molecules/aminolevulinic-acid/) + coenzyme A + CO₂ In the mitochondrial matrix it joins glycine to succinyl-CoA and releases CO₂: the rate-limiting step. **If it fails:** ALAS2 loss of function: X-linked sideroblastic anemia. ALAS2 gain of function: X-linked protoporphyria. [Erythropoietic protoporphyria →](https://durgical.com/en/conditions/erythropoietic-protoporphyria/)
- **Step 2 · [ALA dehydratase (porphobilinogen synthase)](https://durgical.com/en/biochemistry/enzymes/ala-dehydratase/)** irreversible [δ-Aminolevulinic acid](https://durgical.com/en/biochemistry/molecules/aminolevulinic-acid/) → [Porphobilinogen](https://durgical.com/en/biochemistry/molecules/porphobilinogen/) + H₂O In the cytosol it condenses two ALA into one pyrrole ring, porphobilinogen. **If it fails:** Lead inhibits it: urine ALA rises while porphobilinogen stays normal. Its inherited deficiency (Doss porphyria) is a very rare acute porphyria. [Lead poisoning →](https://durgical.com/en/conditions/lead-poisoning/)
- **Step 3 · [Porphobilinogen deaminase (hydroxymethylbilane synthase)](https://durgical.com/en/biochemistry/enzymes/porphobilinogen-deaminase/)** irreversible [Porphobilinogen](https://durgical.com/en/biochemistry/molecules/porphobilinogen/) + H₂O → Hydroxymethylbilane + nh3 It links four porphobilinogens into a linear chain (hydroxymethylbilane) and releases four NH₃. **If it fails:** With half the activity (HMBS gene) ALA and porphobilinogen build up: acute intermittent porphyria. [Acute intermittent porphyria →](https://durgical.com/en/conditions/acute-intermittent-porphyria/)
- **Step 4 · Uroporphyrinogen III synthase** irreversible Hydroxymethylbilane → Uroporphyrinogen III + H₂O It closes the chain into a ring and flips the last pyrrole: this makes the III isomer, the only useful one. **If it fails:** Without this enzyme hydroxymethylbilane closes on its own as the I isomer: congenital erythropoietic porphyria (Günther), with mutilating photosensitivity and red urine from birth.
- **Step 5 · [Uroporphyrinogen decarboxylase](https://durgical.com/en/biochemistry/enzymes/uroporphyrinogen-decarboxylase/)** irreversible Uroporphyrinogen III → Coproporphyrinogen III + CO₂ It removes four carboxyls (acetates become methyls), leaving coproporphyrinogen III, which goes back into the mitochondrion. **If it fails:** Its liver activity falls below about 25 %: porphyria cutanea tarda, the most common porphyria. [Porphyria cutanea tarda →](https://durgical.com/en/conditions/porphyria-cutanea-tarda/)
- **Step 6 · Coproporphyrinogen oxidase** irreversible Coproporphyrinogen III + o2 → Protoporphyrinogen IX + CO₂ In the intermembrane space it turns two propionates into vinyl groups and releases two CO₂. **If it fails:** Its deficiency causes hereditary coproporphyria: acute attacks and sometimes skin blisters.
- **Step 7 · Protoporphyrinogen oxidase** irreversible Protoporphyrinogen IX + o2 → [Protoporphyrin IX](https://durgical.com/en/biochemistry/molecules/protoporphyrin-ix/) It oxidises the ring (removing six electrons), giving protoporphyrin IX, coloured and fluorescent. **If it fails:** Its deficiency causes variegate porphyria: acute attacks plus skin lesions; common among Afrikaners in South Africa.
- **Step 8 · [Ferrochelatase](https://durgical.com/en/biochemistry/enzymes/ferrochelatase/)** irreversible [Protoporphyrin IX](https://durgical.com/en/biochemistry/molecules/protoporphyrin-ix/) + Ferrous iron (Fe²⁺) → [Heme](https://durgical.com/en/biochemistry/molecules/heme/) + h On the inner side of the mitochondrial inner membrane it puts Fe²⁺ into the centre of protoporphyrin: heme is born. **If it fails:** Its deficiency piles up free protoporphyrin in red cells, skin and liver: erythropoietic protoporphyria, with burning pain in sunlight. [Erythropoietic protoporphyria →](https://durgical.com/en/conditions/erythropoietic-protoporphyria/)

## Clinical notes

- Acute porphyrias (failure of steps 2, 3, 6 and 7): ALA and porphobilinogen build up and are neurotoxic; they cause abdominal pain, neuropathy and psychiatric symptoms without skin lesions (except coproporphyria and variegate porphyria).
- Cutaneous porphyrias (steps 4, 5 and 8): porphyrins that absorb light build up and damage sun-exposed skin.
- Vitamin B6 deficiency (for example with isoniazid) or an ALAS2 mutation causes sideroblastic anemia: iron trapped in erythroblast mitochondria (ring sideroblasts).
- In iron deficiency, ferrochelatase inserts zinc instead: high zinc protoporphyrin points to iron deficiency or lead.

## Related conditions

- [Acute intermittent porphyria](https://durgical.com/en/conditions/acute-intermittent-porphyria/)
- [Porphyria cutanea tarda](https://durgical.com/en/conditions/porphyria-cutanea-tarda/)
- [Erythropoietic protoporphyria](https://durgical.com/en/conditions/erythropoietic-protoporphyria/)
- [Lead poisoning](https://durgical.com/en/conditions/lead-poisoning/)
- [Iron deficiency anaemia](https://durgical.com/en/conditions/iron-deficiency-anaemia/)

## Related

- [ALA synthase](https://durgical.com/en/biochemistry/enzymes/ala-synthase/)
- [ALA dehydratase](https://durgical.com/en/biochemistry/enzymes/ala-dehydratase/)
- [Porphobilinogen deaminase](https://durgical.com/en/biochemistry/enzymes/porphobilinogen-deaminase/)
- [Uroporphyrinogen decarboxylase](https://durgical.com/en/biochemistry/enzymes/uroporphyrinogen-decarboxylase/)
- [Ferrochelatase](https://durgical.com/en/biochemistry/enzymes/ferrochelatase/)
- [δ-Aminolevulinic acid (ALA)](https://durgical.com/en/biochemistry/molecules/aminolevulinic-acid/)
- [Porphobilinogen](https://durgical.com/en/biochemistry/molecules/porphobilinogen/)
- [Protoporphyrin IX](https://durgical.com/en/biochemistry/molecules/protoporphyrin-ix/)
- [Heme](https://durgical.com/en/biochemistry/molecules/heme/)
- [Hemoglobin and 2,3-BPG](https://durgical.com/en/biochemistry/enzymes/hemoglobin-and-2-3-bpg/)
- [Heme breakdown and bilirubin](https://durgical.com/en/biochemistry/pathways/heme-breakdown-and-bilirubin/)
- [Iron metabolism](https://durgical.com/en/biochemistry/topics/iron-metabolism/)
- [Krebs cycle (citric acid cycle)](https://durgical.com/en/biochemistry/pathways/krebs-cycle/)

## Test yourself

Think of the answer, then tap the question to see it.

## What is the rate-limiting step of heme synthesis, and which vitamin does it need?

ALA synthase, in the mitochondrion; it uses pyridoxal phosphate (vitamin B6).

## Which two enzymes of the pathway does lead inhibit?

ALA dehydratase (ALA rises) and ferrochelatase (zinc protoporphyrin rises).

## Why do glucose and heme help in an acute porphyria attack?

Both repress ALAS1, so less ALA and porphobilinogen are made.

## Which steps of heme synthesis take place in the cytosol?

Steps 2 to 5: ALA dehydratase, PBG deaminase, uroporphyrinogen III synthase and uroporphyrinogen decarboxylase.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: [Reactome | Heme biosynthesis](https://reactome.org/PathwayBrowser/#/R-HSA-189451) (Reactome, 2026); [Porphyria: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/porphyria/) (MedlinePlus, US National Library of Medicine, 2026); [ALAS2 gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/alas2/) (MedlinePlus, US National Library of Medicine, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).

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Representative model, for educational purposes only.

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