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 +14nh3 +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) irreversible Glycine + succinyl-CoA → δ-Aminolevulinic acid + coenzyme A + CO₂In 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 →
- Step 2 · ALA dehydratase (porphobilinogen synthase) irreversible δ-Aminolevulinic acid → Porphobilinogen + H₂OIn 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 →
- Step 3 · Porphobilinogen deaminase (hydroxymethylbilane synthase) irreversible Porphobilinogen + H₂O → Hydroxymethylbilane + nh3It 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 →
- Step 4 · Uroporphyrinogen III synthase irreversible Hydroxymethylbilane → Uroporphyrinogen III + H₂OIt 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 irreversible Uroporphyrinogen III → Coproporphyrinogen III + CO₂It 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 →
- Step 6 · Coproporphyrinogen oxidase irreversible Coproporphyrinogen III + o2 → Protoporphyrinogen IX + CO₂In 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 IXIt 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 irreversible Protoporphyrin IX + Ferrous iron (Fe²⁺) → Heme + hOn 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 →
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
- Porphyria cutanea tarda
- Erythropoietic protoporphyria
- Lead poisoning
- Iron deficiency anaemia
Related
- ALA synthase
- ALA dehydratase
- Porphobilinogen deaminase
- Uroporphyrinogen decarboxylase
- Ferrochelatase
- δ-Aminolevulinic acid (ALA)
- Porphobilinogen
- Protoporphyrin IX
- Heme
- Hemoglobin and 2,3-BPG
- Heme breakdown and bilirubin
- Iron metabolism
- Krebs cycle (citric acid 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.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Reactome | Heme biosynthesis (Reactome, 2026); Porphyria: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); ALAS2 gene: MedlinePlus Genetics (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.