Heme Biosynthesis (Porphyrin Pathway)

1. 1

   Glycine + succinyl-CoA → δ-aminolevulinate (ALA) + CO₂ + CoA

   Mitochondrial ALA synthase (ALAS) 2.3.1.37 ST-0177 Irreversible/directional rate-limiting PLP (B6)
   In Glycine Succinyl-CoA

   Out delta--aminolevulinate (ALA) CO2 CoA-SH
   › Notes

   Mitochondrial ALA synthase (ALAS) requires PLP (vitamin B6). ALAS1 is the rate-limiting and committed step in nonerythroid cells and is feedback-inhibited at transcriptional, translational, and mitochondrial-import levels by heme/hemin; erythroid ALAS2 is rate-limited by iron-dependent translation through an iron-responsive element.

2. 2

   2 ALA → porphobilinogen (PBG) + 2 H₂O

   ALA dehydratase (ALAD; porphobilinogen synthase) 4.2.1.24 ST-0178 Irreversible H2O
   In delta-Aminolevulinate (ALA)

   Out Porphobilinogen (PBG) H2O
   › Notes

   Cytosolic ALA dehydratase (porphobilinogen synthase) condenses two ALA molecules and requires catalytic zinc and sulfhydryl integrity. This is an essentially irreversible condensation; lead inhibits the enzyme by disrupting zinc/sulfhydryl-dependent function.

3. 3

   4 porphobilinogen → hydroxymethylbilane + 4 NH₃

   Porphobilinogen deaminase (HMBS) 2.5.1.61 ST-0179 Irreversible/directional Dipyrromethane
   In Porphobilinogen

   Out Hydroxymethylbilane NH3
   › Notes

   Porphobilinogen deaminase, also called hydroxymethylbilane synthase (HMBS), polymerizes four PBG units using a dipyrromethane cofactor covalently attached to the enzyme. The linear tetrapyrrole product is unstable and is normally consumed immediately.

4. 4

   Hydroxymethylbilane → uroporphyrinogen III

   Uroporphyrinogen III synthase (UROS) 4.2.1.75 ST-0180 Irreversible/directional
   In Hydroxymethylbilane

   Out Uroporphyrinogen III
   › Notes

   Uroporphyrinogen III synthase (UROS) cyclizes and inverts ring D to form the asymmetric type III isomer. Without UROS, hydroxymethylbilane can spontaneously cyclize to uroporphyrinogen I, which cannot proceed efficiently to heme.

5. 5

   Uroporphyrinogen III → coproporphyrinogen III + 4 CO₂

   Cytosolic uroporphyrinogen decarboxylase (UROD) 4.1.1.37 ST-0181 Irreversible
   In Uroporphyrinogen III

   Out Coproporphyrinogen III CO2
   › Notes

   Cytosolic uroporphyrinogen decarboxylase (UROD) decarboxylates the four acetate side chains to methyl groups. No ATP or redox cofactor is required; this is an essentially irreversible decarboxylation.

6. 6

   Coproporphyrinogen III + O₂ → protoporphyrinogen IX + 2 CO₂

   Coproporphyrinogen oxidase (CPOX) 1.3.3.3 ST-0182 Irreversible/directional O2
   In Coproporphyrinogen III O2

   Out Protoporphyrinogen IX CO2
   › Notes

   Mitochondrial intermembrane-space-facing coproporphyrinogen oxidase (CPOX) oxidatively decarboxylates two propionate side chains to vinyl groups. Molecular oxygen is required, and the product re-enters the mitochondrial compartment for final steps.

7. 7

   Protoporphyrinogen IX + 3 O₂ → protoporphyrin IX + 3 H₂O₂ (net oxidation)

   Protoporphyrinogen oxidase (PPOX) 1.3.3.4 ST-0183 Irreversible FAD O2
   In Protoporphyrinogen IX O2

   Out Protoporphyrin IX H2O2
   › Notes

   Protoporphyrinogen oxidase (PPOX), a FAD-dependent enzyme associated with the inner mitochondrial membrane, oxidizes the reduced porphyrinogen to the conjugated porphyrin. Molecular oxygen is the terminal electron acceptor; this step is essentially irreversible.

8. 8

   Protoporphyrin IX + Fe²⁺ → heme (protoheme IX) + 2 H⁺

   Ferrochelatase (FECH) 4.99.1.1 ST-0184 Irreversible Fe2+ Heme/cytochrome
   In Protoporphyrin IX Fe2+

   Out Heme (protoheme IX) H+
   › Notes

   Ferrochelatase (FECH) inserts ferrous iron into protoporphyrin IX on the matrix side of the inner mitochondrial membrane. This final step requires bioavailable Fe²⁺ and is effectively irreversible; lead also inhibits ferrochelatase.

Showing all 8 steps.

Overview

Heme biosynthesis forms protoporphyrin IX and inserts ferrous iron to generate heme, an essential prosthetic group for hemoglobin, myoglobin, cytochromes, catalases, peroxidases, nitric-oxide synthases, and tryptophan pyrrolase. The pathway begins with glycine and succinyl-CoA and alternates between mitochondrial and cytosolic compartments. Erythroid precursors generate large amounts for hemoglobin, whereas hepatocytes require heme for cytochrome P450 and other hemoproteins.

Cellular location

Step 1 and the final three enzymatic steps occur in the mitochondria; steps 2–5 occur in the cytosol. The pathway is especially active in bone-marrow erythroid cells and liver. The erythroid-specific ALAS2 isoform is controlled by iron availability, whereas ubiquitous hepatic ALAS1 is responsive to the heme pool and to xenobiotic induction of CYP enzymes.

Net energetics

Formation of one heme consumes 8 glycine and 8 succinyl-CoA through eight ALA molecules and incorporates 1 Fe²⁺. The pathway does not directly consume ATP in its eight core enzymatic steps, although succinyl-CoA production and mitochondrial iron delivery require cellular energy; ALAS consumes PLP but not ATP. Oxidative steps require molecular oxygen, and heme synthesis incurs an indirect carbon/energy cost because eight succinyl-CoA-derived carbons are lost as CO₂ during ALA formation.

Clinical significance

Heme is indispensable for oxygen transport and electron transfer, but porphyrin intermediates are photoreactive or neurotoxic when they accumulate. Acute intermittent porphyria results from HMBS deficiency and typically causes neurovisceral attacks without photosensitivity; porphyria cutanea tarda results from UROD deficiency and causes photosensitive blistering. Lead poisoning inhibits ALA dehydratase and ferrochelatase, increases ALA and zinc protoporphyrin, and can cause microcytic/sideroblastic anemia and neurologic or gastrointestinal manifestations.