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Ferrochelatase – Function, Deficiency and EPP

Ferrochelatase is a mitochondrial enzyme that catalyzes the final step of heme biosynthesis. A genetic defect in this enzyme causes Erythropoietic Protoporphyria.

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Things worth knowing about "Ferrochelatase"

Ferrochelatase is a mitochondrial enzyme that catalyzes the final step of heme biosynthesis. A genetic defect in this enzyme causes Erythropoietic Protoporphyria.

What is Ferrochelatase?

Ferrochelatase (also known as protoheme ferro-lyase, EC 4.99.1.1) is a mitochondrial enzyme found in virtually all tissues of the human body. It catalyzes the final and decisive step of heme biosynthesis: the insertion of ferrous iron (Fe²⁺) into the porphyrin ring of protoporphyrin IX to form heme. Heme is an essential cofactor for numerous proteins, including hemoglobin, myoglobin, and various cytochromes.

Mechanism of Action

Ferrochelatase is anchored in the inner mitochondrial membrane and works in close cooperation with iron transport proteins. The reaction mechanism involves the following steps:

Binding of protoporphyrin IX to the active site of the enzyme
Uptake of ferrous iron (Fe²⁺) from the mitochondrial iron pool
Catalytic insertion of the Fe²⁺ ion into the porphyrin macrocycle with the release of two protons
Release of the completed heme molecule for use within the cell

The human ferrochelatase gene (FECH) is located on chromosome 18q21.3 and encodes a precursor protein that is processed after import into the mitochondria. The mature enzyme contains a [2Fe-2S] iron-sulfur cluster, which is essential for its catalytic activity and structural stability.

Biological Importance

Since heme is indispensable for a wide range of biological processes, ferrochelatase plays a central role in cellular metabolism:

Erythropoiesis: In red blood cells, heme is the oxygen-binding cofactor of hemoglobin. Adequate ferrochelatase activity is essential for the efficient production of red blood cells.
Respiratory chain: Heme is a component of the cytochrome complexes in the mitochondrial respiratory chain and is therefore necessary for cellular energy production.
Detoxification: Cytochrome P450 enzymes, which metabolize numerous foreign substances, are also heme-dependent.

Ferrochelatase Deficiency and Erythropoietic Protoporphyria

A genetically determined deficiency of ferrochelatase leads to Erythropoietic Protoporphyria (EPP), a rare metabolic disorder belonging to the group of porphyrias. It is inherited in an autosomal recessive manner and typically manifests in childhood.

Causes

EPP is caused by pathogenic variants in the FECH gene. In most cases, there is a combination of a severe mutation on one allele and a common hypomorphic polymorphism (IVS3-48C) on the other allele, which further reduces enzyme activity.

Symptoms

The hallmark symptom of EPP is severe photosensitivity of the skin. Even brief sun exposure can cause intense pain, burning, and redness. Additional symptoms include:

Swelling and itching of light-exposed skin
Chronic skin changes with repeated sun exposure
Elevated concentrations of free protoporphyrin IX in erythrocytes and plasma
In rare, severe cases: hepatic complications including cirrhosis due to protoporphyrin deposition in the liver

Diagnosis

Diagnosis is established through:

Measurement of free protoporphyrin in erythrocytes (markedly elevated in EPP)
Fluorescence spectroscopy of blood
Molecular genetic analysis of the FECH gene
Regular liver function monitoring to detect hepatic complications

Treatment

No curative therapy is currently available. Treatment focuses on symptom control and prevention of complications:

Photoprotection: Consistent avoidance of direct sunlight, wearing protective clothing
Afamelanotide (Scenesse): A melanocortin receptor agonist that stimulates melanin production and thereby increases light tolerance. Approved for the treatment of EPP in Europe.
Antioxidants such as beta-carotene may provide some relief in certain patients
Regular monitoring of liver function
In cases of severe liver involvement: liver transplantation as a last resort

Clinical Relevance and Research

Beyond EPP, ferrochelatase is also being studied in the context of other diseases. Reduced ferrochelatase activity has been described in certain forms of sideroblastic anemia. Furthermore, the enzyme is a potential target in cancer research, as heme synthesis pathways are frequently altered in tumor cells. The precise regulation of ferrochelatase and its interactions with cellular iron metabolism remain active areas of biomedical research.

References

Whatley SD, Ducamp S, Gouya L et al. - C-terminal deletions in the FECH gene in erythropoietic protoporphyria: Genotype-phenotype correlation and frequency. American Journal of Human Genetics, 2008.
Balwani M, Desnick RJ - The porphyrias: advances in diagnosis and treatment. Blood, 2012; 120(23): 4496-4504.
European Porphyria Network (EPNET) - Clinical guidelines for the diagnosis and management of erythropoietic protoporphyria. www.porphyria.eu, accessed 2024.

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