Ferrochelatase (mitochondrial) (FECH) (FECH)

Ferrochelatase (mitochondrial) (FECH) is the terminal enzyme of the heme biosynthetic pathway, located on the matrix-facing side of the inner mitochondrial membrane [1]. It catalyzes the chelation of ferrous iron into the protoporphyrin IX (PPIX) ring to produce heme, a critical component of hemoglobin, myoglobin, and cytochromes [1, 4]. A deficiency in ferrochelatase activity, typically due to autosomal dominant mutations, results in Erythropoietic Protoporphyria (EPP), where the accumulation of the substrate PPIX leads to severe cutaneous photosensitivity and potential hepatobiliary disease [2]. In the field of oncology, the ferrochelatase-PPIX axis is leveraged for photodynamic therapy (PDT); the administration of 5-aminolevulinic acid (5-ALA) leads to the selective accumulation of PPIX in tumor cells, which acts as a potent photosensitizer for light-induced cell death [4]. Furthermore, ferrochelatase is highly sensitive to inhibition by heavy metals such as lead, which interferes with the final step of heme synthesis and contributes to the development of microcytic anemia [3]. Monitoring erythrocyte protoporphyrin levels is a standard clinical practice for diagnosing both EPP and lead poisoning [2, 3]. Therapeutic strategies for EPP focus on reducing PPIX production or protecting the skin from light, while PDT research explores ways to modulate FECH activity to enhance PPIX accumulation in tumors [2, 4].

Other names

Heme synthaseProtoheme ferro-lyaseProtoporphyrin ferrochelataseFECH

Ferrochelatase is targeted primarily through inhibition, which prevents the conversion of protoporphyrin IX to heme, or through substrate loading to induce the accumulation of protoporphyrin IX for photodynamic therapy.