FECH is ferrochelatase (protoheme ferro-lyase; EC 4.98.1.1), the enzyme that catalyses the eighth and final, committed step of heme biosynthesis: the insertion of ferrous iron (Fe2+) into protoporphyrin IX to form protoheme (heme b). The mature protein is a homodimer bound to the matrix face of the mitochondrial inner membrane as a peripheral membrane protein, and each subunit carries a [2Fe-2S] cluster (coordinated by three C-terminal cysteines plus one additional ligand) that is required for enzyme activity and stability and may act as a nitric-oxide sensor. Iron for the reaction is delivered at the matrix-side active site, with frataxin implicated as an iron donor, and FECH associates with a mitochondrial heme-biosynthesis metabolon that includes the ABC transporters ABCB7 and ABCB10, mitoferrin-1 (SLC25A37) and the upstream enzyme protoporphyrinogen oxidase, coupling iron import to heme production. Loss-of-function variants cause erythropoietic protoporphyria (EPP1), in which protoporphyrin IX accumulates in erythrocytes, plasma and liver and produces painful cutaneous photosensitivity.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004325 protoporphyrin ferrochelatase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assignment of ferrochelatase activity, the core molecular function of FECH. This is the correct enzymatic activity for the family and is strongly supported by direct enzymology and structure. Reason: PAINT IBA (GO_REF:0000033) within PANTHER family PTHR11108 (ferrochelatase). Ferrochelatase activity is the defining, experimentally established function of human FECH (recombinant enzyme assays, substrate-bound crystal structure), so the inherited family function holds for the target. Supporting Evidence: PMID:8276824 Ferrochelatase (EC 4.99.1.1) catalyzes the terminal step in the heme biosynthetic pathway, the insertion of ferrous iron into protoporphyrin IX. PMID:17261801 Ferrochelatase, the terminal enzyme in heme biosynthesis, catalyzes the insertion of ferrous iron into protoporphyrin IX to form protoheme IX. file:human/FECH/FECH-uniprot.txt PANTHER; PTHR11108; FERROCHELATASE; 1. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA (GO_REF:0000033) assignment of mitochondrial localization from PANTHER family PTHR11108. Reason: Root-organelle row checked per the organelle policy: the organelle claim holds, since human FECH is a peripheral protein on the matrix face of the inner mitochondrial membrane (structure, Reactome, MitoCoP proteome), and the family's eukaryotic members are mitochondrial. The organelle term is kept as informative; the inner-membrane sub-compartment is carried by separate rows. Supporting Evidence: PMID:17261801 Human ferrochelatase is a homodimeric, inner mitochondrial membrane-associated enzyme that possesses an essential [2Fe-2S] cluster. Reactome:R-HSA-189465 FECH is localized on the matrix surface of the inner mitochondrial membrane and this reaction takes place within the mitochondrial matrix. file:human/FECH/FECH-uniprot.txt PANTHER; PTHR11108; FERROCHELATASE; 1. |
| GO:0006783 heme biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of the core biological process. FECH catalyses the terminal step of heme biosynthesis, so this is the correct and central BP. Reason: PAINT IBA (GO_REF:0000033) from PTHR11108. FECH itself performs the terminal step of heme biosynthesis (iron insertion into protoporphyrin IX), so this is catalytic participation. Core process. Supporting Evidence: PMID:8276824 Ferrochelatase (EC 4.99.1.1) catalyzes the terminal step in the heme biosynthetic pathway, the insertion of ferrous iron into protoporphyrin IX. file:human/FECH/FECH-uniprot.txt PATHWAY: Porphyrin-containing compound metabolism; protoheme biosynthesis; protoheme from protoporphyrin-IX: step 1/1. file:human/FECH/FECH-uniprot.txt PANTHER; PTHR11108; FERROCHELATASE; 1. |
| GO:0004325 protoporphyrin ferrochelatase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated electronic annotation (GO_REF:0000120; family signatures and the EC/Rhea catalytic-activity annotation) of ferrochelatase activity. Reason: Correct core catalytic function; the curated UniProt catalytic-activity line rests on experimental evidence on the human enzyme, and the HAMAP/InterPro ferrochelatase signatures place the protein in the family. Supporting Evidence: file:human/FECH/FECH-uniprot.txt Reaction=heme b + 2 H(+) = protoporphyrin IX + Fe(2+) file:human/FECH/FECH-uniprot.txt HAMAP; MF_00323; Ferrochelatase; 1. PMID:8276824 Ferrochelatase (EC 4.99.1.1) catalyzes the terminal step in the heme biosynthetic pathway, the insertion of ferrous iron into protoporphyrin IX. |
| GO:0005506 iron ion binding | IEA GO_REF:0000117 | MODIFY | Summary: ARBA electronic annotation (GO_REF:0000117) of generic iron ion binding. Reason: Correct but general. FECH binds ferrous iron as its substrate (inserted into protoporphyrin IX), which is captured by the more specific ferrous iron binding (GO:0008198) that the gene already carries; the iron of the [2Fe-2S] cofactor is captured by 2 iron, 2 sulfur cluster binding. The ARBA rule itself is not evidence; the replacement rests on the curated reaction and the cluster mutagenesis. Proposed replacements: ferrous iron binding 2 iron, 2 sulfur cluster binding Supporting Evidence: file:human/FECH/FECH-uniprot.txt Reaction=heme b + 2 H(+) = protoporphyrin IX + Fe(2+) PMID:8276824 Ferrochelatase (EC 4.99.1.1) catalyzes the terminal step in the heme biosynthetic pathway, the insertion of ferrous iron into protoporphyrin IX. PMID:8973195 The results indicate that three of the conserved cysteines in the 30-residue C-terminal extension of mammalian ferrochelatase are involved in ligating the [2Fe-2S] cluster. |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location vocabulary mapping (GO_REF:0000044) to mitochondrial inner membrane. Reason: Matches the curated subcellular location and experimental characterization of FECH as an inner mitochondrial membrane-associated enzyme. Supporting Evidence: PMID:17261801 Human ferrochelatase is a homodimeric, inner mitochondrial membrane-associated enzyme that possesses an essential [2Fe-2S] cluster. file:human/FECH/FECH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane Reactome:R-HSA-189465 FECH is localized on the matrix surface of the inner mitochondrial membrane and this reaction takes place within the mitochondrial matrix. |
| GO:0006783 heme biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated electronic annotation (GO_REF:0000120) of heme biosynthetic process. Reason: Correct core biological process, consistent with direct experimental evidence. Supporting Evidence: PMID:8276824 Ferrochelatase (EC 4.99.1.1) catalyzes the terminal step in the heme biosynthetic pathway, the insertion of ferrous iron into protoporphyrin IX. file:human/FECH/FECH-uniprot.txt PATHWAY: Porphyrin-containing compound metabolism; protoheme biosynthesis; protoheme from protoporphyrin-IX: step 1/1. |
| GO:0006785 heme B biosynthetic process | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic annotation (GO_REF:0000117) of heme B biosynthetic process. FECH directly produces protoheme (heme b) from protoporphyrin IX. Reason: The product of the FECH reaction is heme b (protoheme IX), so heme B biosynthetic process is accurate and specific. The rule is not itself evidence; the term is supported by the curated reaction and the direct characterization of the human enzyme. Supporting Evidence: PMID:17261801 Ferrochelatase, the terminal enzyme in heme biosynthesis, catalyzes the insertion of ferrous iron into protoporphyrin IX to form protoheme IX. file:human/FECH/FECH-uniprot.txt Reaction=heme b + 2 H(+) = protoporphyrin IX + Fe(2+) file:human/FECH/FECH-uniprot.txt PATHWAY: Porphyrin-containing compound metabolism; protoheme biosynthesis; protoheme from protoporphyrin-IX: step 1/1. |
| GO:0005515 protein binding | IPI PMID:27599036 A Novel Role for Progesterone Receptor Membrane Component 1 ... | REMOVE | Summary: IPI capturing the FECH-PGRMC1 (O00264) interaction. The bare protein binding term is uninformative; the biology (PGRMC1 regulation of FECH) is real but the term itself does not convey molecular function. Reason: Bare protein binding carries no functional information; per the protein-binding policy the row is removed. Removal does not dispute the interaction: the FECH-PGRMC1 interaction is real (PGRMC1 lowers FECH activity in vitro), but it describes a regulator acting on FECH and does not identify a more informative FECH molecular function to MODIFY to. Supporting Evidence: PMID:27599036 In the presence of PGRMC1 in vitro measured FECH activity decreased in a dose dependent manner. PMID:27599036 To better understand the means by which heme synthesis is regulated during erythropoiesis, affinity purification coupled with mass spectrometry (MS) was carried out to identify putative protein partners interacting with ferrochelatase (FECH), the terminal enzyme in the heme biosynthetic pathway. |
| GO:0005515 protein binding | IPI PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i... | REMOVE | Summary: IPI for the interaction with ABCB7 (O75027) / ABCB10 (Q9NRK6) in the mitochondrial heme metabolon. Uninformative bare binding term; the interaction itself is well supported. Reason: Bare protein binding carries no functional information; per the protein-binding policy the row is removed. Removal does not dispute the interaction: the ABCB7/ABCB10 interactions are well supported, and FECH membership of that complex is captured by the ATP-binding cassette (ABC) transporter complex row (part_of) and by protein homodimerization activity. Supporting Evidence: PMID:30765471 By combining chemical crosslinking with tandem mass spectrometry and mutational analyses, we identified a complex formed of ferrochelatase (FECH), ABCB7 and ABCB10 and characterized its overall architecture. PMID:30765471 A functional dimeric ferrochelatase (FECH) bridges ABCB7 and ABCB10 by binding near the nucleotide-binding domains (NDB) of each ATB-binding cassette (ABC) transporter. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI from a high-throughput proteome-scale interactome screen (BioPlex). Generic binding term from large-scale affinity purification. Reason: Bare protein binding carries no functional information; per the protein-binding policy the row is removed. Removal does not dispute the interaction: this is a proteome-scale affinity-purification interactome (BioPlex) detection and implies no specific FECH activity. Supporting Evidence: PMID:33961781 In contrast, affinity-purification mass spectrometry (AP-MS) enables enrichment and detection of even low-abundance proteins, though exogenous expression of tagged baits is required |
| GO:0005515 protein binding | IPI PMID:36836934 Proteomic Analysis of Ferrochelatase Interactome in Erythroi... | REMOVE | Summary: IPI capturing FECH interaction partners (Q9NRK6/ABCB10) from a proteomic analysis of the FECH interactome. Bare binding term. Reason: Bare protein binding carries no functional information; per the protein-binding policy the row is removed. Removal does not dispute the interaction: the FECH-ABCB10/mitoferrin-1 iron-delivery complex is real and is described in core_functions and the notes, but bare binding adds nothing beyond the complex membership rows. Supporting Evidence: PMID:36836934 With respect to iron delivery and homeostasis, FECH forms an oligomeric complex with mitoferrin-1 (MFRN1), a mitochondrial iron transporter, and ATP-binding cassette sub-family B member 10 (ABCB10) to channel iron imported into the mitochondria towards heme biosynthesis |
| GO:0042802 identical protein binding | IPI PMID:17261801 Substrate interactions with human ferrochelatase. | MODIFY | Summary: IPI for self-association (P22830-P22830). FECH is an obligate homodimer, so identical protein binding reflects a real, functionally important property and is more informative than bare protein binding. Reason: Correct but general. The self-association of FECH is specifically a homodimer (crystal structures; the functional dimer that bridges ABCB7 and ABCB10), so the specific descendant protein homodimerization activity (GO:0042803), which the gene already carries by IDA, is the appropriate replacement. UniProt also notes a homotetramer in one crystal form. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:17261801 Human ferrochelatase is a homodimeric, inner mitochondrial membrane-associated enzyme that possesses an essential [2Fe-2S] cluster. PMID:30765471 A functional dimeric ferrochelatase (FECH) bridges ABCB7 and ABCB10 by binding near the nucleotide-binding domains (NDB) of each ATB-binding cassette (ABC) transporter. |
| GO:0042802 identical protein binding | IPI PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i... | MODIFY | Summary: IPI for FECH self-association (P22830-P22830). Supports the homodimer that bridges ABCB7 and ABCB10. Reason: Correct but general. The self-association of FECH is specifically a homodimer (crystal structures; the functional dimer that bridges ABCB7 and ABCB10), so the specific descendant protein homodimerization activity (GO:0042803), which the gene already carries by IDA, is the appropriate replacement. UniProt also notes a homotetramer in one crystal form. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:30765471 A functional dimeric ferrochelatase (FECH) bridges ABCB7 and ABCB10 by binding near the nucleotide-binding domains (NDB) of each ATB-binding cassette (ABC) transporter. file:human/FECH/FECH-uniprot.txt SUBUNIT: Homodimer (PubMed:11175906, PubMed:30765471). |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl ortholog projection from rat. A general stress/toxicology response term not reflecting the molecular function of FECH. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure. No such effect of xenobiotics in general on ferrochelatase was found in the literature read for this review, and FECH is a constitutive mitochondrial enzyme of heme synthesis, so the projected process claim exceeds the evidence for the human gene. Marked as over-annotated rather than removed, because the rat observation may be real. Supporting Evidence: file:human/FECH/FECH-uniprot.txt Catalyzes the ferrous insertion into protoporphyrin IX and participates in the terminal step in the heme biosynthetic pathway. file:human/FECH/FECH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0010038 response to metal ion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog projection from rat; broad response-to-metal term. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog. The response definition covers a change in the activity of a gene product after a stimulus, and ferrochelatase activity is directly decreased by lead (rat liver pretreatment; inhibition of ferrochelatase is a clinically important consequence of lead poisoning). Kept as non-core toxicology-relevant biology; this is not a dedicated sensing or detoxification role. Supporting Evidence: PMID:656697 The activity of the haem biosynthetic enzymes delta-aminolaevulinic acid dehydratase, coproporphyrinogen oxidase and ferrochelatase were decreased by increasing lead pretreatment. Reactome:R-HSA-189465 inhibition of ferrochelatase activity is a clinically important consequence of lead poisoning (Piomelli et al. 1987). |
| GO:0010288 response to lead ion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog projection from rat toxicology data. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog. The response definition covers a change in the activity of a gene product after a stimulus, and ferrochelatase activity is directly decreased by lead (rat liver pretreatment; inhibition of ferrochelatase is a clinically important consequence of lead poisoning). Kept as non-core toxicology-relevant biology; this is not a dedicated sensing or detoxification role. Supporting Evidence: PMID:656697 The activity of the haem biosynthetic enzymes delta-aminolaevulinic acid dehydratase, coproporphyrinogen oxidase and ferrochelatase were decreased by increasing lead pretreatment. Reactome:R-HSA-189465 inhibition of ferrochelatase activity is a clinically important consequence of lead poisoning (Piomelli et al. 1987). |
| GO:0017085 response to insecticide | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog projection from rat. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog. The response definition covers a change in the activity of a gene product after a stimulus, and ferrochelatase activity is directly decreased by the diazinon isomer isodiazinon in rats (100-day treatment). Kept as non-core toxicology-relevant biology; this is not a dedicated sensing or detoxification role. Supporting Evidence: PMID:6626236 Rats treated with isodiazinon over a 100-day period show decreased levels of liver ferrochelatase. PMID:6626236 Rats treated with diazinon and isodiazinon in combination over the same period show a more marked decrease in liver ferrochelatase activity as well as a decrease in the activity of coproporphyrinogen oxidase. |
| GO:0045471 response to ethanol | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl ortholog projection from rat. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure. No such effect of ethanol on ferrochelatase was found in the literature read for this review, and FECH is a constitutive mitochondrial enzyme of heme synthesis, so the projected process claim exceeds the evidence for the human gene. Marked as over-annotated rather than removed, because the rat observation may be real. Supporting Evidence: file:human/FECH/FECH-uniprot.txt Catalyzes the ferrous insertion into protoporphyrin IX and participates in the terminal step in the heme biosynthetic pathway. file:human/FECH/FECH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0046685 response to arsenic-containing substance | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl ortholog projection from rat toxicology data. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure. No such effect of arsenic-containing substances on ferrochelatase was found in the literature read for this review, and FECH is a constitutive mitochondrial enzyme of heme synthesis, so the projected process claim exceeds the evidence for the human gene. Marked as over-annotated rather than removed, because the rat observation may be real. Supporting Evidence: file:human/FECH/FECH-uniprot.txt Catalyzes the ferrous insertion into protoporphyrin IX and participates in the terminal step in the heme biosynthetic pathway. file:human/FECH/FECH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0051597 response to methylmercury | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl ortholog projection from rat. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure. No such effect of methylmercury on ferrochelatase was found in the literature read for this review, and FECH is a constitutive mitochondrial enzyme of heme synthesis, so the projected process claim exceeds the evidence for the human gene. Marked as over-annotated rather than removed, because the rat observation may be real. Supporting Evidence: file:human/FECH/FECH-uniprot.txt Catalyzes the ferrous insertion into protoporphyrin IX and participates in the terminal step in the heme biosynthetic pathway. file:human/FECH/FECH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0070541 response to platinum ion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl ortholog projection from rat. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure. No such effect of platinum ions on ferrochelatase was found in the literature read for this review, and FECH is a constitutive mitochondrial enzyme of heme synthesis, so the projected process claim exceeds the evidence for the human gene. Marked as over-annotated rather than removed, because the rat observation may be real. Supporting Evidence: file:human/FECH/FECH-uniprot.txt Catalyzes the ferrous insertion into protoporphyrin IX and participates in the terminal step in the heme biosynthetic pathway. file:human/FECH/FECH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0071549 cellular response to dexamethasone stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl ortholog projection from rat. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure. No such effect of dexamethasone on ferrochelatase was found in the literature read for this review, and FECH is a constitutive mitochondrial enzyme of heme synthesis, so the projected process claim exceeds the evidence for the human gene. Marked as over-annotated rather than removed, because the rat observation may be real. Supporting Evidence: file:human/FECH/FECH-uniprot.txt Catalyzes the ferrous insertion into protoporphyrin IX and participates in the terminal step in the heme biosynthetic pathway. file:human/FECH/FECH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0004325 protoporphyrin ferrochelatase activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer of ferrochelatase activity from the mouse ortholog (MGI:95513). Correct core molecular function. Reason: Sequence-similarity transfer of the correct enzymatic activity, corroborated by direct human enzymology. Supporting Evidence: PMID:8276824 Ferrochelatase (EC 4.99.1.1) catalyzes the terminal step in the heme biosynthetic pathway, the insertion of ferrous iron into protoporphyrin IX. PMID:8276824 Herein we report the expression, purification, and characterization of the mature processed form of human and mouse ferrochelatase in Escherichia coli JM109. file:human/FECH/FECH-uniprot.txt Reaction=heme b + 2 H(+) = protoporphyrin IX + Fe(2+) |
| GO:0006783 heme biosynthetic process | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer of heme biosynthetic process from the mouse ortholog. Correct core biological process. Reason: Correct central process, supported by direct experimental evidence in human. Supporting Evidence: PMID:8276824 Ferrochelatase (EC 4.99.1.1) catalyzes the terminal step in the heme biosynthetic pathway, the insertion of ferrous iron into protoporphyrin IX. file:human/FECH/FECH-uniprot.txt PATHWAY: Porphyrin-containing compound metabolism; protoheme biosynthesis; protoheme from protoporphyrin-IX: step 1/1. |
| GO:0004325 protoporphyrin ferrochelatase activity | EXP PMID:8276824 Mammalian ferrochelatase. Expression and characterization of... | ACCEPT | Summary: Direct experimental (EXP) evidence: expression, purification and enzymatic characterization of recombinant human ferrochelatase, including mutants. This is the primary experimental support for the core molecular function. Reason: Directly demonstrates ferrochelatase catalytic activity of human FECH by enzyme assay; the defining core function. Supporting Evidence: PMID:8276824 Ferrochelatase (EC 4.99.1.1) catalyzes the terminal step in the heme biosynthetic pathway, the insertion of ferrous iron into protoporphyrin IX. PMID:8276824 Herein we report the expression, purification, and characterization of the mature processed form of human and mouse ferrochelatase in Escherichia coli JM109. PMID:8276824 The F417S mutant has less than 2% of the normal activity. |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer of inner mitochondrial membrane localization from rat P22315. Consistent with human structural/biochemical data. Reason: Matches the curated subcellular location (inner membrane, matrix side, peripheral) and experimental description of FECH. Supporting Evidence: PMID:17261801 Human ferrochelatase is a homodimeric, inner mitochondrial membrane-associated enzyme that possesses an essential [2Fe-2S] cluster. file:human/FECH/FECH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0006783 heme biosynthetic process | NAS PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i... | ACCEPT | Summary: NAS (ComplexPortal) assignment of heme biosynthetic process, associated with the ABCB7-ABCB10-FECH metabolon required for heme synthesis. Correct core BP. Reason: Consistent with the central biological process of FECH; the cited work establishes the FECH-containing complex required for heme biosynthesis. Supporting Evidence: PMID:30765471 Overall, our studies highlight the importance of ABCB7 for mitochondrial function and provide the biochemical characterization of a functional complex formed of ABCB7, FECH and ABCB10, which is required for cellular iron homeostasis, mitochondrial function and heme biosynthesis. |
| GO:0031966 mitochondrial membrane | IDA PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i... | MODIFY | Summary: IDA localization to the mitochondrial membrane from the ABCB7/ABCB10/FECH complex study. Correct though less specific than mitochondrial inner membrane. Reason: Correct but general. FECH is a peripheral protein on the matrix face of the inner mitochondrial membrane, and the cited complex work places it with the inner-membrane ABC transporters ABCB7 and ABCB10; the specific descendant mitochondrial inner membrane (GO:0005743), already carried by the gene, is the appropriate replacement. Proposed replacements: mitochondrial inner membrane Supporting Evidence: PMID:30765471 A functional dimeric ferrochelatase (FECH) bridges ABCB7 and ABCB10 by binding near the nucleotide-binding domains (NDB) of each ATB-binding cassette (ABC) transporter. PMID:17261801 Human ferrochelatase is a homodimeric, inner mitochondrial membrane-associated enzyme that possesses an essential [2Fe-2S] cluster. Reactome:R-HSA-189465 FECH is localized on the matrix surface of the inner mitochondrial membrane and this reaction takes place within the mitochondrial matrix. |
| GO:0043190 ATP-binding cassette (ABC) transporter complex | IPI PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i... | KEEP AS NON CORE | Summary: part_of an ABC transporter complex (ComplexPortal CPX-8302, ABCB10-ABCB7-FECH). FECH itself is not an ABC transporter but a dimeric FECH bridges ABCB7 and ABCB10 homodimers, so it is a component of this defined complex. Reason: Genuine, experimentally defined complex membership (metabolon), but this is an accessory/contextual role for FECH rather than its core catalytic function; keep as non-core. Supporting Evidence: PMID:30765471 By combining chemical crosslinking with tandem mass spectrometry and mutational analyses, we identified a complex formed of ferrochelatase (FECH), ABCB7 and ABCB10 and characterized its overall architecture. PMID:30765471 A functional dimeric ferrochelatase (FECH) bridges ABCB7 and ABCB10 by binding near the nucleotide-binding domains (NDB) of each ATB-binding cassette (ABC) transporter. PMID:30765471 Overall, our studies highlight the importance of ABCB7 for mitochondrial function and provide the biochemical characterization of a functional complex formed of ABCB7, FECH and ABCB10, which is required for cellular iron homeostasis, mitochondrial function and heme biosynthesis. |
| GO:0006783 heme biosynthetic process | IDA PMID:15123683 Frataxin-mediated iron delivery to ferrochelatase in the fin... | ACCEPT | Summary: IDA for heme biosynthetic process from the frataxin iron-delivery study, which reconstitutes FECH-mediated terminal heme synthesis. Correct core BP. Reason: Direct demonstration of FECH participating in the terminal step of heme biosynthesis (iron insertion into protoporphyrin IX). Supporting Evidence: PMID:15123683 Human ferrochelatase, a mitochondrial membrane-associated protein, catalyzes the terminal step of heme biosynthesis by insertion of ferrous iron into protoporphyrin IX. PMID:15123683 Herein we demonstrate Hs holofrataxin to be a high affinity iron binding partner for Hs ferrochelatase that is capable of both delivering iron to ferrochelatase and mediating the terminal step in mitochondrial heme biosynthesis. |
| GO:0006785 heme B biosynthetic process | IDA PMID:27599036 A Novel Role for Progesterone Receptor Membrane Component 1 ... | ACCEPT | Summary: IDA for heme B biosynthetic process, the specific product of FECH (protoheme / heme b). Correct and appropriately specific. Reason: FECH produces heme b; this specific process term is accurate and supported by direct study of FECH activity and its regulation. Supporting Evidence: PMID:27599036 To better understand the means by which heme synthesis is regulated during erythropoiesis, affinity purification coupled with mass spectrometry (MS) was carried out to identify putative protein partners interacting with ferrochelatase (FECH), the terminal enzyme in the heme biosynthetic pathway. PMID:27599036 In the presence of PGRMC1 in vitro measured FECH activity decreased in a dose dependent manner. file:human/FECH/FECH-uniprot.txt Catalyzes the ferrous insertion into protoporphyrin IX and participates in the terminal step in the heme biosynthetic pathway. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput proteomics localization to the mitochondrion. Consistent with the established mitochondrial localization of FECH. Reason: Direct high-throughput detection in the human MitoCoP mitochondrial proteome. This organelle-level assay cannot resolve the sub-compartment, so per the root-organelle policy the row is accepted at the organelle; the inner-membrane location is carried by separate rows. Supporting Evidence: PMID:34800366 We defined a human mitochondrial high-confidence proteome (MitoCoP) of 1,134 protein-coding genes, including 91 proteins previously not localized to mitochondria experimentally. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-189465 | ACCEPT | Summary: Reactome TAS localization to the inner mitochondrial membrane for the reaction "FECH binds Fe2+ to PRIN9 to form heme". Correct specific localization. Reason: Consistent with the curated inner mitochondrial membrane localization of FECH. Supporting Evidence: Reactome:R-HSA-189465 FECH is localized on the matrix surface of the inner mitochondrial membrane and this reaction takes place within the mitochondrial matrix. file:human/FECH/FECH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9838035 | ACCEPT | Summary: Reactome TAS localization to inner mitochondrial membrane (mitochondrial protein degradation context, CLPXP). Localization is correct. Reason: Inner mitochondrial membrane localization is correct; the annotation derives from a Reactome reaction involving mitochondrial matrix/inner-membrane proteins. Supporting Evidence: Reactome:R-HSA-189465 FECH is localized on the matrix surface of the inner mitochondrial membrane and this reaction takes place within the mitochondrial matrix. file:human/FECH/FECH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9838081 | ACCEPT | Summary: Reactome TAS localization to inner mitochondrial membrane (LONP1 degradation context). Localization is correct. Reason: Inner mitochondrial membrane localization is correct and consistent with curated data. Supporting Evidence: Reactome:R-HSA-189465 FECH is localized on the matrix surface of the inner mitochondrial membrane and this reaction takes place within the mitochondrial matrix. file:human/FECH/FECH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9838093 | ACCEPT | Summary: Reactome TAS localization to inner mitochondrial membrane (LONP1 binding context). Localization is correct. Reason: Inner mitochondrial membrane localization is correct and consistent with curated data. Supporting Evidence: Reactome:R-HSA-189465 FECH is localized on the matrix surface of the inner mitochondrial membrane and this reaction takes place within the mitochondrial matrix. file:human/FECH/FECH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9838289 | ACCEPT | Summary: Reactome TAS localization to inner mitochondrial membrane (CLPXP degradation context). Localization is correct. Reason: Inner mitochondrial membrane localization is correct and consistent with curated data. Supporting Evidence: Reactome:R-HSA-189465 FECH is localized on the matrix surface of the inner mitochondrial membrane and this reaction takes place within the mitochondrial matrix. file:human/FECH/FECH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0042803 protein homodimerization activity | IDA PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i... | ACCEPT | Summary: IDA for homodimerization activity. FECH is an obligate homodimer; a dimeric FECH bridges ABCB7 and ABCB10 homodimers. Real, functionally relevant property. Reason: Homodimerization is experimentally established and functionally important for FECH; more informative than bare protein binding. Supporting Evidence: PMID:30765471 A functional dimeric ferrochelatase (FECH) bridges ABCB7 and ABCB10 by binding near the nucleotide-binding domains (NDB) of each ATB-binding cassette (ABC) transporter. PMID:17261801 Human ferrochelatase is a homodimeric, inner mitochondrial membrane-associated enzyme that possesses an essential [2Fe-2S] cluster. |
| GO:0004325 protoporphyrin ferrochelatase activity | IDA PMID:27599036 A Novel Role for Progesterone Receptor Membrane Component 1 ... | ACCEPT | Summary: IDA for ferrochelatase activity from the PGRMC1 study, which measured FECH enzyme activity directly. Core molecular function. Reason: Direct in vitro measurement of FECH catalytic activity; the defining core function. Supporting Evidence: PMID:27599036 In the presence of PGRMC1 in vitro measured FECH activity decreased in a dose dependent manner. file:human/FECH/FECH-uniprot.txt Reaction=heme b + 2 H(+) = protoporphyrin IX + Fe(2+) |
| GO:0006783 heme biosynthetic process | IDA PMID:27599036 A Novel Role for Progesterone Receptor Membrane Component 1 ... | ACCEPT | Summary: IDA for heme biosynthetic process. FECH is the terminal enzyme of the pathway. Core BP. Reason: Correct central process, directly supported by the study of FECH activity and hemoglobinization. Supporting Evidence: PMID:27599036 To better understand the means by which heme synthesis is regulated during erythropoiesis, affinity purification coupled with mass spectrometry (MS) was carried out to identify putative protein partners interacting with ferrochelatase (FECH), the terminal enzyme in the heme biosynthetic pathway. file:human/FECH/FECH-uniprot.txt Catalyzes the ferrous insertion into protoporphyrin IX and participates in the terminal step in the heme biosynthetic pathway. |
| GO:0004325 protoporphyrin ferrochelatase activity | IDA PMID:8973195 Site-directed mutagenesis and spectroscopic characterization... | ACCEPT | Summary: IDA for ferrochelatase activity from the site-directed mutagenesis / spectroscopy study identifying the [2Fe-2S] cluster ligands; wild-type and mutant activities were assayed. Core molecular function. Reason: Directly measures FECH activity and links the [2Fe-2S] cluster (C403/C406/C411) to activity; supports the core enzymatic function. Supporting Evidence: PMID:8973195 Mutations of cysteines at positions 403, 406, and 411 (C403D, C403H, C406D, C406H, C406S, C411H, and C411S mutants) all resulted in inactive enzyme that failed to assemble the [2Fe-2S] cluster as judged by whole-cell EPR studies. PMID:8973195 The results indicate that three of the conserved cysteines in the 30-residue C-terminal extension of mammalian ferrochelatase are involved in ligating the [2Fe-2S] cluster. |
| GO:0004325 protoporphyrin ferrochelatase activity | IDA PMID:15123683 Frataxin-mediated iron delivery to ferrochelatase in the fin... | ACCEPT | Summary: IDA for ferrochelatase activity from the frataxin iron-delivery study, which reconstitutes FECH-mediated iron insertion into protoporphyrin IX. Core MF. Reason: Direct reconstitution of FECH catalysing the terminal step of heme biosynthesis; the defining core function. Supporting Evidence: PMID:15123683 Herein we demonstrate Hs holofrataxin to be a high affinity iron binding partner for Hs ferrochelatase that is capable of both delivering iron to ferrochelatase and mediating the terminal step in mitochondrial heme biosynthesis. PMID:15123683 Human ferrochelatase, a mitochondrial membrane-associated protein, catalyzes the terminal step of heme biosynthesis by insertion of ferrous iron into protoporphyrin IX. |
| GO:0005515 protein binding | IPI PMID:15123683 Frataxin-mediated iron delivery to ferrochelatase in the fin... | REMOVE | Summary: IPI for the FECH-frataxin (Q16595) interaction. Bare binding term; the functional significance (iron delivery to FECH) is real and captured elsewhere. Reason: Bare protein binding carries no functional information; per the protein-binding policy the row is removed. Removal does not dispute the interaction: frataxin binds FECH and can deliver iron to it, but that is an activity of frataxin (iron donor) acting on FECH; no more informative FECH molecular function follows from the binding itself. Supporting Evidence: PMID:15123683 Herein we demonstrate Hs holofrataxin to be a high affinity iron binding partner for Hs ferrochelatase that is capable of both delivering iron to ferrochelatase and mediating the terminal step in mitochondrial heme biosynthesis. |
| GO:0004325 protoporphyrin ferrochelatase activity | TAS PMID:2260980 Molecular cloning and sequence analysis of cDNA encoding hum... | ACCEPT | Summary: TAS for ferrochelatase activity from the original human FECH cDNA cloning paper. Correct core molecular function. Reason: The gene was cloned and characterized as human ferrochelatase; the enzymatic activity is the defining core function. Supporting Evidence: PMID:2260980 The cDNA encoding human ferrochelatase [EC 4.99.1.1] was isolated from a human placenta cDNA library in bacteriophage lambda gt11 by screening with a radiolabeled fragment of mouse ferrochelatase cDNA. PMID:8276824 Ferrochelatase (EC 4.99.1.1) catalyzes the terminal step in the heme biosynthetic pathway, the insertion of ferrous iron into protoporphyrin IX. |
| GO:0006091 generation of precursor metabolites and energy | TAS PMID:1729699 The molecular defect of ferrochelatase in a patient with ery... | MARK AS OVER ANNOTATED | Summary: Legacy ProtInc TAS to a very broad process term. FECH synthesizes heme; the specific and correct process is heme biosynthesis, not the generic generation of precursor metabolites and energy. Reason: Legacy TAS to generation of precursor metabolites and energy. FECH makes heme, a prosthetic group, not an energy-yielding metabolite or a precursor of central carbon metabolism; heme is needed by respiratory cytochromes, but that is an indirect, downstream dependence. The specific, correct process from the same reference is heme biosynthetic process. The claim exceeds what the source supports for FECH; marked as over-annotated. Supporting Evidence: PMID:1729699 Ferrochelatase is the terminal enzyme in the heme biosynthetic pathway and catalyzes the insertion of ferrous iron into protoporphyrin IX to form heme. |
| GO:0006783 heme biosynthetic process | TAS PMID:1729699 The molecular defect of ferrochelatase in a patient with ery... | ACCEPT | Summary: TAS for heme biosynthetic process from an EPP molecular-defect study describing FECH as the terminal enzyme of the pathway. Correct core BP. Reason: Accurate central biological process, supported by the description of FECH as the terminal heme-biosynthesis enzyme. Supporting Evidence: PMID:1729699 Ferrochelatase is the terminal enzyme in the heme biosynthetic pathway and catalyzes the insertion of ferrous iron into protoporphyrin IX to form heme. |
| GO:0008198 ferrous iron binding | TAS PMID:1729699 The molecular defect of ferrochelatase in a patient with ery... | KEEP AS NON CORE | Summary: TAS for ferrous iron binding. FECH binds and handles the ferrous iron substrate that it inserts into protoporphyrin IX. This is a real supporting molecular function, secondary to the catalytic ferrochelatase activity. Reason: Ferrous iron binding is an accurate, more specific substrate-handling function, but it is ancillary to the core catalytic activity (which subsumes iron insertion). Keep as non-core. Supporting Evidence: PMID:1729699 Ferrochelatase is the terminal enzyme in the heme biosynthetic pathway and catalyzes the insertion of ferrous iron into protoporphyrin IX to form heme. file:human/FECH/FECH-uniprot.txt Reaction=heme b + 2 H(+) = protoporphyrin IX + Fe(2+) |
| GO:0009416 response to light stimulus | TAS PMID:1376018 A molecular defect in human protoporphyria. | MARK AS OVER ANNOTATED | Summary: TAS to response to light stimulus, derived from the erythropoietic protoporphyria photosensitivity phenotype (protoporphyrin IX accumulation causes light-triggered skin damage). This is a downstream disease phenotype, not a molecular function of FECH in responding to light. Reason: The light sensitivity is a clinical consequence of loss of FECH activity (protoporphyrin accumulation), not a light-response function of the enzyme itself; this is an over-annotation of the phenotype. FECH does not itself sense or respond to light. Supporting Evidence: PMID:1376018 Protoporphyria is generally an autosomal dominant disease that is characterized clinically by photosensitivity and hepatobiliary disease and that is characterized biochemically by elevated protoporphyrin levels. PMID:1376018 The enzymatic activity of ferrochelatase, which catalyzes the last step in the heme biosynthetic pathway, is deficient in all tissues of patients with protoporphyria. |
| GO:0051537 2 iron, 2 sulfur cluster binding | IDA PMID:8973195 Site-directed mutagenesis and spectroscopic characterization... | NEW | Summary: Proposed annotation: human FECH binds one [2Fe-2S] cluster per subunit, ligated by Cys403, Cys406 and Cys411 plus one non-cysteinyl ligand; the cluster is required for activity. The cluster-binding term is carried in UniProt only through a keyword mapping, not as an experimental GOA row. Reason: Direct mutagenesis and spectroscopy on human FECH show the three C-terminal cysteines ligate an essential [2Fe-2S] cluster (cysteine mutants are inactive and fail to assemble the cluster), and the human crystal structure confirms it. This cofactor-binding function supports the catalytic activity and is listed in core_functions. Supporting Evidence: PMID:8973195 Mutations of cysteines at positions 403, 406, and 411 (C403D, C403H, C406D, C406H, C406S, C411H, and C411S mutants) all resulted in inactive enzyme that failed to assemble the [2Fe-2S] cluster as judged by whole-cell EPR studies. PMID:8973195 The results indicate that three of the conserved cysteines in the 30-residue C-terminal extension of mammalian ferrochelatase are involved in ligating the [2Fe-2S] cluster. PMID:17261801 Human ferrochelatase is a homodimeric, inner mitochondrial membrane-associated enzyme that possesses an essential [2Fe-2S] cluster. file:human/FECH/FECH-uniprot.txt Name=[2Fe-2S] cluster |
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Download this section (compressed HTML)Q: How is FECH activity dynamically regulated in vivo by partners such as PGRMC1 and by the [2Fe-2S] cluster (proposed NO sensor), and how does this coordinate heme output with iron availability?
Q: What is the precise stoichiometry and architecture of the mitochondrial heme metabolon (FECH, ABCB7, ABCB10, mitoferrin-1, PPOX) and how does it channel iron and protoporphyrin IX to FECH?
Experiment: Structure-guided reconstitution of the FECH-ABCB7-ABCB10 and FECH-mitoferrin-1 complexes (cryo-EM) with functional iron-insertion assays to test metabolon channeling.
Experiment: Quantify how EPP1 variants that disrupt the [2Fe-2S] cluster ligands (C403/C406/C411) or substrate binding alter FECH activity, stability and protoporphyrin IX accumulation in erythroid cell models.
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