FECH

Existing Annotations Review

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: Ferrochelatase activity is the defining, experimentally established function of FECH; the IBA is consistent with direct assays and crystal structures. Supporting Evidence: PMID:8276824 catalyzes the terminal step in the heme PMID:17261801 homodimeric, inner mitochondrial membrane-associated enzyme
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic assignment of mitochondrial localization. Correct but general; FECH is more precisely on the matrix side of the mitochondrial inner membrane. Reason: FECH is a mitochondrial enzyme; the mitochondrion localization is correct, and the more specific mitochondrial inner membrane term is captured by other annotations. Supporting Evidence: PMID:17261801 homodimeric, inner mitochondrial membrane-associated enzyme
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: Heme biosynthetic process is the central process for FECH and is supported by direct experimental evidence. Supporting Evidence: PMID:8276824 catalyzes the terminal step in the heme
GO:0004325 protoporphyrin ferrochelatase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assignment (ARBA/InterPro/RHEA/EC) of ferrochelatase activity, redundant with the experimentally supported core function. Reason: The electronic mapping (EC 4.98.1.1, RHEA:22584, InterPro ferrochelatase) is correct and matches the curated catalytic activity. Supporting Evidence: PMID:8276824 the insertion of ferrous iron into protoporphyrin IX
GO:0005506 iron ion binding	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: ARBA electronic assignment of iron ion binding. FECH binds/handles ferrous iron as substrate and coordinates iron in its [2Fe-2S] cluster, so iron ion binding is reasonable, but it is a supporting/secondary molecular function relative to the catalytic ferrochelatase activity. Reason: Iron binding is a real property (substrate ferrous iron and [2Fe-2S] cofactor) but is ancillary to the enzymatic function; the more specific ferrous iron binding term is separately annotated. Supporting Evidence: file:human/FECH/FECH-uniprot.txt Binds 1 [2Fe-2S] cluster.
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000044	ACCEPT	Summary: Electronic assignment from UniProt subcellular-location mapping. Correct and specific: FECH is a peripheral inner-membrane protein on the matrix side. Reason: Matches the curated subcellular location and experimental characterization of FECH as an inner mitochondrial membrane-associated enzyme. Supporting Evidence: PMID:17261801 homodimeric, inner mitochondrial membrane-associated enzyme file:human/FECH/FECH-uniprot.txt Mitochondrion inner membrane
GO:0006783 heme biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assignment of heme biosynthetic process, redundant with the experimentally supported core BP. Reason: Correct core biological process, consistent with direct experimental evidence. Supporting Evidence: PMID:8276824 catalyzes the terminal step in the heme
GO:0006785 heme B biosynthetic process	IEA GO_REF:0000117	ACCEPT	Summary: ARBA electronic assignment of heme B biosynthetic process. FECH specifically produces heme b (protoheme IX) from protoporphyrin IX, so this is a correct and appropriately specific process term. Reason: The product of the FECH reaction is heme b (protoheme), so heme B biosynthetic process is an accurate, more specific process; supported by direct evidence. Supporting Evidence: PMID:17261801 insertion of ferrous iron into protoporphyrin IX to form protoheme IX
GO:0005515 protein binding	IPI PMID:27599036 A Novel Role for Progesterone Receptor Membrane Component 1 ...	MARK AS OVER ANNOTATED	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 is not an informative molecular function. The underlying FECH-PGRMC1 interaction is genuine and is captured functionally in the notes and core functions (regulatory partner controlling FECH activity/heme release); per policy the experimental IPI is retained but marked as over-annotated rather than removed. Supporting Evidence: PMID:27599036 In the presence of PGRMC1 in vitro measured FECH activity decreased in a dose dependent manner
GO:0005515 protein binding	IPI PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i...	MARK AS OVER ANNOTATED	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: protein binding is too generic to be an informative molecular function; the real ABCB7/ABCB10 metabolon association is documented and captured elsewhere. Experimental IPI retained but flagged as over-annotated. Supporting Evidence: PMID:30765471 A dimeric ferrochelatase physically bridged ABCB7 and ABCB10
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: IPI from a high-throughput proteome-scale interactome screen (BioPlex). Generic binding term from large-scale affinity purification. Reason: Uninformative molecular function term derived from a proteome-wide interactome dataset; not a defined functional interaction. Retained but marked as over-annotated per policy on bare protein binding IPIs. Supporting Evidence: PMID:33961781 affinity-purification mass spectrometry
GO:0005515 protein binding	IPI PMID:36836934 Proteomic Analysis of Ferrochelatase Interactome in Erythroi...	MARK AS OVER ANNOTATED	Summary: IPI capturing FECH interaction partners (Q9NRK6/ABCB10) from a proteomic analysis of the FECH interactome. Bare binding term. Reason: protein binding is uninformative; the metabolon interactions (ABCB10, mitoferrin-1, PPOX, PGRMC1) are documented in notes/core functions. Retained but flagged as over-annotated. Supporting Evidence: PMID:36836934 FECH forms an oligomeric complex with mitoferrin-1 (MFRN1), a mitochondrial iron transporter, and ATP-binding cassette sub-family B member 10 (ABCB10)
GO:0042802 identical protein binding	IPI PMID:17261801 Substrate interactions with human ferrochelatase.	ACCEPT	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: FECH functions as a homodimer; identical protein binding accurately captures self-association demonstrated by crystallography. Supporting Evidence: PMID:17261801 homodimeric, inner mitochondrial membrane-associated enzyme
GO:0042802 identical protein binding	IPI PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i...	ACCEPT	Summary: IPI for FECH self-association (P22830-P22830). Supports the homodimer that bridges ABCB7 and ABCB10. Reason: Homodimerization is a real and functionally relevant property confirmed by biochemical/structural analysis of the metabolon complex. Supporting Evidence: PMID:30765471 A dimeric ferrochelatase physically bridged ABCB7 and ABCB10
GO:0009410 response to xenobiotic stimulus	IEA GO_REF:0000107	REMOVE	Summary: Ensembl ortholog projection from rat. A general stress/toxicology response term not reflecting the molecular function of FECH. Reason: Electronically projected (GO_REF:0000107) from a rat ortholog and reflects toxicology stress-response experiments rather than FECH's heme-synthesis function. Over-propagated IEA with no bearing on the enzyme's role; remove.
GO:0010038 response to metal ion	IEA GO_REF:0000107	REMOVE	Summary: Ensembl ortholog projection from rat; broad response-to-metal term. Reason: Electronically projected from a rat ortholog; a generic stress-response term not representative of FECH function. Remove as over-propagated IEA.
GO:0010288 response to lead ion	IEA GO_REF:0000107	REMOVE	Summary: Ensembl ortholog projection from rat toxicology data. Reason: Electronically projected from a rat ortholog; toxicology stress response, not a core FECH function. Remove as over-propagated IEA.
GO:0017085 response to insecticide	IEA GO_REF:0000107	REMOVE	Summary: Ensembl ortholog projection from rat. Reason: Electronically projected from a rat ortholog; toxicology-derived stress response unrelated to FECH's enzymatic role. Remove as over-propagated IEA.
GO:0045471 response to ethanol	IEA GO_REF:0000107	REMOVE	Summary: Ensembl ortholog projection from rat. Reason: Electronically projected from a rat ortholog; generic stress response, not a FECH function. Remove as over-propagated IEA.
GO:0046685 response to arsenic-containing substance	IEA GO_REF:0000107	REMOVE	Summary: Ensembl ortholog projection from rat toxicology data. Reason: Electronically projected from a rat ortholog; toxicology stress response, not a core FECH function. Remove as over-propagated IEA.
GO:0051597 response to methylmercury	IEA GO_REF:0000107	REMOVE	Summary: Ensembl ortholog projection from rat. Reason: Electronically projected from a rat ortholog; toxicology stress response unrelated to FECH function. Remove as over-propagated IEA.
GO:0070541 response to platinum ion	IEA GO_REF:0000107	REMOVE	Summary: Ensembl ortholog projection from rat. Reason: Electronically projected from a rat ortholog; toxicology stress response, not a FECH function. Remove as over-propagated IEA.
GO:0071549 cellular response to dexamethasone stimulus	IEA GO_REF:0000107	REMOVE	Summary: Ensembl ortholog projection from rat. Reason: Electronically projected from a rat ortholog; pharmacological stress response not representative of FECH function. Remove as over-propagated IEA.
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 catalyzes the terminal step in the heme
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 catalyzes the terminal step in the heme
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 catalyzes the terminal step in the heme PMID:8276824 The F417S mutant has less than 2% of the
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 homodimeric, inner mitochondrial membrane-associated enzyme
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 complex required for heme biosynthesis
GO:0031966 mitochondrial membrane	IDA PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i...	ACCEPT	Summary: IDA localization to the mitochondrial membrane from the ABCB7/ABCB10/FECH complex study. Correct though less specific than mitochondrial inner membrane. Reason: FECH associates with the inner mitochondrial membrane; mitochondrial membrane is a correct (if more general) localization supported by the complex analysis. Supporting Evidence: PMID:30765471 A dimeric ferrochelatase physically bridged ABCB7 and ABCB10
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 characterized a complex formed of
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 iron binding partner for Hs ferrochelatase that is capable of both delivering
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 ferrochelatase (FECH), the terminal enzyme 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: Mitochondrial localization is well established; HTP proteomic detection is consistent, though the more specific inner-membrane term is preferred. Supporting Evidence: PMID:34800366 human mitochondrial proteome
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: file:human/FECH/FECH-uniprot.txt 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: file:human/FECH/FECH-uniprot.txt 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: file:human/FECH/FECH-uniprot.txt 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: file:human/FECH/FECH-uniprot.txt 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: file:human/FECH/FECH-uniprot.txt 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 dimeric ferrochelatase physically bridged ABCB7 and ABCB10
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
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 ferrochelatase (FECH), the terminal enzyme 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 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 iron binding partner for Hs ferrochelatase that is capable of both delivering
GO:0005515 protein binding	IPI PMID:15123683 Frataxin-mediated iron delivery to ferrochelatase in the fin...	MARK AS OVER ANNOTATED	Summary: IPI for the FECH-frataxin (Q16595) interaction. Bare binding term; the functional significance (iron delivery to FECH) is real and captured elsewhere. Reason: protein binding is uninformative as a molecular function. The FECH-frataxin interaction (iron donor to the terminal step) is documented in the core function description; the experimental IPI is retained but flagged as over-annotated. Supporting Evidence: PMID:15123683 a potential binding site for an iron donor protein on the matrix side
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
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: Overly general, legacy annotation; heme biosynthetic process (also annotated from the same reference) is the accurate, specific term. Mark as over-annotated. Supporting Evidence: PMID:1729699 terminal enzyme in the heme biosynthetic pathway and catalyzes the insertion of
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 terminal enzyme in the heme biosynthetic pathway and catalyzes the insertion of
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 ferrous iron into protoporphyrin IX to form heme
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 which catalyzes the last step in the heme PMID:1376018 elevated protoporphyrin levels
GO:0051537 2 iron, 2 sulfur cluster binding	IEA GO_REF:0000117	NEW	Summary: [2Fe-2S] cluster binding (UniProt keyword / ARBA). FECH coordinates one [2Fe-2S] cluster per subunit via C-terminal cysteines; the cluster is required for enzyme activity and stability. Real supporting molecular function, secondary to the catalytic ferrochelatase activity. Reason: Not present as a discrete row in the seeded GOA TSV but is a well-supported cofactor-binding function (UniProt DR GO:0051537 IEA:UniProtKB-KW; structural and mutagenesis evidence). Added to reflect the [2Fe-2S] cofactor captured in core_functions. Supporting Evidence: PMID:8973195 in ligating the [2Fe-2S] cluster PMID:17261801 possesses an essential [2Fe-2S] cluster

Gene Description

Existing Annotations Review

Core Functions

FECH is ferrochelatase, catalysing the terminal, committed step of heme biosynthesis: insertion of ferrous iron (Fe2+) into protoporphyrin IX to form protoheme (heme b). It acts as a homodimer on the matrix face of the mitochondrial inner membrane.

Each FECH subunit coordinates a [2Fe-2S] cluster (via three C-terminal cysteines plus one additional ligand) that is required for enzyme activity and stability, and binds the ferrous iron substrate; these metal-binding activities support, but are secondary to, the catalytic ferrochelatase function.

References

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Notes

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