id: P22830
gene_symbol: FECH
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
alternative_products:
- name: '1'
  id: P22830-1
- name: '2'
  id: P22830-2
  sequence_note: VSP_041208
existing_annotations:
- term:
    id: GO:0004325
    label: protoporphyrin ferrochelatase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Ferrochelatase activity is the defining, experimentally established function of
      FECH; the IBA is consistent with direct assays and crystal structures.
    supported_by:
    - reference_id: PMID:8276824
      supporting_text: catalyzes the terminal step in the heme
    - reference_id: PMID:17261801
      supporting_text: homodimeric, inner mitochondrial membrane-associated enzyme
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic assignment of mitochondrial localization. Correct but general;
      FECH is more precisely on the matrix side of the mitochondrial inner membrane.
    action: ACCEPT
    reason: >-
      FECH is a mitochondrial enzyme; the mitochondrion localization is correct, and
      the more specific mitochondrial inner membrane term is captured by other
      annotations.
    supported_by:
    - reference_id: PMID:17261801
      supporting_text: homodimeric, inner mitochondrial membrane-associated enzyme
- term:
    id: GO:0006783
    label: heme biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic assignment of the core biological process. FECH catalyses the
      terminal step of heme biosynthesis, so this is the correct and central BP.
    action: ACCEPT
    reason: >-
      Heme biosynthetic process is the central process for FECH and is supported by
      direct experimental evidence.
    supported_by:
    - reference_id: PMID:8276824
      supporting_text: catalyzes the terminal step in the heme
- term:
    id: GO:0004325
    label: protoporphyrin ferrochelatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assignment (ARBA/InterPro/RHEA/EC) of ferrochelatase activity,
      redundant with the experimentally supported core function.
    action: ACCEPT
    reason: >-
      The electronic mapping (EC 4.98.1.1, RHEA:22584, InterPro ferrochelatase) is
      correct and matches the curated catalytic activity.
    supported_by:
    - reference_id: PMID:8276824
      supporting_text: the insertion of ferrous iron into protoporphyrin IX
- term:
    id: GO:0005506
    label: iron ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/FECH/FECH-uniprot.txt
      supporting_text: Binds 1 [2Fe-2S] cluster.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic assignment from UniProt subcellular-location mapping. Correct and
      specific: FECH is a peripheral inner-membrane protein on the matrix side.
    action: ACCEPT
    reason: >-
      Matches the curated subcellular location and experimental characterization of
      FECH as an inner mitochondrial membrane-associated enzyme.
    supported_by:
    - reference_id: PMID:17261801
      supporting_text: homodimeric, inner mitochondrial membrane-associated enzyme
    - reference_id: file:human/FECH/FECH-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0006783
    label: heme biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic assignment of heme biosynthetic process, redundant with the
      experimentally supported core BP.
    action: ACCEPT
    reason: >-
      Correct core biological process, consistent with direct experimental evidence.
    supported_by:
    - reference_id: PMID:8276824
      supporting_text: catalyzes the terminal step in the heme
- term:
    id: GO:0006785
    label: heme B biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:17261801
      supporting_text: insertion of ferrous iron into protoporphyrin IX to form protoheme IX
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27599036
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:27599036
      supporting_text: In the presence of PGRMC1 in vitro measured FECH activity decreased in a dose dependent manner
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30765471
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:30765471
      supporting_text: A dimeric ferrochelatase physically bridged ABCB7 and ABCB10
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      IPI from a high-throughput proteome-scale interactome screen (BioPlex). Generic
      binding term from large-scale affinity purification.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: affinity-purification mass spectrometry
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36836934
  qualifier: enables
  review:
    summary: >-
      IPI capturing FECH interaction partners (Q9NRK6/ABCB10) from a proteomic
      analysis of the FECH interactome. Bare binding term.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:36836934
      supporting_text: FECH forms an oligomeric complex with mitoferrin-1 (MFRN1), a mitochondrial iron transporter, and ATP-binding cassette sub-family B member 10 (ABCB10)
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:17261801
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      FECH functions as a homodimer; identical protein binding accurately captures
      self-association demonstrated by crystallography.
    supported_by:
    - reference_id: PMID:17261801
      supporting_text: homodimeric, inner mitochondrial membrane-associated enzyme
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:30765471
  qualifier: enables
  review:
    summary: >-
      IPI for FECH self-association (P22830-P22830). Supports the homodimer that
      bridges ABCB7 and ABCB10.
    action: ACCEPT
    reason: >-
      Homodimerization is a real and functionally relevant property confirmed by
      biochemical/structural analysis of the metabolon complex.
    supported_by:
    - reference_id: PMID:30765471
      supporting_text: A dimeric ferrochelatase physically bridged ABCB7 and ABCB10
- term:
    id: GO:0009410
    label: response to xenobiotic stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl ortholog projection from rat. A general stress/toxicology response term
      not reflecting the molecular function of FECH.
    action: REMOVE
    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.
- term:
    id: GO:0010038
    label: response to metal ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl ortholog projection from rat; broad response-to-metal term.
    action: REMOVE
    reason: >-
      Electronically projected from a rat ortholog; a generic stress-response term
      not representative of FECH function. Remove as over-propagated IEA.
- term:
    id: GO:0010288
    label: response to lead ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl ortholog projection from rat toxicology data.
    action: REMOVE
    reason: >-
      Electronically projected from a rat ortholog; toxicology stress response, not a
      core FECH function. Remove as over-propagated IEA.
- term:
    id: GO:0017085
    label: response to insecticide
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl ortholog projection from rat.
    action: REMOVE
    reason: >-
      Electronically projected from a rat ortholog; toxicology-derived stress
      response unrelated to FECH's enzymatic role. Remove as over-propagated IEA.
- term:
    id: GO:0045471
    label: response to ethanol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl ortholog projection from rat.
    action: REMOVE
    reason: >-
      Electronically projected from a rat ortholog; generic stress response, not a
      FECH function. Remove as over-propagated IEA.
- term:
    id: GO:0046685
    label: response to arsenic-containing substance
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl ortholog projection from rat toxicology data.
    action: REMOVE
    reason: >-
      Electronically projected from a rat ortholog; toxicology stress response, not a
      core FECH function. Remove as over-propagated IEA.
- term:
    id: GO:0051597
    label: response to methylmercury
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl ortholog projection from rat.
    action: REMOVE
    reason: >-
      Electronically projected from a rat ortholog; toxicology stress response
      unrelated to FECH function. Remove as over-propagated IEA.
- term:
    id: GO:0070541
    label: response to platinum ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl ortholog projection from rat.
    action: REMOVE
    reason: >-
      Electronically projected from a rat ortholog; toxicology stress response, not a
      FECH function. Remove as over-propagated IEA.
- term:
    id: GO:0071549
    label: cellular response to dexamethasone stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl ortholog projection from rat.
    action: REMOVE
    reason: >-
      Electronically projected from a rat ortholog; pharmacological stress response
      not representative of FECH function. Remove as over-propagated IEA.
- term:
    id: GO:0004325
    label: protoporphyrin ferrochelatase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      ISS transfer of ferrochelatase activity from the mouse ortholog (MGI:95513).
      Correct core molecular function.
    action: ACCEPT
    reason: >-
      Sequence-similarity transfer of the correct enzymatic activity, corroborated by
      direct human enzymology.
    supported_by:
    - reference_id: PMID:8276824
      supporting_text: catalyzes the terminal step in the heme
- term:
    id: GO:0006783
    label: heme biosynthetic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer of heme biosynthetic process from the mouse ortholog. Correct core
      biological process.
    action: ACCEPT
    reason: >-
      Correct central process, supported by direct experimental evidence in human.
    supported_by:
    - reference_id: PMID:8276824
      supporting_text: catalyzes the terminal step in the heme
- term:
    id: GO:0004325
    label: protoporphyrin ferrochelatase activity
  evidence_type: EXP
  original_reference_id: PMID:8276824
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Directly demonstrates ferrochelatase catalytic activity of human FECH by
      enzyme assay; the defining core function.
    supported_by:
    - reference_id: PMID:8276824
      supporting_text: catalyzes the terminal step in the heme
    - reference_id: PMID:8276824
      supporting_text: The F417S mutant has less than 2% of the
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      ISS transfer of inner mitochondrial membrane localization from rat P22315.
      Consistent with human structural/biochemical data.
    action: ACCEPT
    reason: >-
      Matches the curated subcellular location (inner membrane, matrix side,
      peripheral) and experimental description of FECH.
    supported_by:
    - reference_id: PMID:17261801
      supporting_text: homodimeric, inner mitochondrial membrane-associated enzyme
- term:
    id: GO:0006783
    label: heme biosynthetic process
  evidence_type: NAS
  original_reference_id: PMID:30765471
  qualifier: involved_in
  review:
    summary: >-
      NAS (ComplexPortal) assignment of heme biosynthetic process, associated with the
      ABCB7-ABCB10-FECH metabolon required for heme synthesis. Correct core BP.
    action: ACCEPT
    reason: >-
      Consistent with the central biological process of FECH; the cited work
      establishes the FECH-containing complex required for heme biosynthesis.
    supported_by:
    - reference_id: PMID:30765471
      supporting_text: complex required for heme biosynthesis
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: IDA
  original_reference_id: PMID:30765471
  qualifier: located_in
  review:
    summary: >-
      IDA localization to the mitochondrial membrane from the ABCB7/ABCB10/FECH
      complex study. Correct though less specific than mitochondrial inner membrane.
    action: ACCEPT
    reason: >-
      FECH associates with the inner mitochondrial membrane; mitochondrial membrane is
      a correct (if more general) localization supported by the complex analysis.
    supported_by:
    - reference_id: PMID:30765471
      supporting_text: A dimeric ferrochelatase physically bridged ABCB7 and ABCB10
- term:
    id: GO:0043190
    label: ATP-binding cassette (ABC) transporter complex
  evidence_type: IPI
  original_reference_id: PMID:30765471
  qualifier: part_of
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:30765471
      supporting_text: characterized a complex formed of
- term:
    id: GO:0006783
    label: heme biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:15123683
  qualifier: involved_in
  review:
    summary: >-
      IDA for heme biosynthetic process from the frataxin iron-delivery study, which
      reconstitutes FECH-mediated terminal heme synthesis. Correct core BP.
    action: ACCEPT
    reason: >-
      Direct demonstration of FECH participating in the terminal step of heme
      biosynthesis (iron insertion into protoporphyrin IX).
    supported_by:
    - reference_id: PMID:15123683
      supporting_text: iron binding partner for Hs ferrochelatase that is capable of both delivering
- term:
    id: GO:0006785
    label: heme B biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:27599036
  qualifier: involved_in
  review:
    summary: >-
      IDA for heme B biosynthetic process, the specific product of FECH (protoheme /
      heme b). Correct and appropriately specific.
    action: ACCEPT
    reason: >-
      FECH produces heme b; this specific process term is accurate and supported by
      direct study of FECH activity and its regulation.
    supported_by:
    - reference_id: PMID:27599036
      supporting_text: ferrochelatase (FECH), the terminal enzyme in the heme biosynthetic pathway
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomics localization to the mitochondrion. Consistent with
      the established mitochondrial localization of FECH.
    action: ACCEPT
    reason: >-
      Mitochondrial localization is well established; HTP proteomic detection is
      consistent, though the more specific inner-membrane term is preferred.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: human mitochondrial proteome
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-189465
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localization to the inner mitochondrial membrane for the reaction
      "FECH binds Fe2+ to PRIN9 to form heme". Correct specific localization.
    action: ACCEPT
    reason: >-
      Consistent with the curated inner mitochondrial membrane localization of FECH.
    supported_by:
    - reference_id: file:human/FECH/FECH-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838035
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localization to inner mitochondrial membrane (mitochondrial protein
      degradation context, CLPXP). Localization is correct.
    action: ACCEPT
    reason: >-
      Inner mitochondrial membrane localization is correct; the annotation derives from
      a Reactome reaction involving mitochondrial matrix/inner-membrane proteins.
    supported_by:
    - reference_id: file:human/FECH/FECH-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838081
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localization to inner mitochondrial membrane (LONP1 degradation
      context). Localization is correct.
    action: ACCEPT
    reason: >-
      Inner mitochondrial membrane localization is correct and consistent with curated
      data.
    supported_by:
    - reference_id: file:human/FECH/FECH-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838093
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localization to inner mitochondrial membrane (LONP1 binding
      context). Localization is correct.
    action: ACCEPT
    reason: >-
      Inner mitochondrial membrane localization is correct and consistent with curated
      data.
    supported_by:
    - reference_id: file:human/FECH/FECH-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838289
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localization to inner mitochondrial membrane (CLPXP degradation
      context). Localization is correct.
    action: ACCEPT
    reason: >-
      Inner mitochondrial membrane localization is correct and consistent with curated
      data.
    supported_by:
    - reference_id: file:human/FECH/FECH-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:30765471
  qualifier: enables
  review:
    summary: >-
      IDA for homodimerization activity. FECH is an obligate homodimer; a dimeric FECH
      bridges ABCB7 and ABCB10 homodimers. Real, functionally relevant property.
    action: ACCEPT
    reason: >-
      Homodimerization is experimentally established and functionally important for
      FECH; more informative than bare protein binding.
    supported_by:
    - reference_id: PMID:30765471
      supporting_text: A dimeric ferrochelatase physically bridged ABCB7 and ABCB10
- term:
    id: GO:0004325
    label: protoporphyrin ferrochelatase activity
  evidence_type: IDA
  original_reference_id: PMID:27599036
  qualifier: enables
  review:
    summary: >-
      IDA for ferrochelatase activity from the PGRMC1 study, which measured FECH
      enzyme activity directly. Core molecular function.
    action: ACCEPT
    reason: >-
      Direct in vitro measurement of FECH catalytic activity; the defining core
      function.
    supported_by:
    - reference_id: PMID:27599036
      supporting_text: In the presence of PGRMC1 in vitro measured FECH activity decreased in a dose dependent manner
- term:
    id: GO:0006783
    label: heme biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:27599036
  qualifier: involved_in
  review:
    summary: >-
      IDA for heme biosynthetic process. FECH is the terminal enzyme of the pathway.
      Core BP.
    action: ACCEPT
    reason: >-
      Correct central process, directly supported by the study of FECH activity and
      hemoglobinization.
    supported_by:
    - reference_id: PMID:27599036
      supporting_text: ferrochelatase (FECH), the terminal enzyme in the heme biosynthetic pathway
- term:
    id: GO:0004325
    label: protoporphyrin ferrochelatase activity
  evidence_type: IDA
  original_reference_id: PMID:8973195
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Directly measures FECH activity and links the [2Fe-2S] cluster (C403/C406/C411)
      to activity; supports the core enzymatic function.
    supported_by:
    - reference_id: PMID:8973195
      supporting_text: in ligating the [2Fe-2S] cluster
- term:
    id: GO:0004325
    label: protoporphyrin ferrochelatase activity
  evidence_type: IDA
  original_reference_id: PMID:15123683
  qualifier: enables
  review:
    summary: >-
      IDA for ferrochelatase activity from the frataxin iron-delivery study, which
      reconstitutes FECH-mediated iron insertion into protoporphyrin IX. Core MF.
    action: ACCEPT
    reason: >-
      Direct reconstitution of FECH catalysing the terminal step of heme biosynthesis;
      the defining core function.
    supported_by:
    - reference_id: PMID:15123683
      supporting_text: iron binding partner for Hs ferrochelatase that is capable of both delivering
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15123683
  qualifier: enables
  review:
    summary: >-
      IPI for the FECH-frataxin (Q16595) interaction. Bare binding term; the
      functional significance (iron delivery to FECH) is real and captured elsewhere.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:15123683
      supporting_text: a potential binding site for an iron donor protein on the matrix side
- term:
    id: GO:0004325
    label: protoporphyrin ferrochelatase activity
  evidence_type: TAS
  original_reference_id: PMID:2260980
  qualifier: enables
  review:
    summary: >-
      TAS for ferrochelatase activity from the original human FECH cDNA cloning paper.
      Correct core molecular function.
    action: ACCEPT
    reason: >-
      The gene was cloned and characterized as human ferrochelatase; the enzymatic
      activity is the defining core function.
    supported_by:
    - reference_id: PMID:2260980
      supporting_text: The cDNA encoding human ferrochelatase
- term:
    id: GO:0006091
    label: generation of precursor metabolites and energy
  evidence_type: TAS
  original_reference_id: PMID:1729699
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Overly general, legacy annotation; heme biosynthetic process (also annotated
      from the same reference) is the accurate, specific term. Mark as over-annotated.
    supported_by:
    - reference_id: PMID:1729699
      supporting_text: terminal enzyme in the heme biosynthetic pathway and catalyzes the insertion of
- term:
    id: GO:0006783
    label: heme biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:1729699
  qualifier: involved_in
  review:
    summary: >-
      TAS for heme biosynthetic process from an EPP molecular-defect study describing
      FECH as the terminal enzyme of the pathway. Correct core BP.
    action: ACCEPT
    reason: >-
      Accurate central biological process, supported by the description of FECH as the
      terminal heme-biosynthesis enzyme.
    supported_by:
    - reference_id: PMID:1729699
      supporting_text: terminal enzyme in the heme biosynthetic pathway and catalyzes the insertion of
- term:
    id: GO:0008198
    label: ferrous iron binding
  evidence_type: TAS
  original_reference_id: PMID:1729699
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:1729699
      supporting_text: ferrous iron into protoporphyrin IX to form heme
- term:
    id: GO:0009416
    label: response to light stimulus
  evidence_type: TAS
  original_reference_id: PMID:1376018
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:1376018
      supporting_text: which catalyzes the last step in the heme
    - reference_id: PMID:1376018
      supporting_text: elevated protoporphyrin levels
- term:
    id: GO:0051537
    label: 2 iron, 2 sulfur cluster binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    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.
    action: NEW
    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.
    supported_by:
    - reference_id: PMID:8973195
      supporting_text: in ligating the [2Fe-2S] cluster
    - reference_id: PMID:17261801
      supporting_text: possesses an essential [2Fe-2S] cluster
core_functions:
- description: >-
    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.
  molecular_function:
    id: GO:0004325
    label: protoporphyrin ferrochelatase activity
  directly_involved_in:
  - id: GO:0006783
    label: heme biosynthetic process
  - id: GO:0006785
    label: heme B biosynthetic process
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:8276824
    supporting_text: catalyzes the terminal step in the heme
  - reference_id: PMID:8276824
    supporting_text: the insertion of ferrous iron into protoporphyrin IX
  - reference_id: PMID:17261801
    supporting_text: homodimeric, inner mitochondrial membrane-associated enzyme
  - reference_id: PMID:17261801
    supporting_text: insertion of ferrous iron into protoporphyrin IX to form protoheme IX
- description: >-
    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.
  molecular_function:
    id: GO:0051537
    label: 2 iron, 2 sulfur cluster binding
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:8973195
    supporting_text: in ligating the [2Fe-2S] cluster
  - reference_id: PMID:17261801
    supporting_text: possesses an essential [2Fe-2S] cluster
  - reference_id: file:human/FECH/FECH-uniprot.txt
    supporting_text: Binds 1 [2Fe-2S] cluster.
proposed_new_terms: []
suggested_questions:
- question: >-
    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?
- question: >-
    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?
suggested_experiments:
- description: >-
    Structure-guided reconstitution of the FECH-ABCB7-ABCB10 and FECH-mitoferrin-1
    complexes (cryo-EM) with functional iron-insertion assays to test metabolon
    channeling.
- description: >-
    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.
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/FECH/FECH-uniprot.txt
  title: UniProtKB entry P22830 (HEMH_HUMAN), Ferrochelatase, mitochondrial
  findings: []
- id: PMID:1376018
  title: A molecular defect in human protoporphyria.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Identifies the F417S EPP1 variant and confirms FECH catalyses the last step of
      heme biosynthesis; supports disease and pathway framing.
- id: PMID:15123683
  title: Frataxin-mediated iron delivery to ferrochelatase in the final step of heme
    biosynthesis.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Demonstrates frataxin as an iron donor to FECH at the matrix-side site of the
      homodimer for the terminal heme-synthesis step.
- id: PMID:17261801
  title: Substrate interactions with human ferrochelatase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Crystal structure with protoporphyrin IX bound; establishes homodimeric,
      inner-membrane-associated enzyme with an essential [2Fe-2S] cluster.
- id: PMID:1729699
  title: The molecular defect of ferrochelatase in a patient with erythropoietic protoporphyria.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      EPP molecular-defect study; describes FECH as the terminal enzyme of heme
      biosynthesis catalysing ferrous iron insertion into protoporphyrin IX.
- id: PMID:2260980
  title: Molecular cloning and sequence analysis of cDNA encoding human ferrochelatase.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Original human FECH cDNA cloning; 423-aa precursor with 54-aa leader.
- id: PMID:27599036
  title: 'A Novel Role for Progesterone Receptor Membrane Component 1 (PGRMC1): A
    Partner and Regulator of Ferrochelatase.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes PGRMC1 as a FECH partner that decreases FECH activity in vitro;
      FECH is the terminal enzyme of the heme pathway.
- id: PMID:30765471
  title: Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers in an architecturally
    defined molecular complex required for heme biosynthesis.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Defines the FECH-ABCB7-ABCB10 metabolon; dimeric FECH bridges the two ABC
      transporter homodimers in a complex required for heme biosynthesis.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale AP-MS interactome (BioPlex) source of high-throughput protein
      binding IPIs; not a defined FECH functional interaction.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput mitochondrial proteome; supports mitochondrial localization of
      FECH.
- id: PMID:36836934
  title: Proteomic Analysis of Ferrochelatase Interactome in Erythroid and Non-Erythroid
    Cells.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Maps the FECH interactome/heme metabolon (ABCB10, mitoferrin-1, PPOX, PGRMC1/2)
      across erythroid and non-erythroid cells.
- id: PMID:8276824
  title: Mammalian ferrochelatase. Expression and characterization of normal and two
    human protoporphyric ferrochelatases.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary experimental characterization of recombinant human FECH activity and
      EPP mutants (F417S <2% activity); anchors the core catalytic annotation.
- id: PMID:8973195
  title: 'Site-directed mutagenesis and spectroscopic characterization of human ferrochelatase:
    identification of residues coordinating the [2Fe-2S] cluster.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Identifies C403/C406/C411 as [2Fe-2S] cluster ligands required for activity;
      supports the cofactor-binding secondary function.
- id: Reactome:R-HSA-189465
  title: FECH binds Fe2+ to PRIN9 to form heme
  findings: []
- id: Reactome:R-HSA-9838035
  title: CLPXP binds mitochondrial matrix proteins
  findings: []
- id: Reactome:R-HSA-9838081
  title: LONP1 degrades mitochondrial matrix proteins
  findings: []
- id: Reactome:R-HSA-9838093
  title: LONP1 binds mitochondrial matrix proteins
  findings: []
- id: Reactome:R-HSA-9838289
  title: CLPXP degrades mitochondrial matrix proteins
  findings: []