id: P36551
gene_symbol: CPOX
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  CPOX encodes oxygen-dependent coproporphyrinogen-III oxidase (EC 1.3.3.3), the
  enzyme that catalyzes the sixth step of heme biosynthesis. It carries out the
  aerobic (O2-dependent) oxidative decarboxylation of the propionate side chains on
  rings A and B of coproporphyrinogen III to yield the vinyl groups of
  protoporphyrinogen IX, releasing 2 CO2 and 2 H2O. The enzyme is unusual in being
  metal- and cofactor-independent and functions as a homodimer. It is a nuclear-encoded
  mitochondrial protein that, after cleavage of an N-terminal transit peptide, localizes
  to the mitochondrial intermembrane space in association with the inner membrane.
  Loss-of-function mutations cause the acute hepatic porphyria hereditary coproporphyria
  (HCP); a specific set of variants (e.g. K404E, H327R) instead produce the rare
  erythropoietic variant harderoporphyria (HARPO).
alternative_products:
- name: '1'
  id: P36551-1
- name: '2'
  id: P36551-2
  sequence_note: VSP_057182, VSP_057183
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) placement of the enzyme in the cytoplasm. CPOX is a
      nuclear-encoded mitochondrial enzyme that localizes specifically to the
      mitochondrial intermembrane space, so "cytoplasm" is imprecise for the human
      protein.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The enzyme is not a general cytoplasmic protein; it is targeted to the
      mitochondrion via an N-terminal transit peptide and resides in the mitochondrial
      intermembrane space. The more accurate compartment (GO:0005758 / GO:0005739) is
      captured by other, better-supported annotations, so the broad cytoplasm term is an
      over-annotation for this gene.
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - COMPARTMENT_OR_COMPLEX_MISMATCH
      source_entities:
      - source_id: PANTHER:PTN000079415
        source_label: coproporphyrinogen oxidase family node
        comment: >-
          Family-level cytoplasm assignment is too broad; the human ortholog is
          specifically mitochondrial intermembrane space.
    supported_by:
    - reference_id: file:human/CPOX/CPOX-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion intermembrane space'
    - reference_id: PMID:8407975
      supporting_text: mammalian coproporphyrinogen oxidase is mitochondrial enzyme
- term:
    id: GO:0006783
    label: heme biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) assignment to heme biosynthesis, the core biological process
      for CPOX. CPOX catalyzes the sixth (O2-dependent) step of the heme biosynthetic
      pathway, converting coproporphyrinogen III to protoporphyrinogen IX.
    action: ACCEPT
    reason: >-
      This is the central, well-established biological role of the enzyme, agreed across
      IBA, IEA, and experimental/TAS evidence.
    supported_by:
    - reference_id: PMID:8159699
      supporting_text: >-
        Coproporphyrinogen oxidase (EC 1.3.3.3) catalyzes the sixth step in the heme
        biosynthetic pathway, the oxidation of coproporphyrinogen III to
        protoporphyrinogen IX
- term:
    id: GO:0004109
    label: coproporphyrinogen oxidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) assignment of the diagnostic molecular function,
      coproporphyrinogen oxidase activity (EC 1.3.3.3). This is the core catalytic
      activity of CPOX and is directly supported by biochemical experiments.
    action: ACCEPT
    reason: >-
      Core molecular function, concordant with the enzyme's experimentally verified
      activity and EC number.
    supported_by:
    - reference_id: PMID:8159699
      supporting_text: >-
        Coproporphyrinogen oxidase (EC 1.3.3.3) catalyzes the sixth step in the heme
        biosynthetic pathway, the oxidation of coproporphyrinogen III to
        protoporphyrinogen IX
- term:
    id: GO:0004109
    label: coproporphyrinogen oxidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assignment of coproporphyrinogen oxidase activity via combined IEA
      methods (ARBA, InterPro IPR001260/IPR018375/IPR036406, RHEA:18257, EC:1.3.3.3).
      Consistent with the experimentally established catalytic function.
    action: ACCEPT
    reason: >-
      Correct EC/InterPro/RHEA mapping to the enzyme's core catalytic activity; agrees
      with experimental evidence.
    supported_by:
    - reference_id: file:human/CPOX/CPOX-uniprot.txt
      supporting_text: >-
        Catalyzes the aerobic oxidative decarboxylation of propionate
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic assignment (UniProtKB Subcellular Location mapping) of localization to
      the mitochondrial intermembrane space. This is the curated subcellular location of
      the mature enzyme.
    action: ACCEPT
    reason: >-
      Matches the curated UniProt subcellular location and independent TAS/ISS
      annotations to the same term.
    supported_by:
    - reference_id: file:human/CPOX/CPOX-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion intermembrane space'
- term:
    id: GO:0006779
    label: porphyrin-containing compound biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic assignment to porphyrin-containing compound biosynthesis, a broad
      parent process. CPOX participates in this via the heme branch, but the more
      specific and better-supported term is heme biosynthetic process (GO:0006783).
    action: KEEP_AS_NON_CORE
    reason: >-
      Biologically correct but more general than the specific heme biosynthetic role;
      retained as a non-core, broader-parent annotation rather than the core function.
    supported_by:
    - reference_id: file:human/CPOX/CPOX-uniprot.txt
      supporting_text: >-
        protoporphyrinogen-IX from coproporphyrinogen-III (O2
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Electronic transfer (Ensembl Compara, from rat/mouse ortholog) of localization to
      the mitochondrial inner membrane. CPOX is described as residing in the
      intermembrane space in association with the inner membrane, so this is plausible
      but not the primary curated compartment.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with the enzyme being IMS-facing and inner-membrane-associated, but the
      primary, experimentally/curator-supported location is the intermembrane space
      (GO:0005758). Retained as a plausible non-core localization.
    supported_by:
    - reference_id: file:human/CPOX/CPOX-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion intermembrane space'
- term:
    id: GO:0006783
    label: heme biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic assignment (ARBA/combined IEA methods) to heme biosynthetic process,
      the core biological role of CPOX. Concordant with IBA and experimental/TAS
      annotations to the same term.
    action: ACCEPT
    reason: >-
      Correct assignment of the core biological process, agreeing with all other
      evidence lines.
    supported_by:
    - reference_id: PMID:8159699
      supporting_text: >-
        Coproporphyrinogen oxidase (EC 1.3.3.3) catalyzes the sixth step in the heme
        biosynthetic pathway
- term:
    id: GO:0010039
    label: response to iron ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic transfer (Ensembl Compara, from the rat ortholog Q3B7D0) of a "response
      to iron ion" phenotype. This is a peripheral, ortholog-derived stress/metal
      response, not a demonstrated function of human CPOX.
    action: KEEP_AS_NON_CORE
    reason: >-
      Plausible ortholog-transferred physiological response (heme synthesis is
      iron-linked), but not a core function and not directly demonstrated for the human
      protein; retained as non-core rather than removed.
    supported_by:
    - reference_id: file:human/CPOX/CPOX-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion intermembrane space'
- term:
    id: GO:0010288
    label: response to lead ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic transfer (Ensembl Compara, from the rat ortholog) of a "response to
      lead ion" phenotype. Lead inhibits heme-pathway enzymes, so this is a plausible
      ortholog-derived toxicological response, but it is not a demonstrated function of
      human CPOX.
    action: KEEP_AS_NON_CORE
    reason: >-
      Peripheral ortholog-transferred toxicant response; not core and not shown for the
      human protein, but not clearly wrong, so retained as non-core.
    supported_by:
    - reference_id: file:human/CPOX/CPOX-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion intermembrane space'
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Electronic transfer (Ensembl Compara, from mouse ortholog P36552) of the
      uninformative broad location "membrane". The specific, curated compartment is the
      mitochondrial intermembrane space.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "membrane" is an uninformative high-level CC term; the enzyme's location is
      captured precisely by GO:0005758 (and plausibly GO:0005743), making this broad term
      redundant/over-annotated.
    supported_by:
    - reference_id: file:human/CPOX/CPOX-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion intermembrane space'
- term:
    id: GO:0017085
    label: response to insecticide
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic transfer (Ensembl Compara, from the rat ortholog) of a "response to
      insecticide" phenotype. This is a peripheral, ortholog-derived response with no
      direct evidence in human CPOX.
    action: KEEP_AS_NON_CORE
    reason: >-
      Ortholog-transferred toxicant response; peripheral and unverified for the human
      protein, retained as non-core rather than removed.
    supported_by:
    - reference_id: file:human/CPOX/CPOX-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion intermembrane space'
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Electronic transfer (Ensembl Compara, from the rat ortholog) of "identical protein
      binding". CPOX is indeed a homodimer, so it self-associates, but a more informative
      and directly experimentally supported term exists: protein homodimerization
      activity (GO:0042803, IDA from the crystal-structure/AUC study).
    action: MODIFY
    reason: >-
      The self-association is real, but "identical protein binding" is a weak binding
      term. It should be represented by the more specific GO:0042803 protein
      homodimerization activity, which is directly supported for the human enzyme.
    proposed_replacement_terms:
    - id: GO:0042803
      label: protein homodimerization activity
    supported_by:
    - reference_id: PMID:16176984
      supporting_text: >-
        In the biologically active dimer (K(D) =
        5 x 10(-7) M)
- term:
    id: GO:0046685
    label: response to arsenic-containing substance
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic transfer (Ensembl Compara, from the rat ortholog) of a "response to
      arsenic-containing substance" phenotype. Peripheral ortholog-derived response with
      no direct human evidence.
    action: KEEP_AS_NON_CORE
    reason: >-
      Ortholog-transferred toxicant response; peripheral and unverified for human CPOX,
      retained as non-core.
    supported_by:
    - reference_id: file:human/CPOX/CPOX-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion intermembrane space'
- term:
    id: GO:0051597
    label: response to methylmercury
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic transfer (Ensembl Compara, from the rat ortholog) of a "response to
      methylmercury" phenotype. Peripheral ortholog-derived response with no direct human
      evidence.
    action: KEEP_AS_NON_CORE
    reason: >-
      Ortholog-transferred toxicant response; peripheral and unverified for human CPOX,
      retained as non-core.
    supported_by:
    - reference_id: file:human/CPOX/CPOX-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion intermembrane space'
- term:
    id: GO:0006785
    label: heme B biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:7987309
  qualifier: involved_in
  review:
    summary: >-
      Assignment to heme B biosynthetic process. Heme b is the end product of the
      protoporphyrin IX / heme branch that CPOX feeds, so the enzyme is genuinely part of
      heme b biosynthesis. However, CPOX's direct step produces protoporphyrinogen IX,
      several steps upstream of heme b, and the cited reference (PMID:7987309) is a
      gene-organization/exon-6-skipping study rather than a heme-b assay.
    action: KEEP_AS_NON_CORE
    reason: >-
      Biologically correct as a downstream pathway membership, but less direct than the
      core "heme biosynthetic process" and the immediate protoporphyrinogen IX step;
      retained as non-core. The essence of the pathway role is sound, so it is not
      removed.
    supported_by:
    - reference_id: PMID:8159699
      supporting_text: >-
        Coproporphyrinogen oxidase (EC 1.3.3.3) catalyzes the sixth step in the heme
        biosynthetic pathway
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence-based (HPA, IDA) localization to the mitochondrion. Consistent
      with CPOX being a nuclear-encoded mitochondrial enzyme.
    action: ACCEPT
    reason: >-
      Directly observed mitochondrial localization, concordant with the intermembrane
      space annotations and mass-spectrometry evidence.
    supported_by:
    - reference_id: PMID:8407975
      supporting_text: mammalian coproporphyrinogen oxidase is mitochondrial enzyme
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-189421
  qualifier: located_in
  review:
    summary: >-
      Reactome-curated (TAS) localization to the mitochondrial intermembrane space, where
      CPOX catalyzes conversion of coproporphyrinogen III to protoporphyrinogen IX. This
      is the primary curated compartment for the enzyme.
    action: ACCEPT
    reason: >-
      Matches the curated UniProt location and independent ISS/IEA annotations to the
      same term; well supported.
    supported_by:
    - reference_id: file:human/CPOX/CPOX-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion intermembrane space'
- term:
    id: GO:0004109
    label: coproporphyrinogen oxidase activity
  evidence_type: EXP
  original_reference_id: PMID:8159699
  qualifier: enables
  review:
    summary: >-
      Experimental (EXP) demonstration of coproporphyrinogen oxidase activity: expression
      of the human cDNA in E. coli produced a 17-fold increase in coproporphyrinogen
      oxidase activity, directly establishing the catalytic function.
    action: ACCEPT
    reason: >-
      Directly demonstrated core catalytic function of the enzyme; strongest evidence line
      for the molecular function.
    supported_by:
    - reference_id: PMID:8159699
      supporting_text: >-
        17-fold increase in coproporphyrinogen activity over endogenous activity
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity-based (ISS, from the rat ortholog Q3B7D0) localization to the
      mitochondrial intermembrane space. Consistent with the curated UniProt location and
      the Reactome TAS annotation.
    action: ACCEPT
    reason: >-
      Concordant with the curated primary compartment and multiple independent evidence
      lines for the intermembrane space.
    supported_by:
    - reference_id: file:human/CPOX/CPOX-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion intermembrane space'
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput (HTP) mass-spectrometry evidence placing CPOX in the human
      mitochondrial proteome. Consistent with its established mitochondrial localization.
    action: ACCEPT
    reason: >-
      Corroborates mitochondrial localization by an independent proteomic method;
      concordant with IDA and IMS annotations.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: high-confidence human mitochondrial proteome
- term:
    id: GO:0004109
    label: coproporphyrinogen oxidase activity
  evidence_type: IDA
  original_reference_id: PMID:7987309
  qualifier: enables
  review:
    summary: >-
      Direct-assay (IDA) assignment of coproporphyrinogen oxidase activity. This is the
      core, experimentally established catalytic function of CPOX (EC 1.3.3.3), redundant
      with the EXP/IBA/IEA/TAS annotations to the same term.
    action: ACCEPT
    reason: >-
      Core molecular function; duplicate GO id with additional evidence support is
      acceptable and reinforces the annotation.
    supported_by:
    - reference_id: PMID:8159699
      supporting_text: >-
        Coproporphyrinogen oxidase (EC 1.3.3.3) catalyzes the sixth step in the heme
        biosynthetic pathway, the oxidation of coproporphyrinogen III to
        protoporphyrinogen IX
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:16176984
  qualifier: enables
  review:
    summary: >-
      Direct (IDA) evidence that CPOX self-associates into a homodimer, from the 1.58 A
      crystal structure and analytical ultracentrifugation (KD ~5 x 10^-7 M). The dimer
      interface, formed in part by exon-6-encoded residues (392-418), is required for the
      biologically active enzyme.
    action: ACCEPT
    reason: >-
      Well-supported, informative molecular function directly demonstrated for the human
      enzyme; the homodimer is the functional unit. Non-core relative to catalysis but
      correct.
    supported_by:
    - reference_id: PMID:16176984
      supporting_text: >-
        In the biologically active dimer (K(D) =
        5 x 10(-7) M)
    - reference_id: file:human/CPOX/CPOX-uniprot.txt
      supporting_text: 'SUBUNIT: Homodimer'
- term:
    id: GO:0004109
    label: coproporphyrinogen oxidase activity
  evidence_type: TAS
  original_reference_id: PMID:9888388
  qualifier: enables
  review:
    summary: >-
      Author-stated (TAS) coproporphyrinogen oxidase activity in a systematic HCP mutation
      study; several disease mutations abolished or dramatically reduced CPO activity when
      expressed in a prokaryotic system, confirming the catalytic function.
    action: ACCEPT
    reason: >-
      Core catalytic function, supported by functional assessment of disease mutations;
      concordant with the EXP/IDA/IBA evidence.
    supported_by:
    - reference_id: PMID:9888388
      supporting_text: >-
        These mutations resulted in the absence or a dramatic decrease of
        CPO activity
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: TAS
  original_reference_id: PMID:8407975
  qualifier: located_in
  review:
    summary: >-
      Author-stated (TAS) mitochondrial localization: purification/cloning work showed CPO
      activity is mainly present in mitochondria of transfected cells, establishing that
      mammalian coproporphyrinogen oxidase is a mitochondrial enzyme.
    action: ACCEPT
    reason: >-
      Directly supports mitochondrial localization; concordant with IDA/HTP/IMS
      annotations.
    supported_by:
    - reference_id: PMID:8407975
      supporting_text: mammalian coproporphyrinogen oxidase is mitochondrial enzyme
- term:
    id: GO:0006783
    label: heme biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:8159699
  qualifier: involved_in
  review:
    summary: >-
      Author-stated (TAS) participation in heme biosynthesis: CPO catalyzes the sixth step
      of the heme biosynthetic pathway. This is the core biological process for CPOX.
    action: ACCEPT
    reason: >-
      Core biological process, directly stated by the primary functional-expression paper
      and concordant with all other evidence.
    supported_by:
    - reference_id: PMID:8159699
      supporting_text: >-
        Coproporphyrinogen oxidase (EC 1.3.3.3) catalyzes the sixth step in the heme
        biosynthetic pathway
core_functions:
- description: >-
    Oxygen-dependent coproporphyrinogen-III oxidase catalyzing the sixth step of heme
    biosynthesis: the O2-dependent oxidative decarboxylation of the propionate side chains
    on rings A and B of coproporphyrinogen III to vinyl groups, forming protoporphyrinogen
    IX. Acts as a homodimer in the mitochondrial intermembrane space.
  molecular_function:
    id: GO:0004109
    label: coproporphyrinogen oxidase activity
  directly_involved_in:
  - id: GO:0006783
    label: heme biosynthetic process
  locations:
  - id: GO:0005758
    label: mitochondrial intermembrane space
  supported_by:
  - reference_id: PMID:8159699
    supporting_text: >-
      Coproporphyrinogen oxidase (EC 1.3.3.3) catalyzes the sixth step in the heme
      biosynthetic pathway, the oxidation of coproporphyrinogen III to protoporphyrinogen
      IX
  - reference_id: file:human/CPOX/CPOX-uniprot.txt
    supporting_text: >-
      groups in protoporphyrinogen-IX and participates to the sixth step in
proposed_new_terms:
- proposed_name: protoporphyrinogen IX biosynthetic process
  proposed_definition: >-
    The chemical reactions and pathways resulting in the formation of protoporphyrinogen
    IX from coproporphyrinogen III, the immediate product of the coproporphyrinogen oxidase
    reaction in the heme biosynthetic pathway.
  justification: >-
    The most direct biological-process term for CPOX's step is the biosynthesis of
    protoporphyrinogen IX, the immediate product of the coproporphyrinogen oxidase reaction.
    This is more specific than the broadly-annotated heme biosynthetic process. The term
    already exists as GO:0006782 (it is listed in the UniProt DR GO section as
    IDA:UniProt) but is absent from the seeded GOA; adding it would capture the enzyme's
    direct product-level role.
  supported_by:
  - reference_id: PMID:8159699
    supporting_text: >-
      the oxidation of coproporphyrinogen III to protoporphyrinogen IX
  - reference_id: file:human/CPOX/CPOX-uniprot.txt
    supporting_text: >-
      protoporphyrinogen-IX from coproporphyrinogen-III (O2
suggested_questions:
- question: >-
    What is the physiological basis for the mitochondrial intermembrane-space localization,
    and how is coproporphyrinogen III delivered from the cytosol and protoporphyrinogen IX
    handed off to the inner-membrane protoporphyrinogen oxidase (PPOX)?
- question: >-
    Why do a small subset of CPOX mutations (e.g. K404E, H327R) produce the erythropoietic
    harderoporphyria phenotype rather than classic hereditary coproporphyria?
suggested_experiments:
- description: >-
    Steady-state and single-turnover kinetics of purified recombinant human CPOX homodimer
    to define the two sequential decarboxylation steps and the role of O2 as electron
    acceptor.
- description: >-
    Structure-guided mutagenesis of the exon-6-encoded dimer interface (residues 392-418)
    and active-site residues (Ser-244, His-258, Asn-260, Arg-262, Asp-282, Arg-332) to
    correlate dimerization/catalysis with HCP vs HARPO disease phenotypes.
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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16176984
  title: Structural basis of hereditary coproporphyria.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. 1.58 A crystal structure of human CPO; directly supports the
      homodimer (GO:0042803) and defines active-site residues and the cofactor-independent
      mechanism.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      High-throughput proteomics; supports mitochondrial localization (GO:0005739) as an
      HTP corroboration.
- id: PMID:7987309
  title: 'Coproporphyrinogen oxidase: gene organization and description of a mutation
    leading to exon 6 skipping.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Gene organization (7 exons/6 introns) and an exon-6-skipping HCP mutation; used as
      the original reference for a heme-B IDA, which is an indirect fit, but the citation
      itself is correct.
- id: PMID:8159699
  title: Molecular cloning, sequencing, and functional expression of a cDNA encoding
    human coproporphyrinogen oxidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary functional-expression paper; directly establishes the coproporphyrinogen
      oxidase activity (17-fold activity increase in E. coli) and the sixth-step heme role.
- id: PMID:8407975
  title: Coproporphyrinogen oxidase. Purification, molecular cloning, and induction
    of mRNA during erythroid differentiation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Purification/cloning; demonstrates mammalian CPO is a mitochondrial enzyme and its
      induction during erythroid differentiation.
- id: PMID:9888388
  title: Systematic analysis of coproporphyrinogen oxidase gene defects in hereditary
    coproporphyria and mutation update.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Systematic HCP mutation update; disease mutations abolish/reduce CPO activity,
      supporting both the catalytic function and the HCP disease association.
- id: Reactome:R-HSA-189421
  title: CPO transforms COPRO3 to PPGEN9
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction for the CPOX step; supports IMS localization (inferred from the rat
      ortholog) and the homodimeric active form.
- id: file:human/CPOX/CPOX-uniprot.txt
  title: UniProtKB entry P36551 (HEM6_HUMAN), oxygen-dependent coproporphyrinogen-III
    oxidase, mitochondrial
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Curated UniProt record used for FUNCTION, CATALYTIC ACTIVITY, PATHWAY, SUBUNIT, and
      SUBCELLULAR LOCATION supporting quotes.