id: Q96H96
gene_symbol: COQ2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  COQ2 is 4-hydroxybenzoate polyprenyltransferase (para-hydroxybenzoate:polyprenyltransferase,
  PHB:PPT; EC 2.5.1.39), a polytopic integral protein of the mitochondrial inner membrane
  belonging to the UbiA prenyltransferase family. It catalyzes the committed prenylation
  (condensation) step of coenzyme Q (ubiquinone) biosynthesis: transfer of an all-trans
  polyprenyl tail from all-trans-polyprenyl diphosphate onto the aromatic precursor
  4-hydroxybenzoate (4-HB), yielding a 4-hydroxy-3-(all-trans-polyprenyl)benzoate. In
  humans the tail is decaprenyl (10 isoprene units, made by the PDSS1/PDSS2
  decaprenyl-diphosphate synthase), so the product is 3-decaprenyl-4-hydroxybenzoate and
  the ultimate cofactor is CoQ10; the reaction requires Mg2+. The enzyme spans the inner
  membrane with multiple transmembrane helices, its catalytic core faces the matrix, and
  its C-terminus faces the intermembrane space. CoQ10 is an essential lipid electron
  carrier of the mitochondrial respiratory chain, and biallelic loss-of-function COQ2
  variants cause primary coenzyme Q10 deficiency (COQ10D1), a clinically heterogeneous
  autosomal recessive mitochondrial disease; COQ2 variants have also been reported as
  susceptibility factors for multiple system atrophy.
alternative_products:
- name: '1'
  id: Q96H96-1
- name: '3'
  id: Q96H96-3
  sequence_note: VSP_017677, VSP_017678
- name: '4'
  id: Q96H96-4
  sequence_note: VSP_061606
- name: '5'
  id: Q96H96-5
  sequence_note: VSP_061607
- name: '6'
  id: Q96H96-6
  sequence_note: VSP_061608
existing_annotations:
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) propagation of the inner-membrane location. This matches the
      experimentally established, multi-pass inner-membrane topology of COQ2 and its
      matrix-facing active site, so this is where the enzyme acts.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/COQ2/COQ2-uniprot.txt
      supporting_text: >-
        Mitochondrion inner membrane
- term:
    id: GO:0006744
    label: ubiquinone biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) assignment of the core biological process. COQ2 orthologs across
      eukaryotes and bacteria (UbiA/Coq2) all carry out the 4-HB prenylation step of
      ubiquinone biosynthesis; this is the defining BP for the gene.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/COQ2/COQ2-uniprot.txt
      supporting_text: >-
        Mediates the second step in the final reaction sequence of
- term:
    id: GO:0008412
    label: 4-hydroxybenzoate polyprenyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) assignment of the defining molecular function. Consistent with
      the human enzyme's directly demonstrated PHB:polyprenyltransferase activity and the
      UbiA family assignment.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/COQ2/COQ2-uniprot.txt
      supporting_text: >-
        Catalyzes the prenylation of para-
- term:
    id: GO:0004659
    label: prenyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Correct but non-informative parent of the specific activity. The precise function
      GO:0008412 (4-hydroxybenzoate polyprenyltransferase activity) is already annotated
      and directly supported; this general term should be replaced by it.
    action: MODIFY
    proposed_replacement_terms:
    - id: GO:0008412
      label: 4-hydroxybenzoate polyprenyltransferase activity
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic (UniRule/SubCell) assignment of the inner-membrane location, redundant
      with the IDA and IBA annotations to the same term. Correct.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/COQ2/COQ2-uniprot.txt
      supporting_text: >-
        Mitochondrion inner membrane
- term:
    id: GO:0006744
    label: ubiquinone biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic (UniRule/UniPathway) assignment of the core BP, redundant with the
      experimental IDA/IMP and phylogenetic IBA annotations. Correct.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/COQ2/COQ2-uniprot.txt
      supporting_text: >-
        Cofactor biosynthesis; ubiquinone biosynthesis.
- term:
    id: GO:0008299
    label: isoprenoid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  qualifier: involved_in
  review:
    summary: >-
      Over-general and slightly misleading for the molecular event. COQ2 consumes a
      pre-formed all-trans polyprenyl diphosphate (the isoprenoid tail is synthesized by
      the mevalonate pathway and by decaprenyl-diphosphate synthase PDSS1/PDSS2); COQ2
      itself condenses that tail onto 4-hydroxybenzoate rather than synthesizing an
      isoprenoid. The specific and accurate BP is ubiquinone biosynthetic process, which
      is already annotated. Keep only as a non-core electronic inference.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0008412
    label: 4-hydroxybenzoate polyprenyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (UniRule; RHEA/EC:2.5.1.39) assignment of the defining molecular
      function, redundant with the experimental EXP/IMP and phylogenetic IBA/TAS
      annotations. Correct and core.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/COQ2/COQ2-uniprot.txt
      supporting_text: >-
        4-hydroxybenzoate polyprenyltransferase, mitochondrial
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: >-
      Correct but uninformatively general InterPro-based location. COQ2 is specifically an
      integral protein of the mitochondrial inner membrane, which is already annotated;
      replace with that specific term.
    action: MODIFY
    proposed_replacement_terms:
    - id: GO:0005743
      label: mitochondrial inner membrane
- term:
    id: GO:0016765
    label: transferase activity, transferring alkyl or aryl (other than methyl) groups
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Correct but very general InterPro-based grandparent of the specific activity. The
      precise 4-hydroxybenzoate polyprenyltransferase activity (GO:0008412) is already
      annotated and directly demonstrated; replace with that.
    action: MODIFY
    proposed_replacement_terms:
    - id: GO:0008412
      label: 4-hydroxybenzoate polyprenyltransferase activity
- term:
    id: GO:0006744
    label: ubiquinone biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2142789
  qualifier: involved_in
  review:
    summary: >-
      Reactome traceable-author assignment of the core BP (Ubiquinol biosynthesis
      pathway). Correct and core.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/COQ2/COQ2-uniprot.txt
      supporting_text: >-
        Cofactor biosynthesis; ubiquinone biosynthesis.
- term:
    id: GO:0008412
    label: 4-hydroxybenzoate polyprenyltransferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2162192
  qualifier: enables
  review:
    summary: >-
      Reactome traceable-author assignment of the defining molecular function, describing
      the reaction in which COQ2 ligates all-trans-decaprenyl diphosphate to
      4-hydroxybenzoate to form 3-decaprenyl-4-hydroxybenzoate. Correct and core.
    action: ACCEPT
    supported_by:
    - reference_id: Reactome:R-HSA-2162192
      supporting_text: >-
        4-Hydroxybenzoate polyprenyltransferase (COQ2) catalyses the combination of 4-hydroxybenzoic acid, aka para-hydroxybenzoic acid (PHB), with the polyisoprenoid tail all-trans-decaprenyl diphosphate (all-E-10PrP2) to form 3-decaprenyl-4-hydroxybenzoate (DHB)
- term:
    id: GO:0008412
    label: 4-hydroxybenzoate polyprenyltransferase activity
  evidence_type: EXP
  original_reference_id: PMID:15153069
  qualifier: enables
  review:
    summary: >-
      Direct experimental support for the defining molecular function. Forsgren et al.
      cloned human COQ2, expressed it in a yeast coq2-null strain to restore CoQ
      biosynthesis, and showed formation of labelled CoQ from decaprenyl and nonaprenyl
      pyrophosphate precursors, demonstrating active PHB:polyprenyltransferase. Core.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:15153069
      supporting_text: >-
        CoQ formed when cells were incubated with labelled decaprenyl pyrophosphate and nonaprenyl pyrophosphate, showing that the human enzyme is active
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput mitochondrial proteome dataset localizes COQ2 to mitochondrion.
      Correct but coarse; the specific and experimentally supported location is the
      mitochondrial inner membrane, which is separately annotated. Keep as supporting,
      non-core localization evidence.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0004659
    label: prenyltransferase activity
  evidence_type: IGI
  original_reference_id: PMID:15153069
  qualifier: enables
  review:
    summary: >-
      Genetic-interaction (complementation of a yeast coq2-null mutant) support for
      prenyltransferase activity. The evidence is experimental and valid, but the term is
      a non-informative parent of the specific 4-hydroxybenzoate polyprenyltransferase
      activity (GO:0008412) that is directly demonstrated in the same study. Retained as
      an over-annotation rather than removed (experimental evidence).
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0006744
    label: ubiquinone biosynthetic process
  evidence_type: IGI
  original_reference_id: PMID:15153069
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      Genetic-interaction support (human COQ2 rescues CoQ biosynthesis in a yeast coq2
      null mutant) for involvement in ubiquinone biosynthesis. Correct and core; the
      involved_in annotations to the same term capture this more precisely.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:15153069
      supporting_text: >-
        rescued the growth of this yeast strain in the absence of a non-fermentable carbon source and restored CoQ biosynthesis
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:27493029
  qualifier: located_in
  review:
    summary: >-
      Direct experimental localization of COQ2 to the mitochondrial inner membrane, with
      defined topology (C-terminus facing the intermembrane space). This is the core,
      specific cellular component. Core.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:27493029
      supporting_text: >-
        its protein product localizes to mitochondria with the C-terminus facing the intermembrane space
- term:
    id: GO:0006744
    label: ubiquinone biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:16400613
  qualifier: involved_in
  review:
    summary: >-
      Mutant phenotype evidence: a homozygous COQ2 missense variant in patients caused a
      severe defect of CoQ10 biosynthesis (radioisotope assay in patient fibroblasts),
      establishing COQ2's requirement for ubiquinone biosynthesis. Core.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:16400613
      supporting_text: >-
        Radioisotope assays confirmed a severe defect of CoQ(10) biosynthesis in the fibroblasts of one patient
- term:
    id: GO:0006744
    label: ubiquinone biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:17374725
  qualifier: involved_in
  review:
    summary: >-
      Mutant phenotype evidence: wild-type but not mutant COQ2 complements a
      COQ2-defective yeast strain, and COQ2 mutant patient fibroblasts have reduced
      polyprenyl-pHB transferase activity, confirming involvement in ubiquinone
      biosynthesis. Core.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:17374725
      supporting_text: >-
        human wild-type, but not mutant COQ2, functionally complements COQ2 defective yeast
- term:
    id: GO:0006744
    label: ubiquinone biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:27493029
  qualifier: involved_in
  review:
    summary: >-
      Mutant phenotype evidence from a yeast complementation panel of all reported COQ2
      alleles, where residual activity correlates with clinical severity of CoQ10
      deficiency. Confirms COQ2 is required for ubiquinone biosynthesis. Core.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:27493029
      supporting_text: >-
        the residual activity of the mutant proteins correlates with the clinical phenotypes observed in patients
- term:
    id: GO:0008412
    label: 4-hydroxybenzoate polyprenyltransferase activity
  evidence_type: IMP
  original_reference_id: PMID:16400613
  qualifier: enables
  review:
    summary: >-
      Mutant phenotype evidence for the defining molecular function: a COQ2 missense
      variant abolishes/severely reduces CoQ10 biosynthesis in patient fibroblasts,
      consistent with loss of PHB:polyprenyltransferase activity. Core.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:16400613
      supporting_text: >-
        the COQ2 gene, which encodes para-hydroxybenzoate-polyprenyl transferase
- term:
    id: GO:0008412
    label: 4-hydroxybenzoate polyprenyltransferase activity
  evidence_type: IMP
  original_reference_id: PMID:17374725
  qualifier: enables
  review:
    summary: >-
      Mutant phenotype evidence for the defining molecular function: polyprenyl-pHB
      transferase activity was reduced to 33-45% of controls in COQ2 mutant fibroblasts,
      directly linking the variant to loss of this activity. Core.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:17374725
      supporting_text: >-
        Polyprenyl-pHB transferase activity was 33-45% of controls in COQ2 mutant fibroblasts
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2162192
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author assignment of the inner-membrane location, redundant with
      the experimental IDA annotation to the same term. Correct.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/COQ2/COQ2-uniprot.txt
      supporting_text: >-
        Mitochondrion inner membrane
- term:
    id: GO:0006071
    label: glycerol metabolic process
  evidence_type: IGI
  original_reference_id: PMID:15153069
  qualifier: involved_in
  review:
    summary: >-
      Almost certainly a spurious legacy annotation. The IGI with/from is UniProtKB:P32378
      (yeast GPD1, glycerol-3-phosphate dehydrogenase), and neither the cited COQ2 cloning
      paper nor any other evidence links COQ2 to glycerol metabolism; COQ2's demonstrated
      role is exclusively 4-HB prenylation in ubiquinone biosynthesis. Because this is an
      experimental (IGI) annotation it is flagged as over-annotated rather than removed,
      but it should not be treated as a real COQ2 function.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0006744
    label: ubiquinone biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:15153069
  qualifier: involved_in
  review:
    summary: >-
      Direct assay support for involvement in ubiquinone biosynthesis: expressed human
      COQ2 restored CoQ biosynthesis in a yeast coq2-null strain and produced labelled CoQ
      from polyprenyl pyrophosphate precursors. Core.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:15153069
      supporting_text: >-
        showing that the human enzyme is active and that it participates in the biosynthesis of CoQ
core_functions:
- description: >-
    4-hydroxybenzoate polyprenyltransferase (PHB:polyprenyltransferase, EC 2.5.1.39):
    catalyzes the Mg2+-dependent transfer of an all-trans polyprenyl tail (decaprenyl in
    humans) from all-trans-polyprenyl diphosphate onto 4-hydroxybenzoate, producing a
    4-hydroxy-3-(all-trans-polyprenyl)benzoate. This is the committed prenylation step of
    coenzyme Q10 biosynthesis, carried out as a multi-pass protein of the mitochondrial
    inner membrane.
  molecular_function:
    id: GO:0008412
    label: 4-hydroxybenzoate polyprenyltransferase activity
  directly_involved_in:
  - id: GO:0006744
    label: ubiquinone biosynthetic process
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: file:human/COQ2/COQ2-uniprot.txt
    supporting_text: >-
      Catalyzes the prenylation of para-
  - reference_id: PMID:17374725
    supporting_text: >-
      The product of COQ2 catalyzes the transfer of para -hydroxybenzoate to the polyprenyl chain, one of the initial steps of CoQ biosynthesis
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000104
  title: Electronic Gene Ontology annotations created by transferring manual GO annotations
    between related proteins based on shared sequence features
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:15153069
  title: Isolation and functional expression of human COQ2, a gene encoding a polyprenyl
    transferase involved in the synthesis of CoQ.
  findings:
  - statement: >-
      Human COQ2 was cloned and shown to be an active polyprenyltransferase; expressed in
      a yeast coq2-null mutant it restored CoQ biosynthesis and produced labelled CoQ from
      decaprenyl and nonaprenyl pyrophosphate precursors.
    reference_section_type: ABSTRACT
    supporting_text: >-
      The human COQ2 gene, when expressed in yeast Coq2 null mutant cells, rescued the growth of this yeast strain in the absence of a non-fermentable carbon source and restored CoQ biosynthesis.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified primary cloning/functional-expression paper for human COQ2;
      underpins the EXP molecular-function and IGI/IDA process annotations.
- id: PMID:16400613
  title: A mutation in para-hydroxybenzoate-polyprenyl transferase (COQ2) causes primary
    coenzyme Q10 deficiency.
  findings:
  - statement: >-
      A homozygous COQ2 missense mutation caused primary CoQ10 deficiency, with a severe
      biosynthetic defect confirmed by radioisotope assay in patient fibroblasts.
    reference_section_type: ABSTRACT
    supporting_text: >-
      Radioisotope assays confirmed a severe defect of CoQ(10) biosynthesis in the fibroblasts of one patient.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified; first molecular cause of primary CoQ10 deficiency; supports IMP
      annotations for GO:0006744 and GO:0008412.
- id: PMID:17374725
  title: Missense mutation of the COQ2 gene causes defects of bioenergetics and de
    novo pyrimidine synthesis.
  findings:
  - statement: >-
      Wild-type but not mutant COQ2 complements COQ2-defective yeast, and polyprenyl-pHB
      transferase activity was reduced to 33-45% of controls in COQ2 mutant fibroblasts,
      confirming the enzymatic and biosynthetic defect.
    reference_section_type: ABSTRACT
    supporting_text: >-
      Polyprenyl-pHB transferase activity was 33-45% of controls in COQ2 mutant fibroblasts.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified; full text available. Demonstrates pathogenicity of a COQ2 mutation
      and reduced PHB:polyprenyltransferase activity; pyrimidine-synthesis defect is a
      downstream consequence of CoQ10 deficiency, not a direct COQ2 function.
- id: PMID:27493029
  title: The COQ2 genotype predicts the severity of coenzyme Q10 deficiency.
  findings:
  - statement: >-
      Defined COQ2 structure and subcellular localization (mitochondria, C-terminus facing
      the intermembrane space) and, via yeast complementation of all reported alleles,
      showed that residual COQ2 activity correlates with clinical severity.
    reference_section_type: ABSTRACT
    supporting_text: >-
      its protein product localizes to mitochondria with the C-terminus facing the intermembrane space
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified; source of the IDA inner-membrane localization/topology and IMP
      genotype-phenotype annotations.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings:
  - statement: >-
      COQ2 is detected in a high-confidence quantitative human mitochondrial proteome
      dataset, consistent with mitochondrial localization.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      High-throughput proteomics localization to mitochondrion; corroborates but is
      coarser than the experimental inner-membrane annotation.
- id: Reactome:R-HSA-2142789
  title: Ubiquinol biosynthesis
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome pathway for ubiquinol biosynthesis; source of the TAS GO:0006744
      annotation.
- id: Reactome:R-HSA-2162192
  title: COQ2 ligates all-E-10PrP2 to PHB
  findings:
  - statement: >-
      COQ2 combines 4-hydroxybenzoate (PHB) with all-trans-decaprenyl diphosphate to form
      3-decaprenyl-4-hydroxybenzoate, the human decaprenyl prenylation step of CoQ10
      biosynthesis.
    supporting_text: >-
      4-Hydroxybenzoate polyprenyltransferase (COQ2) catalyses the combination of 4-hydroxybenzoic acid, aka para-hydroxybenzoic acid (PHB), with the polyisoprenoid tail all-trans-decaprenyl diphosphate (all-E-10PrP2) to form 3-decaprenyl-4-hydroxybenzoate (DHB)
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction describing the COQ2-catalyzed step; source of the TAS GO:0008412
      annotation.