id: Q16854
gene_symbol: DGUOK
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  DGUOK is the mitochondrial deoxyguanosine kinase, the purine arm of the
  mitochondrial deoxyribonucleoside salvage pathway. Acting in the mitochondrial
  matrix, it catalyses the initial, rate-limiting phosphorylation of the purine
  deoxyribonucleosides deoxyguanosine and deoxyadenosine (and deoxyinosine) to
  their monophosphates dGMP and dAMP, using ATP (or another nucleoside
  triphosphate) as phosphate donor. It is a nuclear-encoded protein imported into
  mitochondria via a cleaved N-terminal transit peptide, functions as a homodimer,
  and belongs to the DCK/DGK deoxyribonucleoside kinase family. Together with
  thymidine kinase 2 (TK2, the pyrimidine arm), DGUOK supplies the dNTP precursors
  required for mitochondrial DNA replication, a role that becomes essential in
  non-proliferating, post-mitotic tissues where cytosolic de-novo dNTP synthesis is
  down-regulated. Loss-of-function variants cause hepatocerebral mitochondrial DNA
  depletion syndrome (MTDPS3), and DGUOK mutations are also associated with
  non-cirrhotic portal hypertension and adult-onset progressive external
  ophthalmoplegia with multiple mtDNA deletions.
alternative_products:
- name: '1'
  id: Q16854-1
- name: '2'
  id: Q16854-2
  sequence_note: VSP_003025
- name: '3'
  id: Q16854-3
  sequence_note: VSP_003024
- name: '4'
  id: Q16854-4
  sequence_note: VSP_003024, VSP_003025
- name: '5'
  id: Q16854-5
  sequence_note: VSP_003026, VSP_003024
- name: '6'
  id: Q16854-6
  sequence_note: VSP_056026, VSP_056027
existing_annotations:
- term:
    id: GO:0004136
    label: deoxyadenosine kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) assignment of deoxyadenosine kinase activity. This is a
      genuine, experimentally confirmed activity of DGUOK: recombinant human dGK
      phosphorylates deoxyadenosine (EC 2.7.1.76) in addition to its preferred
      substrate deoxyguanosine. Correct and part of the core molecular function.
    action: ACCEPT
    reason: >-
      DGUOK phosphorylates deoxyadenosine as well as deoxyguanosine, an activity
      demonstrated directly for the recombinant human enzyme and encoded as
      EC 2.7.1.76 in UniProt.
    supported_by:
      - reference_id: PMID:8706825
        supporting_text: >-
          phosphorylation of dGuo, arabinosyl guanine, dAdo, 2-chloro-2'-deoxyadenosine
      - reference_id: file:human/DGUOK/DGUOK-uniprot.txt
        supporting_text: "EC=2.7.1.76"
- term:
    id: GO:0004137
    label: deoxycytidine kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) assignment of deoxycytidine kinase activity. DGUOK is a
      purine-specific deoxyribonucleoside kinase; deoxycytidine is the substrate of
      the paralog deoxycytidine kinase (DCK), not DGUOK. This IBA over-reaches from
      the shared DCK/DGK family tree onto DGUOK.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Human DGUOK efficiently phosphorylates the purine deoxyribonucleosides
      deoxyguanosine and deoxyadenosine, whereas pyrimidine deoxyribonucleosides
      (deoxycytidine) are handled by other kinases; deoxycytidine kinase activity is
      not a demonstrated DGUOK function and is inappropriately transferred across the
      family tree. The related paralog DCK carries this activity. The seeding PANTHER
      family (PTN002236991) groups purine-specific DGUOK/DGK orthologs together with
      the broader-specificity deoxycytidine kinase (DCK) clade, so deoxycytidine
      (a DCK substrate) kinase activity leaks onto DGUOK.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
        - WRONG_ORTHOLOG_OR_PARALOG
        - FUNCTIONAL_DIVERGENCE
      source_entities:
        - source_id: PANTHER:PTN002236991
          source_label: DCK/DGK deoxyribonucleoside kinase family node
        - source_id: UniProtKB:P27707
          source_label: DCK (deoxycytidine kinase paralog carrying dCyd activity)
    supported_by:
      - reference_id: PMID:11687801
        supporting_text: >-
          efficiently phosphorylates
      - reference_id: PMID:11687801
        supporting_text: >-
          deoxyguanosine and deoxyadenosine, whereas TK2 phosphorylates
- term:
    id: GO:0004138
    label: deoxyguanosine kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) assignment of deoxyguanosine kinase activity. This is the
      defining, best-supported molecular function of DGUOK (EC 2.7.1.113): it
      phosphorylates deoxyguanosine with highest efficiency. Core function.
    action: ACCEPT
    reason: >-
      Deoxyguanosine kinase activity is the primary, experimentally established
      catalytic activity of DGUOK and is consistent across the phylogeny; this is
      the core molecular function.
    supported_by:
      - reference_id: PMID:11687801
        supporting_text: >-
          efficiently phosphorylates
      - reference_id: file:human/DGUOK/DGUOK-uniprot.txt
        supporting_text: "EC=2.7.1.113"
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) is_active_in cytoplasm. DGUOK is a mitochondrial
      matrix-resident enzyme (nuclear-encoded, imported via a cleaved N-terminal
      transit peptide). The pan-family IBA reflects the cytosolic paralogs (e.g. DCK)
      rather than DGUOK itself; the specific, correct compartment is the
      mitochondrion / mitochondrial matrix.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      DGUOK acts in the mitochondrial matrix, not the general cytoplasm; the cytoplasm
      IBA is transferred from cytosolic family members and is superseded by the more
      specific and experimentally supported mitochondrial/matrix localisation. The
      seeding family node (PTN000053758) includes cytosolic deoxyribonucleoside
      kinases (e.g. DCK), whose cytoplasmic localisation does not apply to the
      matrix-targeted DGUOK.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
        - COMPARTMENT_OR_COMPLEX_MISMATCH
        - WRONG_ORTHOLOG_OR_PARALOG
      source_entities:
        - source_id: PANTHER:PTN000053758
          source_label: deoxyribonucleoside kinase family node (mixed cytosolic/mitochondrial members)
        - source_id: UniProtKB:P27707
          source_label: DCK (cytosolic paralog)
    supported_by:
      - reference_id: PMID:8706825
        supporting_text: >-
          phosphorylation of purine deoxyribonucleosides in the
      - reference_id: file:human/DGUOK/DGUOK-uniprot.txt
        supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) is_active_in mitochondrion. Correct: DGUOK is a
      mitochondrial deoxyribonucleoside salvage enzyme acting in the matrix.
    action: ACCEPT
    reason: >-
      DGUOK is localised to and active within the mitochondrion (matrix), consistent
      with its role in supplying dNTP precursors for mtDNA replication.
    supported_by:
      - reference_id: PMID:8706825
        supporting_text: >-
          phosphorylation of purine deoxyribonucleosides in the
      - reference_id: file:human/DGUOK/DGUOK-uniprot.txt
        supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
- term:
    id: GO:0004136
    label: deoxyadenosine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated EC/RHEA-based (IEA) assignment of deoxyadenosine kinase activity
      (EC 2.7.1.76, RHEA:23452). Consistent with the experimentally verified activity.
    action: ACCEPT
    reason: >-
      Mapping matches the UniProt EC 2.7.1.76 catalytic activity and the
      experimentally demonstrated deoxyadenosine phosphorylation by DGUOK.
    supported_by:
      - reference_id: file:human/DGUOK/DGUOK-uniprot.txt
        supporting_text: "EC=2.7.1.76"
- term:
    id: GO:0004138
    label: deoxyguanosine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated EC/RHEA-based (IEA) assignment of deoxyguanosine kinase activity
      (EC 2.7.1.113, RHEA:19201). Matches the core, experimentally verified activity.
    action: ACCEPT
    reason: >-
      Mapping matches the UniProt EC 2.7.1.113 catalytic activity and the primary
      experimentally demonstrated function of DGUOK.
    supported_by:
      - reference_id: file:human/DGUOK/DGUOK-uniprot.txt
        supporting_text: "EC=2.7.1.113"
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based (IEA) ATP binding. DGUOK uses ATP (or another NTP) as the
      phosphate donor; the crystal structure defines discrete ATP-binding residues
      (P-loop / glycine-rich motif). Correct supporting molecular function.
    action: ACCEPT
    reason: >-
      ATP binding is required for the phosphotransfer reaction and is directly
      supported by the ligand-binding residues resolved in the DGUOK crystal structure.
    supported_by:
      - reference_id: file:human/DGUOK/DGUOK-uniprot.txt
        supporting_text: >-
          Reaction=2'-deoxyguanosine + ATP = dGMP + ADP + H(+)
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt Subcellular Location mapping (IEA) to mitochondrion. Correct primary
      localisation of DGUOK.
    action: ACCEPT
    reason: >-
      DGUOK is a nuclear-encoded mitochondrial matrix protein; the SubCell mapping is
      accurate.
    supported_by:
      - reference_id: file:human/DGUOK/DGUOK-uniprot.txt
        supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
- term:
    id: GO:0019136
    label: deoxynucleoside kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated (IEA) assignment of the broad parent term deoxynucleoside kinase
      activity. Correct but generic: DGUOK is a deoxyribonucleoside (deoxyguanosine/
      deoxyadenosine) kinase. Valid umbrella term above the specific EC-based terms.
    action: ACCEPT
    reason: >-
      DGUOK is a deoxyribonucleoside kinase; this parent term is accurate though less
      informative than the specific deoxyguanosine/deoxyadenosine kinase activities.
    supported_by:
      - reference_id: file:human/DGUOK/DGUOK-uniprot.txt
        supporting_text: "Belongs to the DCK/DGK family"
- term:
    id: GO:1901135
    label: carbohydrate derivative metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA machine-learning (IEA) assignment of a very high-level process term.
      Nucleotides/nucleosides are carbohydrate derivatives, so this is technically
      correct but far too generic to be informative about DGUOK's function.
    action: KEEP_AS_NON_CORE
    reason: >-
      The term is a broad, non-specific umbrella; it is not wrong (deoxyribonucleotides
      are carbohydrate derivatives) but conveys nothing about the specific
      deoxyribonucleoside salvage role. Retained as non-core.
    supported_by:
      - reference_id: file:human/DGUOK/DGUOK-uniprot.txt
        supporting_text: >-
          phosphorylation of purine deoxyribonucleosides in the
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      IntAct/BioPlex high-throughput AP-MS interaction (WITH/FROM DCK, P27707).
      "Protein binding" is uninformative about molecular function; the underlying
      DGUOK-DCK interaction is documented in UniProt but does not describe a
      distinct molecular function of DGUOK.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding provides no functional information and derives from a
      proteome-scale AP-MS screen; per curation policy it is marked as over-annotated
      rather than removed. The captured DCK interaction is recorded in the UniProt
      INTERACTION block.
    supported_by:
      - reference_id: PMID:33961781
        supporting_text: >-
          suggesting functions for thousands of proteins
      - reference_id: file:human/DGUOK/DGUOK-uniprot.txt
        supporting_text: "Q16854; P27707: DCK;"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: >-
      IntAct interaction from a genome-scale multimodal cell-map study
      (WITH/FROM DCK, P27707). As with the BioPlex IPI, "protein binding" is a
      non-informative molecular-function term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative bare protein-binding term from a high-throughput interactome map;
      marked as over-annotated (not removed) per policy. The DGUOK-DCK interaction it
      captures is already recorded in UniProt.
    supported_by:
      - reference_id: file:human/DGUOK/DGUOK-uniprot.txt
        supporting_text: "Q16854; P27707: DCK;"
- term:
    id: GO:0010977
    label: negative regulation of neuron projection development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl-Compara ortholog transfer (IEA) from a rat gene of a neuronal
      developmental process. DGUOK is a housekeeping mitochondrial salvage kinase;
      there is no evidence that it functions in negative regulation of neuron
      projection development in human. This is an over-propagated, biologically
      implausible electronic inference.
    action: REMOVE
    reason: >-
      No experimental or family-level support for DGUOK participating in neuron
      projection development; the annotation is an automated ortholog transfer that
      does not reflect DGUOK's established molecular/cellular role.
    supported_by:
      - reference_id: file:human/DGUOK/DGUOK-uniprot.txt
        supporting_text: >-
          phosphorylation of purine deoxyribonucleosides in the
- term:
    id: GO:0042775
    label: mitochondrial ATP synthesis coupled electron transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl-Compara ortholog transfer (IEA) from a rat gene, assigning DGUOK to
      the respiratory-chain electron-transport process. DGUOK is a deoxyribonucleoside
      salvage kinase, not an OXPHOS/electron-transport-chain component; although DGUOK
      deficiency secondarily impairs the mtDNA-encoded respiratory chain (via mtDNA
      depletion), DGUOK itself is not involved_in electron transport.
    action: REMOVE
    reason: >-
      DGUOK does not participate in mitochondrial electron transport; any respiratory
      chain deficit in DGUOK disease is a downstream consequence of mtDNA depletion,
      not a direct role. This is an incorrect over-propagated electronic inference.
    supported_by:
      - reference_id: PMID:11687801
        supporting_text: >-
          mtDNA synthesis depends solely on the mitochondrial
- term:
    id: GO:0004136
    label: deoxyadenosine kinase activity
  evidence_type: EXP
  original_reference_id: PMID:17073823
  qualifier: enables
  review:
    summary: >-
      Experimental (EXP) deoxyadenosine kinase activity. Kinetic characterisation of
      normal and mutant DGUOK in mitochondrial preparations measured activity with
      deoxyadenosine as a phosphate acceptor, confirming dAdo phosphorylation.
    action: ACCEPT
    reason: >-
      Direct kinetic assays of DGUOK with deoxyadenosine as substrate confirm this
      catalytic activity; it is part of the core molecular function (purine arm).
    supported_by:
      - reference_id: PMID:17073823
        supporting_text: >-
          rate-limiting phosphorylation of the purine deoxynucleosides, using a nucleoside
- term:
    id: GO:0004136
    label: deoxyadenosine kinase activity
  evidence_type: EXP
  original_reference_id: PMID:8692979
  qualifier: enables
  review:
    summary: >-
      Experimental (EXP) deoxyadenosine kinase activity from the original cloning/
      expression study; recombinant human dGK showed the same substrate specificity
      as purified mitochondrial dGK, which phosphorylates purine deoxyribonucleosides
      including deoxyadenosine.
    action: ACCEPT
    reason: >-
      The cloned, expressed enzyme reproduced the mitochondrial dGK substrate
      specificity (purine deoxyribonucleosides), supporting deoxyadenosine kinase
      activity as a core function.
    supported_by:
      - reference_id: PMID:8692979
        supporting_text: >-
          with the same substrate specificity as described for the mitochondrial
- term:
    id: GO:0004136
    label: deoxyadenosine kinase activity
  evidence_type: EXP
  original_reference_id: PMID:8706825
  qualifier: enables
  review:
    summary: >-
      Experimental (EXP) deoxyadenosine kinase activity. Recombinant human dGK
      catalysed efficient phosphorylation of dAdo (and 2-chloro-2'-deoxyadenosine),
      confirming deoxyadenosine kinase activity.
    action: ACCEPT
    reason: >-
      Purified recombinant DGUOK phosphorylates deoxyadenosine directly; core
      molecular function of the purine salvage arm.
    supported_by:
      - reference_id: PMID:8706825
        supporting_text: >-
          phosphorylation of dGuo, arabinosyl guanine, dAdo, 2-chloro-2'-deoxyadenosine
- term:
    id: GO:0004138
    label: deoxyguanosine kinase activity
  evidence_type: EXP
  original_reference_id: PMID:11687801
  qualifier: enables
  review:
    summary: >-
      Experimental (EXP) deoxyguanosine kinase activity. Human dGK is described as
      efficiently phosphorylating deoxyguanosine (and deoxyadenosine) as one of the
      two mitochondrial deoxyribonucleoside kinases. Core molecular function.
    action: ACCEPT
    reason: >-
      Deoxyguanosine kinase activity is the primary, experimentally established
      function of DGUOK.
    supported_by:
      - reference_id: PMID:11687801
        supporting_text: >-
          deoxyguanosine and deoxyadenosine, whereas TK2 phosphorylates
- term:
    id: GO:0004138
    label: deoxyguanosine kinase activity
  evidence_type: EXP
  original_reference_id: PMID:17073823
  qualifier: enables
  review:
    summary: >-
      Experimental (EXP) deoxyguanosine kinase activity from kinetic characterisation
      of normal and mutant DGUOK in mitochondrial preparations, with deoxyguanosine as
      phosphate acceptor. Confirms the core catalytic activity.
    action: ACCEPT
    reason: >-
      Direct kinetic assay of DGUOK activity with deoxyguanosine substrate; the
      rate-limiting phosphorylation step of the purine salvage arm.
    supported_by:
      - reference_id: PMID:17073823
        supporting_text: >-
          rate-limiting phosphorylation of the purine deoxynucleosides, using a nucleoside
- term:
    id: GO:0004138
    label: deoxyguanosine kinase activity
  evidence_type: EXP
  original_reference_id: PMID:23043144
  qualifier: enables
  review:
    summary: >-
      Experimental (EXP) deoxyguanosine kinase activity. DGUOK mutations in patients
      impaired muscle DGUOK activity and protein stability, confirming that the
      encoded protein carries deoxyguanosine kinase activity.
    action: ACCEPT
    reason: >-
      Patient DGUOK variants reduced measured DGUOK enzymatic activity, corroborating
      the core deoxyguanosine kinase function.
    supported_by:
      - reference_id: PMID:23043144
        supporting_text: >-
          DGUOK activity and protein stability
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity (ISS) transfer of mitochondrial localisation from the mouse
      ortholog (Q9QX60). Consistent with the experimentally established mitochondrial
      localisation of DGUOK.
    action: ACCEPT
    reason: >-
      DGUOK localises to mitochondria; the ISS transfer is accurate and corroborated
      by multiple independent lines of evidence.
    supported_by:
      - reference_id: file:human/DGUOK/DGUOK-uniprot.txt
        supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput (HTP) localisation from a quantitative high-confidence human
      mitochondrial proteome study (MitoCoP). Supports DGUOK as a bona fide
      mitochondrial protein.
    action: ACCEPT
    reason: >-
      DGUOK is recovered in a high-confidence mitochondrial proteome, consistent with
      its established mitochondrial matrix localisation.
    supported_by:
      - reference_id: file:human/DGUOK/DGUOK-uniprot.txt
        supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:19221117
  qualifier: is_active_in
  review:
    summary: >-
      Direct-assay (IDA) is_active_in mitochondrion. DGUOK-deficient patient cells were
      studied for mtDNA content and rescue by dAMP/dGMP supplementation, consistent
      with DGUOK acting within mitochondria on the mtDNA salvage pathway.
    action: ACCEPT
    reason: >-
      DGUOK functions within mitochondria as part of the mtDNA-supporting salvage
      pathway, consistent with the experimental context.
    supported_by:
      - reference_id: PMID:19221117
        supporting_text: >-
          rescue of mtDNA depletion in DGUOK deficiency
- term:
    id: GO:0106383
    label: dAMP salvage
  evidence_type: IDA
  original_reference_id: PMID:19221117
  qualifier: involved_in
  review:
    summary: >-
      Direct-assay (IDA) involvement in dAMP salvage. DGUOK phosphorylates
      deoxyadenosine to dAMP; supplementation with dAMP/dGMP significantly and
      reproducibly rescued mtDNA depletion in DGUOK-deficient cells, tying DGUOK to
      salvage production of dAMP. Core biological process.
    action: ACCEPT
    reason: >-
      DGUOK generates dAMP from deoxyadenosine as part of the mitochondrial purine
      deoxyribonucleoside salvage pathway; this is a core process for the enzyme.
    supported_by:
      - reference_id: PMID:19221117
        supporting_text: >-
          Supplementation with dAMP/dGMP leads to a significant and reproducible
      - reference_id: PMID:19221117
        supporting_text: >-
          rescue of mtDNA depletion in DGUOK deficiency
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomics (HDA) detecting DGUOK in an isolated human sperm
      nucleus preparation (a 403-protein catalogue). DGUOK is a mitochondrial matrix
      enzyme; nuclear detection in a specialised sperm proteome most likely reflects
      residual co-isolation rather than a functional nuclear localisation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The nuclear assignment comes from a single specialised sperm-nucleus proteome and
      is inconsistent with DGUOK's well-established mitochondrial matrix localisation
      and function; it is treated as an over-annotation rather than a core location.
    supported_by:
      - reference_id: PMID:21630459
        supporting_text: >-
          sperm nuclei were obtained
      - reference_id: file:human/DGUOK/DGUOK-uniprot.txt
        supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-74207
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) localisation to the mitochondrial matrix, the most specific and
      correct compartment for DGUOK, where purine deoxyribonucleoside salvage occurs.
    action: ACCEPT
    reason: >-
      DGUOK phosphorylates purine deoxyribonucleosides in the mitochondrial matrix;
      this is the precise, correct subcellular location.
    supported_by:
      - reference_id: PMID:8706825
        supporting_text: >-
          phosphorylation of purine deoxyribonucleosides in the
- term:
    id: GO:0004138
    label: deoxyguanosine kinase activity
  evidence_type: IDA
  original_reference_id: PMID:8706825
  qualifier: enables
  review:
    summary: >-
      Direct-assay (IDA) deoxyguanosine kinase activity. Purified recombinant human
      dGK efficiently phosphorylated deoxyguanosine, directly demonstrating the core
      catalytic activity.
    action: ACCEPT
    reason: >-
      Enzyme-assay evidence for deoxyguanosine phosphorylation by DGUOK; the defining
      molecular function.
    supported_by:
      - reference_id: PMID:8706825
        supporting_text: >-
          phosphorylation of dGuo, arabinosyl guanine, dAdo, 2-chloro-2'-deoxyadenosine
- term:
    id: GO:0046122
    label: purine deoxyribonucleoside metabolic process
  evidence_type: IDA
  original_reference_id: PMID:8706825
  qualifier: involved_in
  review:
    summary: >-
      Direct-assay (IDA) involvement in purine deoxyribonucleoside metabolism. DGUOK
      is responsible for phosphorylation of purine deoxyribonucleosides (deoxyguanosine,
      deoxyadenosine, deoxyinosine) in the mitochondrial matrix, the salvage arm that
      feeds mtDNA precursor supply. Core biological process.
    action: ACCEPT
    reason: >-
      DGUOK phosphorylates purine deoxyribonucleosides as the committed salvage step;
      this accurately captures the enzyme's core metabolic process.
    supported_by:
      - reference_id: PMID:8706825
        supporting_text: >-
          phosphorylation of purine deoxyribonucleosides in the
- term:
    id: GO:0004138
    label: deoxyguanosine kinase activity
  evidence_type: TAS
  original_reference_id: PMID:8692979
  qualifier: enables
  review:
    summary: >-
      Author-statement (TAS) deoxyguanosine kinase activity from the original cloning
      paper, which reported that the expressed cDNA encodes a protein with the same
      substrate specificity as mitochondrial dGK (EC 2.7.1.113). Core function.
    action: ACCEPT
    reason: >-
      Corroborates the core deoxyguanosine kinase activity of DGUOK.
    supported_by:
      - reference_id: PMID:8692979
        supporting_text: >-
          with the same substrate specificity as described for the mitochondrial
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: TAS
  original_reference_id: PMID:8692979
  qualifier: located_in
  review:
    summary: >-
      Author-statement (TAS) mitochondrial localisation. The cloning paper described a
      protein with an N-terminal mitochondrial translocation signal and matching the
      mitochondrial dGK. Correct localisation.
    action: ACCEPT
    reason: >-
      DGUOK carries a mitochondrial targeting/transit sequence and is the mitochondrial
      deoxyguanosine kinase; the mitochondrial localisation is well supported.
    supported_by:
      - reference_id: PMID:8692979
        supporting_text: >-
          N terminus of the deduced amino
- term:
    id: GO:0008617
    label: guanosine metabolic process
  evidence_type: TAS
  original_reference_id: PMID:8692979
  qualifier: involved_in
  review:
    summary: >-
      Author-statement (TAS) involvement in guanosine metabolic process. DGUOK's
      substrate is 2'-deoxyguanosine, not guanosine (a ribonucleoside); the process
      term is slightly mis-specified. The accurate parent process is purine
      deoxyribonucleoside metabolism.
    action: MODIFY
    reason: >-
      DGUOK metabolises the deoxyribonucleoside deoxyguanosine, not the ribonucleoside
      guanosine; the term should be replaced by the deoxyribonucleoside-level process.
    proposed_replacement_terms:
      - id: GO:0046122
        label: purine deoxyribonucleoside metabolic process
    supported_by:
      - reference_id: PMID:8706825
        supporting_text: >-
          phosphorylation of purine deoxyribonucleosides in the
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- 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: PMID:11687801
  title: Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy.
  findings: []
- id: PMID:17073823
  title: Kinetic properties of mutant deoxyguanosine kinase in a case of reversible
    hepatic mtDNA depletion.
  findings: []
- id: PMID:19221117
  title: In vitro supplementation with dAMP/dGMP leads to partial restoration of mtDNA
    levels in mitochondrial depletion syndromes.
  findings: []
- id: PMID:21630459
  title: Proteomic characterization of the human sperm nucleus.
  findings: []
- id: PMID:23043144
  title: Next-generation sequencing reveals DGUOK mutations in adult patients with
    mitochondrial DNA multiple deletions.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: PMID:8692979
  title: Cloning and expression of human deoxyguanosine kinase cDNA.
  findings: []
- id: PMID:8706825
  title: Cloning and expression of human mitochondrial deoxyguanosine kinase cDNA.
  findings: []
- id: Reactome:R-HSA-74207
  title: dA, dG, or dI + ATP => dAMP, dGMP, or dIMP + ADP (DGUOK)
  findings: []
- id: file:human/DGUOK/DGUOK-uniprot.txt
  title: UniProtKB entry Q16854 (DGUOK_HUMAN), Deoxyguanosine kinase, mitochondrial
  findings: []
core_functions:
- description: >-
    Deoxyguanosine kinase activity: phosphorylates deoxyguanosine to dGMP in the
    mitochondrial matrix, using ATP as phosphate donor. This is the defining,
    rate-limiting purine-salvage activity of DGUOK.
  molecular_function:
    id: GO:0004138
    label: deoxyguanosine kinase activity
  directly_involved_in:
    - id: GO:0046122
      label: purine deoxyribonucleoside metabolic process
  locations:
    - id: GO:0005759
      label: mitochondrial matrix
    - id: GO:0005739
      label: mitochondrion
  supported_by:
    - reference_id: PMID:8706825
      supporting_text: >-
        phosphorylation of purine deoxyribonucleosides in the
    - reference_id: file:human/DGUOK/DGUOK-uniprot.txt
      supporting_text: "EC=2.7.1.113"
- description: >-
    Deoxyadenosine kinase activity: phosphorylates deoxyadenosine to dAMP (also
    deoxyinosine) in the mitochondrial matrix, the second purine substrate of the
    mitochondrial deoxyribonucleoside salvage pathway, feeding dAMP salvage.
  molecular_function:
    id: GO:0004136
    label: deoxyadenosine kinase activity
  directly_involved_in:
    - id: GO:0106383
      label: dAMP salvage
  locations:
    - id: GO:0005759
      label: mitochondrial matrix
    - id: GO:0005739
      label: mitochondrion
  supported_by:
    - reference_id: PMID:8706825
      supporting_text: >-
        phosphorylation of dGuo, arabinosyl guanine, dAdo, 2-chloro-2'-deoxyadenosine
    - reference_id: file:human/DGUOK/DGUOK-uniprot.txt
      supporting_text: "EC=2.7.1.76"