id: P19971
gene_symbol: TYMP
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Thymidine phosphorylase (TYMP; EC 2.4.2.4), also known as platelet-derived
  endothelial cell growth factor (PD-ECGF) and gliostatin, is a cytosolic homodimeric
  enzyme that catalyzes the reversible phosphorolysis of thymidine (and 2'-deoxyuridine),
  converting thymidine + phosphate into thymine + 2-deoxy-alpha-D-ribose 1-phosphate
  (and 2'-deoxyuridine into uracil + 2-deoxy-alpha-D-ribose 1-phosphate). Through this
  activity it feeds pyrimidine catabolism and the thymine-to-dTMP salvage pathway,
  and by controlling systemic levels of thymidine and 2'-deoxyuridine it protects the
  mitochondrial deoxyribonucleotide (dNTP) pool from imbalance. TYMP additionally has
  an extracellular moonlighting role as an angiogenic growth factor, promoting
  endothelial cell growth and chemotaxis. Loss-of-function mutations in TYMP cause
  mitochondrial neurogastrointestinal encephalomyopathy (MNGIE; mitochondrial DNA
  depletion syndrome 1, MTDPS1), in which accumulation of thymidine and deoxyuridine
  drives mitochondrial DNA instability and depletion, producing gastrointestinal
  dysmotility, cachexia, peripheral neuropathy, and leukoencephalopathy.
alternative_products:
- name: '1'
  id: P19971-1
- name: '2'
  id: P19971-2
  sequence_note: VSP_045556
existing_annotations:
- term:
    id: GO:0009032
    label: thymidine phosphorylase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetically inferred thymidine phosphorylase activity, the defining
      and experimentally validated molecular function of TYMP. This is the core MF.
    action: ACCEPT
    reason: TYMP is thymidine phosphorylase (EC 2.4.2.4), catalyzing the reversible
      phosphorolysis of thymidine to thymine and 2-deoxy-alpha-D-ribose 1-phosphate.
      The IBA propagation across the thymidine/pyrimidine-nucleoside phosphorylase
      family (PTN000054065) matches direct enzymatic evidence for the human protein.
    supported_by:
    - reference_id: PMID:1590793
      supporting_text: PD-ECGF has thymidine phosphorylase activity
    - reference_id: file:human/TYMP/TYMP-uniprot.txt
      supporting_text: Catalyzes the reversible phosphorolysis of thymidine
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: TYMP is a cytosolic enzyme; phylogenetic inference of cytosolic localization
      is consistent with Reactome and UniProt.
    action: ACCEPT
    reason: Thymidine phosphorylase acts in the cytosol, where it participates in
      cytosolic pyrimidine salvage/catabolism. This is corroborated by Reactome
      (both catalytic reactions localized to the cytosol) and by the enzyme lacking
      any organellar targeting signal.
    supported_by:
    - reference_id: Reactome:R-HSA-112265
      supporting_text: Cytosolic thymidine phosphorylase (TYMP) catalyzes the reversible
        reactions of thymidine or deoxyuridine with orthophosphate to form  thymine
        or uracil and 2-deoxy-D-ribose 1-phosphate.
- term:
    id: GO:0004645
    label: 1,4-alpha-oligoglucan phosphorylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Electronic InterPro2GO mapping (IPR000053) assigning glycogen/starch
      phosphorylase activity. This is incorrect for TYMP.
    action: REMOVE
    reason: GO:0004645 (1,4-alpha-oligoglucan phosphorylase activity, i.e. glycogen/starch
      phosphorylase) is a distinct enzyme acting on alpha-1,4-glucan polysaccharides,
      not on nucleosides. TYMP is a pyrimidine-nucleoside phosphorylase (EC 2.4.2.4)
      that phosphorolyses thymidine/deoxyuridine; it has no activity on oligoglucans.
      This is a demonstrably wrong IEA arising from the InterPro entry being over-broad
      relative to the actual catalytic specificity; the correct MF is GO:0009032.
    supported_by:
    - reference_id: file:human/TYMP/TYMP-uniprot.txt
      supporting_text: Catalyzes the reversible phosphorolysis of thymidine
- term:
    id: GO:0006206
    label: pyrimidine nucleobase metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: TYMP produces the pyrimidine nucleobase thymine (and uracil from
      deoxyuridine) and, in the reverse direction, consumes them, so it participates
      in pyrimidine nucleobase metabolism.
    action: ACCEPT
    reason: The phosphorolysis reaction produces thymine/uracil from thymidine/deoxyuridine
      (and the reverse builds nucleosides from nucleobases), placing TYMP directly
      in pyrimidine nucleobase metabolism. This is an accurate InterPro2GO mapping.
    supported_by:
    - reference_id: Reactome:R-HSA-112265
      supporting_text: Cytosolic thymidine phosphorylase (TYMP) catalyzes the reversible
        reactions of thymidine or deoxyuridine with orthophosphate to form  thymine
        or uracil and 2-deoxy-D-ribose 1-phosphate.
- term:
    id: GO:0006213
    label: pyrimidine nucleoside metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: TYMP metabolizes the pyrimidine nucleosides thymidine and 2'-deoxyuridine;
      this is the core biological process for the enzyme and is well supported by
      the IDA/IMP experimental annotations below.
    action: ACCEPT
    reason: Phosphorolysis of thymidine/2'-deoxyuridine is precisely pyrimidine
      nucleoside metabolism. This InterPro2GO mapping is accurate and duplicates the
      experimentally supported (IDA, IMP) annotations to the same term.
    supported_by:
    - reference_id: file:human/TYMP/TYMP-uniprot.txt
      supporting_text: Catalyzes the reversible phosphorolysis of thymidine
- term:
    id: GO:0009032
    label: thymidine phosphorylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic assignment of thymidine phosphorylase activity via EC 2.4.2.4 /
      RHEA:16037. Correct and matches the experimental IDA/IMP annotations.
    action: ACCEPT
    reason: This IEA mapping (ARBA/EC:2.4.2.4/RHEA:16037) reproduces the core,
      experimentally validated molecular function of TYMP.
    supported_by:
    - reference_id: file:human/TYMP/TYMP-uniprot.txt
      supporting_text: Reaction=thymidine + phosphate = 2-deoxy-alpha-D-ribose 1-phosphate +
- term:
    id: GO:0016154
    label: pyrimidine-nucleoside phosphorylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Parent MF term for TYMP's activity. TYMP phosphorolyses not only thymidine
      but also 2'-deoxyuridine, so it genuinely has pyrimidine-nucleoside phosphorylase
      activity; the more specific thymidine phosphorylase activity term is preferred
      as the core annotation.
    action: ACCEPT
    reason: Accurate InterPro2GO mapping. TYMP acts on multiple pyrimidine
      2'-deoxyribonucleosides (thymidine and 2'-deoxyuridine), justifying this broader
      activity term alongside the specific GO:0009032.
    supported_by:
    - reference_id: Reactome:R-HSA-112265
      supporting_text: Cytosolic thymidine phosphorylase (TYMP) catalyzes the reversible
        reactions of thymidine or deoxyuridine with orthophosphate to form  thymine
        or uracil and 2-deoxy-D-ribose 1-phosphate.
- term:
    id: GO:0016757
    label: glycosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Very general MF derived from the glycosyltransferase-family-3 (IPR000312)
      fold. Not wrong in the broadest sense (a pentosyl group is transferred) but
      uninformative relative to the specific thymidine phosphorylase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: TYMP belongs to the glycosyltransferase family 3 fold, so this high-level
      term is technically compatible, but it conveys no useful functional information
      beyond the specific and experimentally supported GO:0009032. Retain the specific
      MF terms instead.
    supported_by:
    - reference_id: file:human/TYMP/TYMP-uniprot.txt
      supporting_text: Catalyzes the reversible phosphorolysis of thymidine
- term:
    id: GO:0016763
    label: pentosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: General parent term (pentosyltransferase) above thymidine/pyrimidine-nucleoside
      phosphorylase activity. Correct in ancestry but too broad to be informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Thymidine phosphorylase activity (GO:0009032) is a subtype of
      pentosyltransferase activity (transfer of the 2-deoxyribose pentosyl group),
      so this term is an ancestor rather than a distinct function. The specific
      terms should carry the annotation.
    supported_by:
    - reference_id: file:human/TYMP/TYMP-uniprot.txt
      supporting_text: Reaction=thymidine + phosphate = 2-deoxy-alpha-D-ribose 1-phosphate +
- term:
    id: GO:0055086
    label: nucleobase-containing small molecule metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: High-level ARBA-derived BP term. True but far more general than the
      specific pyrimidine nucleoside/nucleobase metabolic process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Thymidine, deoxyuridine, thymine and uracil are nucleobase-containing small
      molecules, so the term is an accurate ancestor, but it is uninformative relative
      to GO:0006213 and GO:0006206 which are already annotated.
    supported_by:
    - reference_id: file:human/TYMP/TYMP-uniprot.txt
      supporting_text: Catalyzes the reversible phosphorolysis of thymidine
- term:
    id: GO:0072527
    label: pyrimidine-containing compound metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: General ARBA-derived parent of pyrimidine nucleoside/nucleobase metabolic
      process. Correct but too broad.
    action: MARK_AS_OVER_ANNOTATED
    reason: This is a direct ancestor of the more specific pyrimidine nucleoside
      (GO:0006213) and nucleobase (GO:0006206) metabolic process terms that already
      capture TYMP's role; the broad term adds no specific information.
    supported_by:
    - reference_id: file:human/TYMP/TYMP-uniprot.txt
      supporting_text: Catalyzes the reversible phosphorolysis of thymidine
- term:
    id: GO:1901135
    label: carbohydrate derivative metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Very general ARBA-derived BP term. The reaction does generate the
      sugar-phosphate 2-deoxy-alpha-D-ribose 1-phosphate, but this broad term is
      uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The 2-deoxy-alpha-D-ribose 1-phosphate product is a carbohydrate derivative,
      so the term is technically compatible, but it is far too general to convey
      TYMP's function; the specific pyrimidine metabolic process terms are preferred.
    supported_by:
    - reference_id: file:human/TYMP/TYMP-uniprot.txt
      supporting_text: Reaction=thymidine + phosphate = 2-deoxy-alpha-D-ribose 1-phosphate +
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Bare 'protein binding' from a high-throughput binary interactome screen
      (HuRI; interactions with MESD/Q14696 and ZMYND12/Q9H0C1). Uninformative as a
      molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 protein binding does not describe a specific molecular function
      and conveys nothing about TYMP's biology; the reported partners are from a
      systematic yeast-two-hybrid interactome map with no established functional
      consequence for TYMP. Per curation policy this is retained but marked as an
      over-annotation rather than removed.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: reference interactome map of human binary protein interactions
- term:
    id: GO:0006213
    label: pyrimidine nucleoside metabolic process
  evidence_type: IDA
  original_reference_id: PMID:1590793
  qualifier: involved_in
  review:
    summary: Direct demonstration that recombinant human PD-ECGF (TYMP) has thymidine
      phosphorylase activity, i.e. metabolizes the pyrimidine nucleoside thymidine.
      Core biological process.
    action: ACCEPT
    reason: Usuki et al. showed recombinant human PD-ECGF phosphorolyses thymidine,
      directly establishing TYMP's participation in pyrimidine nucleoside metabolism.
    supported_by:
    - reference_id: PMID:1590793
      supporting_text: PD-ECGF has thymidine phosphorylase activity
- term:
    id: GO:0006213
    label: pyrimidine nucleoside metabolic process
  evidence_type: IMP
  original_reference_id: PMID:9924029
  qualifier: involved_in
  review:
    summary: Loss-of-function TYMP mutations in MNGIE patients reduce TP activity to
      <5% of controls and are linked to aberrant thymidine metabolism and mtDNA
      instability, confirming TYMP's in vivo role in pyrimidine nucleoside metabolism.
    action: ACCEPT
    reason: The MNGIE genetic evidence (mutation phenotype) demonstrates that TYMP
      is required for normal pyrimidine (thymidine/deoxyuridine) metabolism in humans;
      its loss causes thymidine accumulation that destabilizes mitochondrial DNA.
    supported_by:
    - reference_id: PMID:9924029
      supporting_text: loss-of-function mutations in TP cause the disease
    - reference_id: PMID:9924029
      supporting_text: 'aberrant thymidine metabolism, leading to '
- term:
    id: GO:0009032
    label: thymidine phosphorylase activity
  evidence_type: IDA
  original_reference_id: PMID:1590793
  qualifier: enables
  review:
    summary: Direct experimental demonstration that recombinant human PD-ECGF/TYMP
      has thymidine phosphorylase activity. This is the defining, core molecular
      function.
    action: ACCEPT
    reason: Usuki et al. assayed recombinant human PD-ECGF and showed it possesses
      thymidine phosphorylase activity, establishing EC 2.4.2.4 for the human protein.
    supported_by:
    - reference_id: PMID:1590793
      supporting_text: PD-ECGF has thymidine phosphorylase activity
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:1590793
  qualifier: enables
  review:
    summary: TYMP is a homodimer; recombinant human PD-ECGF was shown to occur as a
      90 kDa homodimer, and multiple crystal structures confirm the homodimeric
      assembly.
    action: ACCEPT
    reason: Homodimerization is well established biochemically (gel chromatography of
      recombinant PD-ECGF, PMID:1590793) and structurally (X-ray structures, UniProt
      SUBUNIT). This is the functional oligomeric state of the active enzyme.
    supported_by:
    - reference_id: PMID:1590793
      supporting_text: recombinant human PD-ECGF occurs as a 90 kDa homodimer
    - reference_id: file:human/TYMP/TYMP-uniprot.txt
      supporting_text: 'SUBUNIT: Homodimer'
- term:
    id: GO:0009032
    label: thymidine phosphorylase activity
  evidence_type: IMP
  original_reference_id: PMID:9924029
  qualifier: enables
  review:
    summary: MNGIE mutations reduce leukocyte thymidine phosphorylase (TP) activity
      to <5% of controls, showing TYMP is the enzyme responsible for this activity
      in vivo. Core molecular function.
    action: ACCEPT
    reason: The mutation phenotype (near-total loss of TP activity in patients with
      biallelic TYMP mutations) provides genetic (IMP) evidence that TYMP enables
      thymidine phosphorylase activity.
    supported_by:
    - reference_id: PMID:9924029
      supporting_text: TP activity
    - reference_id: PMID:9924029
      supporting_text: loss-of-function mutations in TP cause the disease
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-112265
  qualifier: located_in
  review:
    summary: Reactome localizes TYMP's catalytic reaction to the cytosol. Consistent
      with the IBA cytosol annotation.
    action: ACCEPT
    reason: TYMP is a cytosolic enzyme carrying out cytosolic pyrimidine salvage and
      catabolism, as curated by Reactome.
    supported_by:
    - reference_id: Reactome:R-HSA-112265
      supporting_text: Cytosolic thymidine phosphorylase (TYMP) catalyzes the reversible
        reactions of thymidine or deoxyuridine with orthophosphate to form  thymine
        or uracil and 2-deoxy-D-ribose 1-phosphate.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-112266
  qualifier: located_in
  review:
    summary: Reactome localizes the reverse (synthetic) TYMP reaction to the cytosol.
      Consistent with the IBA and other cytosol annotations.
    action: ACCEPT
    reason: The reverse reaction (nucleobase + deoxyribose-1-phosphate -> nucleoside)
      catalyzed by TYMP also occurs in the cytosol per Reactome.
    supported_by:
    - reference_id: Reactome:R-HSA-112266
      supporting_text: Cytosolic thymidine phosphorylase (TYMP) catalyzes the reversible
        reactions of thymine or uracil with 2-deoxy-D-ribose 1-phosphate to form  thymidine
        or deoxyuridine and orthiophosphate.
- term:
    id: GO:0046104
    label: thymidine metabolic process
  evidence_type: IDA
  original_reference_id: PMID:1590793
  qualifier: involved_in
  review:
    summary: The most specific biological process for TYMP - metabolism of thymidine
      itself, via its phosphorolysis to thymine and 2-deoxy-alpha-D-ribose 1-phosphate.
      Proposed as a more specific complement to the existing pyrimidine nucleoside
      metabolic process annotations.
    action: NEW
    reason: TYMP directly metabolizes thymidine (its eponymous substrate); GO:0046104
      thymidine metabolic process is a more precise descendant of the annotated
      GO:0006213 pyrimidine nucleoside metabolic process and better captures the core
      biology. Supported by direct enzymatic evidence and the MNGIE thymidine-accumulation
      phenotype.
    supported_by:
    - reference_id: PMID:1590793
      supporting_text: PD-ECGF has thymidine phosphorylase activity
    - reference_id: PMID:9924029
      supporting_text: 'aberrant thymidine metabolism, leading to '
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: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:1590793
  title: Platelet-derived endothelial cell growth factor has thymidine phosphorylase
    activity.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:9924029
  title: Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.
  findings: []
- id: Reactome:R-HSA-112265
  title: thymidine or deoxyuridine + orthophosphate <=> thymine or uracil + 2-deoxy-D-ribose
    1-phosphate [TYMP]
  findings: []
- id: Reactome:R-HSA-112266
  title: thymine or uracil + 2-deoxy-D-ribose 1-phosphate <=> thymidine or deoxyuridine
    + orthophosphate [TYMP]
  findings: []
- id: file:human/TYMP/TYMP-uniprot.txt
  title: UniProtKB entry P19971 (TYPH_HUMAN), Thymidine phosphorylase
  findings: []
core_functions:
- description: Thymidine phosphorylase activity - catalyzes the reversible phosphorolysis
    of thymidine (and 2'-deoxyuridine) to thymine (uracil) + 2-deoxy-alpha-D-ribose
    1-phosphate, the defining enzymatic function of TYMP.
  molecular_function:
    id: GO:0009032
    label: thymidine phosphorylase activity
  directly_involved_in:
  - id: GO:0006213
    label: pyrimidine nucleoside metabolic process
  - id: GO:0046104
    label: thymidine metabolic process
  - id: GO:0006206
    label: pyrimidine nucleobase metabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:1590793
    supporting_text: PD-ECGF has thymidine phosphorylase activity
  - reference_id: file:human/TYMP/TYMP-uniprot.txt
    supporting_text: Catalyzes the reversible phosphorolysis of thymidine