TYMS

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006231 dTMP biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) propagation of the deeply conserved role of thymidylate synthase in de novo dTMP synthesis. This is the core biological process of TYMS and is directly supported by experimental annotations and by the enzyme's reaction. Reason: Correct core BP for TYMS; consistent with the catalysed reaction (dUMP -> dTMP) and the UniProt PATHWAY assignment. Well supported at the right level of specificity by orthologs across the thymidylate synthase family. Supporting Evidence: file:human/TYMS/TYMS-uniprot.txt PATHWAY: Pyrimidine metabolism; dTTP biosynthesis.
GO:0005739 mitochondrion	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA propagation of a mitochondrial location. A de novo dTMP synthesis pathway (SHMT2, TYMS, DHFRL1) operates in mammalian mitochondria and TYMS is experimentally localized there, so a mitochondrial annotation is supported, though it is a secondary compartment relative to the cytosol. Reason: TYMS was experimentally localized to mitochondria (matrix and inner membrane) as part of a mitochondrial de novo dTMP pathway, so the IBA location is defensible. It is a non-core compartment relative to the predominant cytosolic/nuclear activity. Supporting Evidence: PMID:21876188 Human DHFRL1, SHMT2, and TYMS were localized to mitochondrial matrix and inner membrane
GO:0004799 thymidylate synthase activity	IBA GO_REF:0000033	ACCEPT	Summary: IBA propagation of thymidylate synthase catalytic activity, the defining molecular function of TYMS and its orthologs. Directly corroborated by multiple experimental (IDA) annotations and by the UniProt catalytic-activity record (EC 2.1.1.45, RHEA:12104). Reason: This is the core molecular function of TYMS and is unambiguous across the family. Correct term at the correct level of specificity. Supporting Evidence: file:human/TYMS/TYMS-uniprot.txt Catalyzes the reductive methylation of 2'-deoxyuridine 5'-
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: IBA propagation of a cytosolic location. Thymidylate synthase is classically a cytosolic enzyme, consistent with Reactome and with the general subcellular distribution of nucleotide biosynthetic enzymes. Reason: Cytosol is the principal site of TYMS activity and is well established. This is the core cellular component annotation. Supporting Evidence: Reactome:R-HSA-73605 Cytosolic thymidylate synthase catalyzes the reaction of dUMP and N5,N10-methylene tetrahydrofolate to form TMP and dihydrofolate
GO:0004799 thymidylate synthase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (multiple-method) assignment of thymidylate synthase activity based on InterPro/ARBA signatures, RHEA:12104 and EC 2.1.1.45. Redundant with, and fully consistent with, the experimental and IBA annotations of the same term. Reason: Correct MF; the InterPro/RHEA/EC mapping is accurate for this well-characterized enzyme. Supporting Evidence: file:human/TYMS/TYMS-uniprot.txt EC=2.1.1.45
GO:0005634 nucleus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Electronic transfer from the UniProt Subcellular Location vocabulary (nucleus). TYMS localizes to the nucleus during S and G2/M as part of the de novo thymidylate complex at replication forks; this IEA is corroborated by experimental annotations. Reason: Nuclear localization is experimentally documented and cell-cycle dependent; it is a genuine but secondary compartment relative to the bulk cytosolic enzyme. Supporting Evidence: file:human/TYMS/TYMS-uniprot.txt Localized to the nucleus during S
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Electronic transfer from the UniProt Subcellular Location vocabulary (cytoplasm). This is the general parent of the more specific and better-supported cytosol annotation. Reason: Correct but general; TYMS is a cytoplasmic/cytosolic enzyme. The more specific cytosol term (GO:0005829) is preferred for the core annotation, but this broader term is not wrong. Supporting Evidence: PMID:21876188 Human DHFRL1, SHMT2, and TYMS were localized to mitochondrial matrix and inner membrane
GO:0005739 mitochondrion	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Electronic transfer from the UniProt Subcellular Location vocabulary (mitochondrion), corroborated by experimental localization of TYMS to mitochondria as part of a mitochondrial de novo dTMP pathway. Reason: Experimentally supported non-core compartment; consistent with the IDA mitochondrion annotation from PMID:21876188. Supporting Evidence: PMID:21876188 de novo dTMP synthesis occurs within mitochondria
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Electronic transfer from the UniProt Subcellular Location vocabulary (mitochondrion inner membrane), corroborated by experimental localization of TYMS to the mitochondrial inner membrane. Reason: Supported by the experimental IDA annotation (PMID:21876188) placing TYMS at the mitochondrial matrix/inner membrane; a non-core compartment. Supporting Evidence: PMID:21876188 Human DHFRL1, SHMT2, and TYMS were localized to mitochondrial matrix and inner membrane
GO:0005759 mitochondrial matrix	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Electronic transfer from the UniProt Subcellular Location vocabulary (mitochondrion matrix), corroborated by experimental localization of TYMS to the mitochondrial matrix. Reason: Supported by the experimental IDA annotation (PMID:21876188); a non-core compartment. Supporting Evidence: PMID:21876188 Human DHFRL1, SHMT2, and TYMS were localized to mitochondrial matrix and inner membrane
GO:0006231 dTMP biosynthetic process	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic mapping of the thymidylate synthase domain to de novo dTMP biosynthesis. Redundant with, and consistent with, the experimental and IBA annotations of this core process. Reason: Correct core BP; the InterPro-to-GO mapping is accurate for TYMS. Supporting Evidence: file:human/TYMS/TYMS-uniprot.txt PATHWAY: Pyrimidine metabolism; dTTP biosynthesis.
GO:0016741 transferase activity, transferring one-carbon groups	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro2GO electronic mapping to a broad one-carbon transferase parent. This is a general ancestor of the specific and experimentally supported thymidylate synthase activity (GO:0004799) already annotated to TYMS. Reason: Not wrong (TYMS transfers a one-carbon methylene/methyl group), but it is a high-level parent term that is uninformative given the specific GO:0004799 annotation. The specific term should carry the molecular-function annotation. Supporting Evidence: file:human/TYMS/TYMS-uniprot.txt methylenetetrahydrofolate (CH2H4folate) as a 1-
GO:0006235 dTTP biosynthetic process	IEA GO_REF:0000041	ACCEPT	Summary: UniPathway-derived electronic mapping to dTTP biosynthesis. TYMS provides dTMP, the committed de novo precursor that is subsequently phosphorylated to dTTP; UniProt assigns the pathway 'Pyrimidine metabolism; dTTP biosynthesis'. Reason: Correct pathway-level BP; consistent with the UniProt PATHWAY statement. TYMS is the de novo entry point to the dTTP pathway. Supporting Evidence: file:human/TYMS/TYMS-uniprot.txt PATHWAY: Pyrimidine metabolism; dTTP biosynthesis.
GO:0005634 nucleus	EXP PMID:22235121 Serine hydroxymethyltransferase anchors de novo thymidylate ...	KEEP AS NON CORE	Summary: Experimental localization of the de novo thymidylate synthesis complex (including TYMS) to the nuclear lamina and to sites of DNA replication initiation during S phase. Reason: Experimentally supported nuclear localization; a genuine but cell-cycle-restricted, non-core compartment relative to the bulk cytosolic enzyme. Supporting Evidence: PMID:22235121 The metabolic complex is enriched at sites of DNA replication initiation and associated with proliferating cell nuclear antigen
GO:0006260 DNA replication	IDA PMID:22235121 Serine hydroxymethyltransferase anchors de novo thymidylate ...	KEEP AS NON CORE	Summary: TYMS, as part of the de novo thymidylate synthesis complex localized at replication forks, supplies dTMP for DNA replication; the complex is enriched at DNA replication initiation sites and associates with PCNA and the replication machinery. Reason: TYMS supports DNA replication by providing the dTMP building block rather than acting directly in the replication reaction; this is a downstream, contextual process, so it is retained as non-core. Supporting Evidence: PMID:22235121 de novo thymidylate biosynthesis occurs at replication forks
GO:0005657 replication fork	IDA PMID:22235121 Serine hydroxymethyltransferase anchors de novo thymidylate ...	KEEP AS NON CORE	Summary: The de novo thymidylate synthesis complex (SHMT1, DHFR, TYMS) localizes to replication forks during DNA synthesis, placing TYMS activity at the fork. Reason: Experimentally supported localization of TYMS activity to replication forks, but this reflects the S-phase nuclear complex rather than the enzyme's core cytosolic site; retained as non-core. Supporting Evidence: PMID:22235121 de novo thymidylate biosynthesis occurs at replication forks
GO:0006207 'de novo' pyrimidine nucleobase biosynthetic process	IDA PMID:22235121 Serine hydroxymethyltransferase anchors de novo thymidylate ...	KEEP AS NON CORE	Summary: TYMS contributes to de novo synthesis of the pyrimidine nucleotide thymidylate. The strictly correct process is de novo dTMP/dTTP biosynthesis (already annotated); this term names the broader de novo pyrimidine nucleobase process. Reason: The essence is correct (de novo pyrimidine nucleotide synthesis), but the specific and directly supported processes are dTMP/dTTP biosynthesis (GO:0006231, GO:0006235). Retained as a non-core broader-process annotation rather than removed. Supporting Evidence: PMID:22235121 The de novo thymidylate biosynthetic pathway in mammalian cells translocates to
GO:0005515 protein binding	IPI PMID:22235121 Serine hydroxymethyltransferase anchors de novo thymidylate ...	MARK AS OVER ANNOTATED	Summary: IPI capturing physical interaction of TYMS with SHMT1 (P34896) and DHFR (P00374) within the de novo thymidylate synthesis complex. The specific interactions are biologically meaningful, but the GO term 'protein binding' itself is uninformative. Reason: Bare 'protein binding' does not convey a specific molecular function. The underlying SHMT1/DHFR complex interactions are real and are better captured by the complex/subunit description rather than this generic MF term. Supporting Evidence: PMID:22235121 this pathway forms a multienzyme complex that is associated with the nuclear lamina
GO:0004799 thymidylate synthase activity	IDA PMID:11278511 Structure of human thymidylate synthase suggests advantages ...	ACCEPT	Summary: Direct assay of human thymidylate synthase catalytic activity, with the 2.0 A crystal structure and kinetics of the dUMP reaction defining the enzyme's active-site mechanism. Reason: Core molecular function, experimentally demonstrated for the human enzyme. Supporting Evidence: PMID:11278511 analogs of its substrates, dUMP and CH(2)H(4)folate
GO:0004799 thymidylate synthase activity	IDA PMID:8845352 Crystal structure of human thymidylate synthase: a structura...	ACCEPT	Summary: Human thymidylate synthase catalytic activity supported by the 3.0 A crystal structure characterizing the active-site loop and substrate docking mechanism. Reason: Core molecular function; the structure resolves the human TS active site and confirms the catalytic enzyme. Supporting Evidence: PMID:8845352 The crystal structure of human thymidylate synthase, a target for anti-cancer drugs
GO:0006231 dTMP biosynthetic process	IDA PMID:11278511 Structure of human thymidylate synthase suggests advantages ...	ACCEPT	Summary: The catalytic characterization of human TS establishes its role in dTMP biosynthesis via the dUMP reaction. Reason: Core BP directly supported by the human enzyme's catalytic activity. Supporting Evidence: PMID:11278511 analogs of its substrates, dUMP and CH(2)H(4)folate
GO:0006231 dTMP biosynthetic process	IDA PMID:8845352 Crystal structure of human thymidylate synthase: a structura...	ACCEPT	Summary: The structural characterization of human TS as an anti-cancer drug target supports its role in dTMP biosynthesis. Reason: Core BP; consistent with the enzyme's dUMP-to-dTMP reaction. Supporting Evidence: PMID:8845352 The crystal structure of human thymidylate synthase, a target for anti-cancer drugs
GO:0004799 thymidylate synthase activity	TAS PMID:1924359 Autoregulation of human thymidylate synthase messenger RNA t...	ACCEPT	Summary: Traceable statement of thymidylate synthase catalytic activity (EC 2.1.1.45, 5,10-methylenetetrahydrofolate:dUMP C-methyltransferase) in the context of the autoregulation study. Reason: Core molecular function, correctly stated. Supporting Evidence: PMID:1924359 essential for the de novo synthesis of
GO:0000900 mRNA regulatory element binding translation repressor activity	IDA PMID:1924359 Autoregulation of human thymidylate synthase messenger RNA t...	KEEP AS NON CORE	Summary: TS protein binds its own mRNA and represses its translation in vitro; this autoregulatory RNA-binding repressor activity is a documented moonlighting function distinct from its catalytic role. Reason: Experimentally supported moonlighting activity (translational autoregulation), but not the core metabolic function of TYMS; retained as non-core. Supporting Evidence: PMID:1924359 translation of TS mRNA is controlled by its own protein end product, TS, in an autoregulatory manner
GO:0017148 negative regulation of translation	IDA PMID:1924359 Autoregulation of human thymidylate synthase messenger RNA t...	KEEP AS NON CORE	Summary: Addition of recombinant TS protein inhibits translation of TS mRNA in vitro, a specific negative regulation of its own translation. Reason: Experimentally supported moonlighting/regulatory role; not the core metabolic function, so retained as non-core. Supporting Evidence: PMID:1924359 recombinant TS protein to in vitro translation reactions inhibited translation of TS mRNA
GO:1990825 sequence-specific mRNA binding	IDA PMID:1924359 Autoregulation of human thymidylate synthase messenger RNA t...	KEEP AS NON CORE	Summary: Gel-retardation assays demonstrate a specific interaction between TS protein and its own mRNA but not unrelated mRNAs, supporting sequence-specific mRNA binding. Reason: Experimentally supported RNA-binding moonlighting activity underlying autoregulation; not the core metabolic function. Supporting Evidence: PMID:1924359 a specific interaction between TS protein and its corresponding mRNA but not with unrelated mRNAs
GO:0004799 thymidylate synthase activity	IDA PMID:15093541 Thymidylate synthase as an oncogene: a novel role for an ess...	ACCEPT	Summary: TYMS is treated as a catalytically active enzyme essential for DNA synthesis; catalytically dead point mutants lack the transforming activity, tying the phenotype to catalytic thymidylate synthase activity. Reason: Core molecular function; the study depends on and confirms catalytic TS activity. Supporting Evidence: PMID:15093541 ectopic expression of catalytically active
GO:0005542 folic acid binding	IC PMID:15093541 Thymidylate synthase as an oncogene: a novel role for an ess...	ACCEPT	Summary: Inferred from thymidylate synthase activity (GO:0004799); the enzyme binds the folate cosubstrate (6R)-5,10-methylenetetrahydrofolate as its one-carbon donor and reductant, consistent with folate binding. Reason: TYMS binds a folate cofactor during catalysis (UniProt records methylenetetrahydrofolate-binding residues), so folate binding is a well-justified molecular function inferred from its catalytic activity. Supporting Evidence: file:human/TYMS/TYMS-uniprot.txt methylenetetrahydrofolate (CH2H4folate) as a 1-
GO:0006231 dTMP biosynthetic process	IDA PMID:15093541 Thymidylate synthase as an oncogene: a novel role for an ess...	ACCEPT	Summary: TYMS is characterized as essential for DNA synthesis through de novo thymidylate production; its catalytic role in dTMP biosynthesis is central to the oncogene-like phenotype. Reason: Core BP; supported by the enzyme's essential role in de novo thymidylate synthesis. Supporting Evidence: PMID:15093541 is an E2F1-regulated enzyme that is essential for DNA
GO:0035999 tetrahydrofolate interconversion	IDA PMID:15093541 Thymidylate synthase as an oncogene: a novel role for an ess...	ACCEPT	Summary: The TYMS reaction oxidises 5,10-methylenetetrahydrofolate to 7,8-dihydrofolate, participating in the interconversion of folate cofactors that is coupled to dTMP synthesis. Reason: Mechanistically correct - TYMS consumes methylene-THF and produces DHF, a folate-interconversion step tightly linked to the thymidylate cycle. Supporting Evidence: file:human/TYMS/TYMS-uniprot.txt carbon donor and reductant and
GO:0071897 DNA biosynthetic process	IC PMID:15093541 Thymidylate synthase as an oncogene: a novel role for an ess...	KEEP AS NON CORE	Summary: Inferred (IC) from thymidylate synthase activity - by supplying dTMP/dTTP, TYMS enables DNA biosynthesis. This is a broad downstream process rather than a direct activity of the enzyme. Reason: TYMS enables DNA synthesis by providing the thymidine nucleotide precursor rather than participating directly in DNA polymerization; retained as a non-core downstream process. Supporting Evidence: PMID:15093541 is an E2F1-regulated enzyme that is essential for DNA
GO:0005829 cytosol	TAS Reactome:R-HSA-73605	ACCEPT	Summary: Reactome traceable statement placing thymidylate synthase in the cytosol, where it catalyses the conversion of dUMP to dTMP as a homodimer. Reason: Cytosol is the principal, well-established site of TYMS activity; correct core cellular component. Supporting Evidence: Reactome:R-HSA-73605 Cytosolic thymidylate synthase catalyzes the reaction of dUMP and N5,N10-methylene tetrahydrofolate to form TMP and dihydrofolate
GO:0005829 cytosol	TAS Reactome:R-HSA-8962050	ACCEPT	Summary: Reactome cytosol annotation associated with the TYMS gene expression event (E2F1-regulated expression). Consistent with the enzyme's established cytosolic localization. Reason: Correct core cellular component; redundant with the other cytosol annotations. Supporting Evidence: Reactome:R-HSA-73605 Cytosolic thymidylate synthase catalyzes the reaction of dUMP and N5,N10-methylene tetrahydrofolate to form TMP and dihydrofolate
GO:0005634 nucleus	IDA PMID:21876188 Identification of a de novo thymidylate biosynthesis pathway...	KEEP AS NON CORE	Summary: Experimental localization consistent with TYMS's nuclear presence as part of the de novo thymidylate pathway. The primary focus of PMID:21876188 is the mitochondrial pathway; the nuclear/S-phase localization is documented in the companion work PMID:22235121. Reason: Experimentally supported nuclear localization (cell-cycle restricted); a non-core compartment relative to the bulk cytosolic enzyme. Supporting Evidence: PMID:22235121 The metabolic complex is enriched at sites of DNA replication initiation and associated with proliferating cell nuclear antigen
GO:0005737 cytoplasm	IDA PMID:21876188 Identification of a de novo thymidylate biosynthesis pathway...	ACCEPT	Summary: Experimental (IDA) cytoplasmic localization of TYMS. This is the general parent of the better-supported cytosol annotation. Reason: Correct but general; TYMS is a cytoplasmic/cytosolic enzyme. The specific cytosol term is preferred for the core annotation. Supporting Evidence: PMID:21876188 converted dUMP to dTMP in the presence of NADPH
GO:0005739 mitochondrion	IDA PMID:21876188 Identification of a de novo thymidylate biosynthesis pathway...	KEEP AS NON CORE	Summary: Direct experimental localization of TYMS to mitochondria, where it participates in a de novo dTMP synthesis pathway (with SHMT2 and DHFRL1) that protects mtDNA from uracil misincorporation. Reason: Experimentally supported mitochondrial localization; a genuine but non-core compartment for this predominantly cytosolic/nuclear enzyme. Supporting Evidence: PMID:21876188 de novo dTMP synthesis occurs within mitochondria
GO:0005743 mitochondrial inner membrane	IDA PMID:21876188 Identification of a de novo thymidylate biosynthesis pathway...	KEEP AS NON CORE	Summary: TYMS was localized to the mitochondrial matrix and inner membrane, confirming the mitochondrial de novo dTMP pathway. Reason: Directly experimentally supported; a non-core compartment. Supporting Evidence: PMID:21876188 Human DHFRL1, SHMT2, and TYMS were localized to mitochondrial matrix and inner membrane
GO:0005759 mitochondrial matrix	IDA PMID:21876188 Identification of a de novo thymidylate biosynthesis pathway...	KEEP AS NON CORE	Summary: TYMS was localized to the mitochondrial matrix and inner membrane, part of the mitochondrial de novo dTMP synthesis pathway. Reason: Directly experimentally supported; a non-core compartment. Supporting Evidence: PMID:21876188 Human DHFRL1, SHMT2, and TYMS were localized to mitochondrial matrix and inner membrane

📄 View Raw YAML

id: P04818
gene_symbol: TYMS
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Thymidylate synthase (TYMS, EC 2.1.1.45) catalyses the reductive methylation
  of 2'-deoxyuridine-5'-monophosphate (dUMP) to 2'-deoxythymidine-5'-monophosphate
  (dTMP), using (6R)-5,10-methylenetetrahydrofolate as both the one-carbon donor and
  the reductant, which is oxidised in the reaction to 7,8-dihydrofolate (DHF; regenerated
  by dihydrofolate reductase). This is the sole de novo route to thymidylate and is
  essential for DNA replication and repair. The enzyme is a cytosolic homodimer with
  an active-site cysteine nucleophile; a de novo thymidylate synthesis multienzyme complex
  (with SHMT1/SHMT2 and DHFR/DHFRL1) also operates in the nucleus at replication forks
  during S phase and in mitochondria, supplying dTMP for nuclear and mitochondrial DNA.
  TYMS is a central chemotherapy target, inhibited by the 5-fluorouracil metabolite FdUMP
  and by antifolates such as raltitrexed and pemetrexed. Beyond catalysis, TYMS moonlights
  as an RNA-binding translational repressor, binding its own mRNA to autoregulate its
  translation.
alternative_products:
- name: '1'
  id: P04818-1
- name: 2 (delta4)
  id: P04818-2
  sequence_note: VSP_047746
- name: 3 (delta2+3)
  id: P04818-3
  sequence_note: VSP_047745
existing_annotations:
- term:
    id: GO:0006231
    label: dTMP biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) propagation of the deeply conserved role of thymidylate
      synthase in de novo dTMP synthesis. This is the core biological process of TYMS
      and is directly supported by experimental annotations and by the enzyme's reaction.
    action: ACCEPT
    reason: Correct core BP for TYMS; consistent with the catalysed reaction (dUMP ->
      dTMP) and the UniProt PATHWAY assignment. Well supported at the right level of
      specificity by orthologs across the thymidylate synthase family.
    supported_by:
    - reference_id: file:human/TYMS/TYMS-uniprot.txt
      supporting_text: 'PATHWAY: Pyrimidine metabolism; dTTP biosynthesis.'
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: IBA propagation of a mitochondrial location. A de novo dTMP synthesis
      pathway (SHMT2, TYMS, DHFRL1) operates in mammalian mitochondria and TYMS is
      experimentally localized there, so a mitochondrial annotation is supported, though
      it is a secondary compartment relative to the cytosol.
    action: KEEP_AS_NON_CORE
    reason: TYMS was experimentally localized to mitochondria (matrix and inner membrane)
      as part of a mitochondrial de novo dTMP pathway, so the IBA location is defensible.
      It is a non-core compartment relative to the predominant cytosolic/nuclear activity.
    supported_by:
    - reference_id: PMID:21876188
      supporting_text: Human DHFRL1, SHMT2, and TYMS were localized to mitochondrial
        matrix and inner membrane
- term:
    id: GO:0004799
    label: thymidylate synthase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: IBA propagation of thymidylate synthase catalytic activity, the defining
      molecular function of TYMS and its orthologs. Directly corroborated by multiple
      experimental (IDA) annotations and by the UniProt catalytic-activity record (EC
      2.1.1.45, RHEA:12104).
    action: ACCEPT
    reason: This is the core molecular function of TYMS and is unambiguous across the
      family. Correct term at the correct level of specificity.
    supported_by:
    - reference_id: file:human/TYMS/TYMS-uniprot.txt
      supporting_text: Catalyzes the reductive methylation of 2'-deoxyuridine 5'-
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: IBA propagation of a cytosolic location. Thymidylate synthase is classically
      a cytosolic enzyme, consistent with Reactome and with the general subcellular
      distribution of nucleotide biosynthetic enzymes.
    action: ACCEPT
    reason: Cytosol is the principal site of TYMS activity and is well established.
      This is the core cellular component annotation.
    supported_by:
    - reference_id: Reactome:R-HSA-73605
      supporting_text: Cytosolic thymidylate synthase catalyzes the reaction of dUMP
        and N5,N10-methylene tetrahydrofolate to form TMP and dihydrofolate
- term:
    id: GO:0004799
    label: thymidylate synthase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic (multiple-method) assignment of thymidylate synthase activity
      based on InterPro/ARBA signatures, RHEA:12104 and EC 2.1.1.45. Redundant with,
      and fully consistent with, the experimental and IBA annotations of the same term.
    action: ACCEPT
    reason: Correct MF; the InterPro/RHEA/EC mapping is accurate for this well-characterized
      enzyme.
    supported_by:
    - reference_id: file:human/TYMS/TYMS-uniprot.txt
      supporting_text: EC=2.1.1.45
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer from the UniProt Subcellular Location vocabulary (nucleus).
      TYMS localizes to the nucleus during S and G2/M as part of the de novo thymidylate
      complex at replication forks; this IEA is corroborated by experimental annotations.
    action: KEEP_AS_NON_CORE
    reason: Nuclear localization is experimentally documented and cell-cycle dependent;
      it is a genuine but secondary compartment relative to the bulk cytosolic enzyme.
    supported_by:
    - reference_id: file:human/TYMS/TYMS-uniprot.txt
      supporting_text: Localized to the nucleus during S
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer from the UniProt Subcellular Location vocabulary (cytoplasm).
      This is the general parent of the more specific and better-supported cytosol
      annotation.
    action: ACCEPT
    reason: Correct but general; TYMS is a cytoplasmic/cytosolic enzyme. The more specific
      cytosol term (GO:0005829) is preferred for the core annotation, but this broader
      term is not wrong.
    supported_by:
    - reference_id: PMID:21876188
      supporting_text: Human DHFRL1, SHMT2, and TYMS were localized to mitochondrial
        matrix and inner membrane
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer from the UniProt Subcellular Location vocabulary (mitochondrion),
      corroborated by experimental localization of TYMS to mitochondria as part of
      a mitochondrial de novo dTMP pathway.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported non-core compartment; consistent with the IDA
      mitochondrion annotation from PMID:21876188.
    supported_by:
    - reference_id: PMID:21876188
      supporting_text: de novo dTMP synthesis occurs within mitochondria
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer from the UniProt Subcellular Location vocabulary (mitochondrion
      inner membrane), corroborated by experimental localization of TYMS to the mitochondrial
      inner membrane.
    action: KEEP_AS_NON_CORE
    reason: Supported by the experimental IDA annotation (PMID:21876188) placing TYMS
      at the mitochondrial matrix/inner membrane; a non-core compartment.
    supported_by:
    - reference_id: PMID:21876188
      supporting_text: Human DHFRL1, SHMT2, and TYMS were localized to mitochondrial
        matrix and inner membrane
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer from the UniProt Subcellular Location vocabulary (mitochondrion
      matrix), corroborated by experimental localization of TYMS to the mitochondrial
      matrix.
    action: KEEP_AS_NON_CORE
    reason: Supported by the experimental IDA annotation (PMID:21876188); a non-core
      compartment.
    supported_by:
    - reference_id: PMID:21876188
      supporting_text: Human DHFRL1, SHMT2, and TYMS were localized to mitochondrial
        matrix and inner membrane
- term:
    id: GO:0006231
    label: dTMP biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro2GO electronic mapping of the thymidylate synthase domain to de
      novo dTMP biosynthesis. Redundant with, and consistent with, the experimental
      and IBA annotations of this core process.
    action: ACCEPT
    reason: Correct core BP; the InterPro-to-GO mapping is accurate for TYMS.
    supported_by:
    - reference_id: file:human/TYMS/TYMS-uniprot.txt
      supporting_text: 'PATHWAY: Pyrimidine metabolism; dTTP biosynthesis.'
- term:
    id: GO:0016741
    label: transferase activity, transferring one-carbon groups
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO electronic mapping to a broad one-carbon transferase parent.
      This is a general ancestor of the specific and experimentally supported thymidylate
      synthase activity (GO:0004799) already annotated to TYMS.
    action: MARK_AS_OVER_ANNOTATED
    reason: Not wrong (TYMS transfers a one-carbon methylene/methyl group), but it is
      a high-level parent term that is uninformative given the specific GO:0004799 annotation.
      The specific term should carry the molecular-function annotation.
    supported_by:
    - reference_id: file:human/TYMS/TYMS-uniprot.txt
      supporting_text: methylenetetrahydrofolate (CH2H4folate) as a 1-
- term:
    id: GO:0006235
    label: dTTP biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: UniPathway-derived electronic mapping to dTTP biosynthesis. TYMS provides
      dTMP, the committed de novo precursor that is subsequently phosphorylated to dTTP;
      UniProt assigns the pathway 'Pyrimidine metabolism; dTTP biosynthesis'.
    action: ACCEPT
    reason: Correct pathway-level BP; consistent with the UniProt PATHWAY statement.
      TYMS is the de novo entry point to the dTTP pathway.
    supported_by:
    - reference_id: file:human/TYMS/TYMS-uniprot.txt
      supporting_text: 'PATHWAY: Pyrimidine metabolism; dTTP biosynthesis.'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:22235121
  qualifier: located_in
  review:
    summary: Experimental localization of the de novo thymidylate synthesis complex
      (including TYMS) to the nuclear lamina and to sites of DNA replication initiation
      during S phase.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported nuclear localization; a genuine but cell-cycle-restricted,
      non-core compartment relative to the bulk cytosolic enzyme.
    supported_by:
    - reference_id: PMID:22235121
      supporting_text: The metabolic complex is enriched at sites of DNA replication
        initiation and associated with proliferating cell nuclear antigen
- term:
    id: GO:0006260
    label: DNA replication
  evidence_type: IDA
  original_reference_id: PMID:22235121
  qualifier: involved_in
  review:
    summary: TYMS, as part of the de novo thymidylate synthesis complex localized at
      replication forks, supplies dTMP for DNA replication; the complex is enriched
      at DNA replication initiation sites and associates with PCNA and the replication
      machinery.
    action: KEEP_AS_NON_CORE
    reason: TYMS supports DNA replication by providing the dTMP building block rather
      than acting directly in the replication reaction; this is a downstream, contextual
      process, so it is retained as non-core.
    supported_by:
    - reference_id: PMID:22235121
      supporting_text: de novo thymidylate biosynthesis occurs at replication forks
- term:
    id: GO:0005657
    label: replication fork
  evidence_type: IDA
  original_reference_id: PMID:22235121
  qualifier: is_active_in
  review:
    summary: The de novo thymidylate synthesis complex (SHMT1, DHFR, TYMS) localizes
      to replication forks during DNA synthesis, placing TYMS activity at the fork.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported localization of TYMS activity to replication forks,
      but this reflects the S-phase nuclear complex rather than the enzyme's core cytosolic
      site; retained as non-core.
    supported_by:
    - reference_id: PMID:22235121
      supporting_text: de novo thymidylate biosynthesis occurs at replication forks
- term:
    id: GO:0006207
    label: '''de novo'' pyrimidine nucleobase biosynthetic process'
  evidence_type: IDA
  original_reference_id: PMID:22235121
  qualifier: involved_in
  review:
    summary: TYMS contributes to de novo synthesis of the pyrimidine nucleotide thymidylate.
      The strictly correct process is de novo dTMP/dTTP biosynthesis (already annotated);
      this term names the broader de novo pyrimidine nucleobase process.
    action: KEEP_AS_NON_CORE
    reason: The essence is correct (de novo pyrimidine nucleotide synthesis), but the
      specific and directly supported processes are dTMP/dTTP biosynthesis (GO:0006231,
      GO:0006235). Retained as a non-core broader-process annotation rather than removed.
    supported_by:
    - reference_id: PMID:22235121
      supporting_text: The de novo thymidylate biosynthetic pathway in mammalian cells
        translocates to
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22235121
  qualifier: enables
  review:
    summary: IPI capturing physical interaction of TYMS with SHMT1 (P34896) and DHFR
      (P00374) within the de novo thymidylate synthesis complex. The specific interactions
      are biologically meaningful, but the GO term 'protein binding' itself is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare 'protein binding' does not convey a specific molecular function. The
      underlying SHMT1/DHFR complex interactions are real and are better captured by
      the complex/subunit description rather than this generic MF term.
    supported_by:
    - reference_id: PMID:22235121
      supporting_text: this pathway forms a multienzyme complex that is associated with
        the nuclear lamina
- term:
    id: GO:0004799
    label: thymidylate synthase activity
  evidence_type: IDA
  original_reference_id: PMID:11278511
  qualifier: enables
  review:
    summary: Direct assay of human thymidylate synthase catalytic activity, with the
      2.0 A crystal structure and kinetics of the dUMP reaction defining the enzyme's
      active-site mechanism.
    action: ACCEPT
    reason: Core molecular function, experimentally demonstrated for the human enzyme.
    supported_by:
    - reference_id: PMID:11278511
      supporting_text: analogs of its substrates, dUMP and CH(2)H(4)folate
- term:
    id: GO:0004799
    label: thymidylate synthase activity
  evidence_type: IDA
  original_reference_id: PMID:8845352
  qualifier: enables
  review:
    summary: Human thymidylate synthase catalytic activity supported by the 3.0 A crystal
      structure characterizing the active-site loop and substrate docking mechanism.
    action: ACCEPT
    reason: Core molecular function; the structure resolves the human TS active site
      and confirms the catalytic enzyme.
    supported_by:
    - reference_id: PMID:8845352
      supporting_text: The crystal structure of human thymidylate synthase, a target
        for anti-cancer drugs
- term:
    id: GO:0006231
    label: dTMP biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:11278511
  qualifier: involved_in
  review:
    summary: The catalytic characterization of human TS establishes its role in dTMP
      biosynthesis via the dUMP reaction.
    action: ACCEPT
    reason: Core BP directly supported by the human enzyme's catalytic activity.
    supported_by:
    - reference_id: PMID:11278511
      supporting_text: analogs of its substrates, dUMP and CH(2)H(4)folate
- term:
    id: GO:0006231
    label: dTMP biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:8845352
  qualifier: involved_in
  review:
    summary: The structural characterization of human TS as an anti-cancer drug target
      supports its role in dTMP biosynthesis.
    action: ACCEPT
    reason: Core BP; consistent with the enzyme's dUMP-to-dTMP reaction.
    supported_by:
    - reference_id: PMID:8845352
      supporting_text: The crystal structure of human thymidylate synthase, a target
        for anti-cancer drugs
- term:
    id: GO:0004799
    label: thymidylate synthase activity
  evidence_type: TAS
  original_reference_id: PMID:1924359
  qualifier: enables
  review:
    summary: Traceable statement of thymidylate synthase catalytic activity (EC 2.1.1.45,
      5,10-methylenetetrahydrofolate:dUMP C-methyltransferase) in the context of the
      autoregulation study.
    action: ACCEPT
    reason: Core molecular function, correctly stated.
    supported_by:
    - reference_id: PMID:1924359
      supporting_text: essential for the de novo synthesis of
- term:
    id: GO:0000900
    label: mRNA regulatory element binding translation repressor activity
  evidence_type: IDA
  original_reference_id: PMID:1924359
  qualifier: enables
  review:
    summary: TS protein binds its own mRNA and represses its translation in vitro; this
      autoregulatory RNA-binding repressor activity is a documented moonlighting function
      distinct from its catalytic role.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported moonlighting activity (translational autoregulation),
      but not the core metabolic function of TYMS; retained as non-core.
    supported_by:
    - reference_id: PMID:1924359
      supporting_text: translation of TS mRNA is controlled by its own protein end product,
        TS, in an autoregulatory manner
- term:
    id: GO:0017148
    label: negative regulation of translation
  evidence_type: IDA
  original_reference_id: PMID:1924359
  qualifier: involved_in
  review:
    summary: Addition of recombinant TS protein inhibits translation of TS mRNA in vitro,
      a specific negative regulation of its own translation.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported moonlighting/regulatory role; not the core metabolic
      function, so retained as non-core.
    supported_by:
    - reference_id: PMID:1924359
      supporting_text: recombinant TS protein to in vitro translation reactions inhibited
        translation of TS mRNA
- term:
    id: GO:1990825
    label: sequence-specific mRNA binding
  evidence_type: IDA
  original_reference_id: PMID:1924359
  qualifier: enables
  review:
    summary: Gel-retardation assays demonstrate a specific interaction between TS protein
      and its own mRNA but not unrelated mRNAs, supporting sequence-specific mRNA binding.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported RNA-binding moonlighting activity underlying autoregulation;
      not the core metabolic function.
    supported_by:
    - reference_id: PMID:1924359
      supporting_text: a specific interaction between TS protein and its corresponding
        mRNA but not with unrelated mRNAs
- term:
    id: GO:0004799
    label: thymidylate synthase activity
  evidence_type: IDA
  original_reference_id: PMID:15093541
  qualifier: enables
  review:
    summary: TYMS is treated as a catalytically active enzyme essential for DNA synthesis;
      catalytically dead point mutants lack the transforming activity, tying the phenotype
      to catalytic thymidylate synthase activity.
    action: ACCEPT
    reason: Core molecular function; the study depends on and confirms catalytic TS
      activity.
    supported_by:
    - reference_id: PMID:15093541
      supporting_text: ectopic expression of catalytically active
- term:
    id: GO:0005542
    label: folic acid binding
  evidence_type: IC
  original_reference_id: PMID:15093541
  qualifier: enables
  review:
    summary: Inferred from thymidylate synthase activity (GO:0004799); the enzyme binds
      the folate cosubstrate (6R)-5,10-methylenetetrahydrofolate as its one-carbon donor
      and reductant, consistent with folate binding.
    action: ACCEPT
    reason: TYMS binds a folate cofactor during catalysis (UniProt records methylenetetrahydrofolate-binding
      residues), so folate binding is a well-justified molecular function inferred from
      its catalytic activity.
    supported_by:
    - reference_id: file:human/TYMS/TYMS-uniprot.txt
      supporting_text: methylenetetrahydrofolate (CH2H4folate) as a 1-
- term:
    id: GO:0006231
    label: dTMP biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:15093541
  qualifier: involved_in
  review:
    summary: TYMS is characterized as essential for DNA synthesis through de novo thymidylate
      production; its catalytic role in dTMP biosynthesis is central to the oncogene-like
      phenotype.
    action: ACCEPT
    reason: Core BP; supported by the enzyme's essential role in de novo thymidylate
      synthesis.
    supported_by:
    - reference_id: PMID:15093541
      supporting_text: is an E2F1-regulated enzyme that is essential for DNA
- term:
    id: GO:0035999
    label: tetrahydrofolate interconversion
  evidence_type: IDA
  original_reference_id: PMID:15093541
  qualifier: involved_in
  review:
    summary: The TYMS reaction oxidises 5,10-methylenetetrahydrofolate to 7,8-dihydrofolate,
      participating in the interconversion of folate cofactors that is coupled to dTMP
      synthesis.
    action: ACCEPT
    reason: Mechanistically correct - TYMS consumes methylene-THF and produces DHF,
      a folate-interconversion step tightly linked to the thymidylate cycle.
    supported_by:
    - reference_id: file:human/TYMS/TYMS-uniprot.txt
      supporting_text: carbon donor and reductant and
- term:
    id: GO:0071897
    label: DNA biosynthetic process
  evidence_type: IC
  original_reference_id: PMID:15093541
  qualifier: involved_in
  review:
    summary: Inferred (IC) from thymidylate synthase activity - by supplying dTMP/dTTP,
      TYMS enables DNA biosynthesis. This is a broad downstream process rather than
      a direct activity of the enzyme.
    action: KEEP_AS_NON_CORE
    reason: TYMS enables DNA synthesis by providing the thymidine nucleotide precursor
      rather than participating directly in DNA polymerization; retained as a non-core
      downstream process.
    supported_by:
    - reference_id: PMID:15093541
      supporting_text: is an E2F1-regulated enzyme that is essential for DNA
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73605
  qualifier: located_in
  review:
    summary: Reactome traceable statement placing thymidylate synthase in the cytosol,
      where it catalyses the conversion of dUMP to dTMP as a homodimer.
    action: ACCEPT
    reason: Cytosol is the principal, well-established site of TYMS activity; correct
      core cellular component.
    supported_by:
    - reference_id: Reactome:R-HSA-73605
      supporting_text: Cytosolic thymidylate synthase catalyzes the reaction of dUMP
        and N5,N10-methylene tetrahydrofolate to form TMP and dihydrofolate
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8962050
  qualifier: located_in
  review:
    summary: Reactome cytosol annotation associated with the TYMS gene expression event
      (E2F1-regulated expression). Consistent with the enzyme's established cytosolic
      localization.
    action: ACCEPT
    reason: Correct core cellular component; redundant with the other cytosol annotations.
    supported_by:
    - reference_id: Reactome:R-HSA-73605
      supporting_text: Cytosolic thymidylate synthase catalyzes the reaction of dUMP
        and N5,N10-methylene tetrahydrofolate to form TMP and dihydrofolate
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:21876188
  qualifier: located_in
  review:
    summary: Experimental localization consistent with TYMS's nuclear presence as part
      of the de novo thymidylate pathway. The primary focus of PMID:21876188 is the
      mitochondrial pathway; the nuclear/S-phase localization is documented in the companion
      work PMID:22235121.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported nuclear localization (cell-cycle restricted); a
      non-core compartment relative to the bulk cytosolic enzyme.
    supported_by:
    - reference_id: PMID:22235121
      supporting_text: The metabolic complex is enriched at sites of DNA replication
        initiation and associated with proliferating cell nuclear antigen
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:21876188
  qualifier: located_in
  review:
    summary: Experimental (IDA) cytoplasmic localization of TYMS. This is the general
      parent of the better-supported cytosol annotation.
    action: ACCEPT
    reason: Correct but general; TYMS is a cytoplasmic/cytosolic enzyme. The specific
      cytosol term is preferred for the core annotation.
    supported_by:
    - reference_id: PMID:21876188
      supporting_text: converted dUMP to dTMP in the presence of NADPH
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:21876188
  qualifier: located_in
  review:
    summary: Direct experimental localization of TYMS to mitochondria, where it participates
      in a de novo dTMP synthesis pathway (with SHMT2 and DHFRL1) that protects mtDNA
      from uracil misincorporation.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported mitochondrial localization; a genuine but non-core
      compartment for this predominantly cytosolic/nuclear enzyme.
    supported_by:
    - reference_id: PMID:21876188
      supporting_text: de novo dTMP synthesis occurs within mitochondria
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:21876188
  qualifier: located_in
  review:
    summary: TYMS was localized to the mitochondrial matrix and inner membrane, confirming
      the mitochondrial de novo dTMP pathway.
    action: KEEP_AS_NON_CORE
    reason: Directly experimentally supported; a non-core compartment.
    supported_by:
    - reference_id: PMID:21876188
      supporting_text: Human DHFRL1, SHMT2, and TYMS were localized to mitochondrial
        matrix and inner membrane
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IDA
  original_reference_id: PMID:21876188
  qualifier: located_in
  review:
    summary: TYMS was localized to the mitochondrial matrix and inner membrane, part
      of the mitochondrial de novo dTMP synthesis pathway.
    action: KEEP_AS_NON_CORE
    reason: Directly experimentally supported; a non-core compartment.
    supported_by:
    - reference_id: PMID:21876188
      supporting_text: Human DHFRL1, SHMT2, and TYMS were localized to mitochondrial
        matrix and inner membrane
core_functions:
- description: Thymidylate synthase catalytic activity - reductive methylation of dUMP
    to dTMP using 5,10-methylenetetrahydrofolate as one-carbon donor and reductant,
    the sole de novo source of thymidylate.
  molecular_function:
    id: GO:0004799
    label: thymidylate synthase activity
  supported_by:
  - reference_id: file:human/TYMS/TYMS-uniprot.txt
    supporting_text: Catalyzes the reductive methylation of 2'-deoxyuridine 5'-
  - reference_id: PMID:11278511
    supporting_text: analogs of its substrates, dUMP and CH(2)H(4)folate
- description: De novo dTMP biosynthesis - TYMS provides the committed de novo step
    supplying thymidylate for DNA replication and repair, feeding the dTTP biosynthesis
    pathway.
  molecular_function:
    id: GO:0004799
    label: thymidylate synthase activity
  directly_involved_in:
  - id: GO:0006231
    label: dTMP biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/TYMS/TYMS-uniprot.txt
    supporting_text: 'PATHWAY: Pyrimidine metabolism; dTTP biosynthesis.'
  - reference_id: Reactome:R-HSA-73605
    supporting_text: Cytosolic thymidylate synthase catalyzes the reaction of dUMP
      and N5,N10-methylene tetrahydrofolate to form TMP and dihydrofolate
- description: Folate cofactor binding - TYMS binds the folate cosubstrate methylenetetrahydrofolate
    during catalysis, coupling dTMP synthesis to folate (tetrahydrofolate) interconversion.
  molecular_function:
    id: GO:0005542
    label: folic acid binding
  supported_by:
  - reference_id: file:human/TYMS/TYMS-uniprot.txt
    supporting_text: methylenetetrahydrofolate (CH2H4folate) as a 1-
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:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11278511
  title: Structure of human thymidylate synthase suggests advantages of chemotherapy
    with noncompetitive inhibitors.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Human TS 2.0 A crystal structure with catalytic activity; supports
      the core thymidylate synthase MF and the FdUMP/dUMP-substrate chemotherapy context.
      Abstract-only in cache.
- id: PMID:15093541
  title: 'Thymidylate synthase as an oncogene: a novel role for an essential DNA synthesis
    enzyme.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes TYMS as an E2F1-regulated, catalytically-dependent DNA-synthesis
      enzyme with oncogene-like activity; grounds the dTMP/DNA-synthesis and folate-binding
      IC annotations. Abstract-only in cache.
- id: PMID:1924359
  title: Autoregulation of human thymidylate synthase messenger RNA translation by
    thymidylate synthase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Primary evidence for the moonlighting RNA-binding translational-repressor
      role (autoregulation of TS mRNA); grounds GO:0000900, GO:1990825, GO:0017148.
      Abstract-only in cache.
- id: PMID:21876188
  title: Identification of a de novo thymidylate biosynthesis pathway in mammalian
    mitochondria.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Localizes TYMS (with SHMT2, DHFRL1) to mitochondrial matrix/inner
      membrane and demonstrates mitochondrial de novo dTMP synthesis; grounds the mitochondrial
      location annotations. Abstract-only in cache.
- id: PMID:22235121
  title: Serine hydroxymethyltransferase anchors de novo thymidylate synthesis pathway
    to nuclear lamina for DNA synthesis.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Shows the de novo thymidylate complex (SHMT1/DHFR/TYMS) at the nuclear
      lamina and replication forks; grounds nucleus, replication fork, DNA replication,
      and the SHMT1/DHFR protein-interaction annotations. Abstract-only in cache.
- id: PMID:8845352
  title: 'Crystal structure of human thymidylate synthase: a structural mechanism
    for guiding substrates into the active site.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Human TS crystal structure; supports the core thymidylate synthase
      MF and the anti-cancer drug-target context. Abstract-only in cache.
- id: Reactome:R-HSA-73605
  title: conversion of dUMP to dTMP
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome reaction for cytosolic TYMS converting dUMP to dTMP; supports
      the cytosol location and core reaction.
- id: Reactome:R-HSA-8962050
  title: TYMS gene expression
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Reactome event for E2F1-regulated TYMS gene expression; supporting
      context for regulation and the cytosol annotation.
- id: file:human/TYMS/TYMS-uniprot.txt
  title: UniProtKB entry P04818 (TYSY_HUMAN), thymidylate synthase
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached UniProt record providing the catalytic-activity/reaction, PATHWAY,
      SUBUNIT (homodimer), and subcellular-location statements used to ground several
      annotations and core functions.
suggested_questions:
- question: Is the moonlighting RNA-binding/translational-repressor activity of TYMS
    physiologically significant in vivo, or primarily an in vitro/regulatory phenomenon?
- question: What is the quantitative contribution of the mitochondrial de novo dTMP
    pathway (TYMS/SHMT2/DHFRL1) versus the cytosolic/nuclear pathway to total cellular
    dTMP?
suggested_experiments:
- description: Compartment-specific rescue (cytosolic vs nuclear-targeted vs mitochondrial-targeted
    TYMS) in TYMS-null cells to dissect the relative importance of each localization
    for genome integrity.
- description: Structure-guided separation-of-function mutants that abolish mRNA binding
    while retaining catalysis, to test the biological role of translational autoregulation.

Gene Description

Existing Annotations Review

Core Functions

Thymidylate synthase catalytic activity - reductive methylation of dUMP to dTMP using 5,10-methylenetetrahydrofolate as one-carbon donor and reductant, the sole de novo source of thymidylate.

De novo dTMP biosynthesis - TYMS provides the committed de novo step supplying thymidylate for DNA replication and repair, feeding the dTTP biosynthesis pathway.

Folate cofactor binding - TYMS binds the folate cosubstrate methylenetetrahydrofolate during catalysis, coupling dTMP synthesis to folate (tetrahydrofolate) interconversion.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

TYMS (thymidylate synthase) review notes

Core biology

Localization

Moonlighting / regulation (non-core)

Curation decisions (summary)

📄 View Raw YAML