ATIC

id: P31939
gene_symbol: ATIC
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ATIC (bifunctional purine biosynthesis protein; AICAR transformylase / IMP
  cyclohydrolase, also known as PURH) is a cytosolic homodimeric enzyme that
  catalyzes the final two steps of de novo purine (IMP) biosynthesis. Its AICAR
  transformylase activity (EC 2.1.2.3) transfers a formyl group from
  10-formyltetrahydrofolate to 5-aminoimidazole-4-carboxamide ribonucleotide
  (AICAR), producing 5-formamido-AICAR (FAICAR); its IMP cyclohydrolase activity
  (EC 3.5.4.10) then cyclizes FAICAR to inosine 5'-monophosphate (IMP) plus
  water. The two catalytic activities reside on a single polypeptide in all
  species studied, with the IMP cyclohydrolase activity in the N-terminal
  MGS-like region (approximately residues 1-198) and the AICAR transformylase
  activity in the C-terminal region (approximately residues 199-592); the
  transformylase active site is formed at the dimer interface. The cyclohydrolase
  step is essentially irreversible and drives the otherwise unfavorable overall
  conversion of AICAR to IMP toward completion. Because the transformylase step
  is folate-dependent, ATIC is a pharmacological target of antifolates: the
  AICAR-transformylase activity is inhibited by methotrexate polyglutamates and
  pemetrexed and by nonclassical antifolates developed for tumor suppression, and
  elevated AICAR (as with the AMPK-activating AICA-riboside) reflects this node in
  folate/purine metabolism. Biallelic loss-of-function variants in ATIC cause
  AICA-ribosiduria, an extremely rare autosomal-recessive inborn error of purine
  biosynthesis characterized by profound intellectual disability, epilepsy,
  dysmorphic features and congenital blindness, with massive urinary excretion and
  tissue accumulation of AICA-riboside/AICA-ribotide.
alternative_products:
- name: '1'
  id: P31939-1
- name: '2'
  id: P31939-2
  sequence_note: VSP_053495
existing_annotations:
- term:
    id: GO:0004643
    label: phosphoribosylaminoimidazolecarboxamide formyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      AICAR transformylase (phosphoribosylaminoimidazolecarboxamide
      formyltransferase, EC 2.1.2.3) activity is a core, phylogenetically
      conserved molecular function of ATIC, catalyzing the penultimate step of de
      novo IMP biosynthesis. This IBA is well supported by direct experimental
      characterization of the human enzyme.
    action: ACCEPT
    reason: >-
      Core molecular function of the C-terminal domain, confirmed by kinetic and
      structural studies of the human protein. The IBA sensibly transfers the
      family-conserved activity to human ATIC.
    supported_by:
    - reference_id: PMID:9378707
      supporting_text: >-
        With the cloned cDNA fragment, we constructed expression vectors for
        mature and GST-fused AICAR transformylase. Both recombinant molecules
        possessing
        AICAR transformylase activity were overproduced in Escherichia coli.
    - reference_id: PMID:8567683
      supporting_text: >-
        IMPCHase and AICARFT activities are located within the NH2-terminal
        223 and COOH-terminal 406 amino acids, respectively.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      ATIC is a cytosolic enzyme of the de novo purine biosynthesis pathway;
      cytosolic localization is conserved across the PurH family and is where the
      enzyme carries out its catalytic activities.
    action: ACCEPT
    reason: >-
      Cytosol is the established subcellular location of ATIC (UniProt Cytoplasm,
      cytosol), consistent with its role in the soluble purine biosynthesis
      pathway. The is_active_in qualifier is appropriate because the enzyme
      performs its function in the cytosol.
    supported_by:
    - reference_id: file:human/ATIC/ATIC-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0003937
    label: IMP cyclohydrolase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      IMP cyclohydrolase (EC 3.5.4.10) activity is a core, conserved molecular
      function of ATIC, catalyzing the final step of de novo IMP biosynthesis
      (cyclization of FAICAR to IMP). Directly confirmed for the human enzyme by
      kinetics and mutagenesis.
    action: ACCEPT
    reason: >-
      Core molecular function residing in the N-terminal domain; the IBA
      correctly propagates this family-conserved activity to human ATIC.
    supported_by:
    - reference_id: PMID:14756554
      supporting_text: >-
        The bifunctional enzyme aminoimidazole carboxamide ribonucleotide
        transformylase/inosine monophosphate cyclohydrolase (ATIC) is responsible
        for catalysis of the last two steps in the de novo purine pathway.
    - reference_id: PMID:8567683
      supporting_text: >-
        IMPCHase and AICARFT activities are located within the NH2-terminal
        223 and COOH-terminal 406 amino acids, respectively.
- term:
    id: GO:0006189
    label: '''de novo'' IMP biosynthetic process'
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      ATIC catalyzes the last two steps of the de novo IMP biosynthesis pathway,
      so involvement in de novo IMP biosynthesis is a core biological process for
      this gene.
    action: ACCEPT
    reason: >-
      Directly supported process; ATIC is the terminal bifunctional enzyme of the
      de novo purine (IMP) pathway. The IBA is at the correct level of
      specificity.
    supported_by:
    - reference_id: PMID:11948179
      supporting_text: >-
        is a bifunctional protein possessing two enzymatic activities that
        sequentially catalyze the last two steps in the pathway for de novo
        synthesis of
        inosine 5'-monophosphate
- term:
    id: GO:0003937
    label: IMP cyclohydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assertion (ARBA/RHEA/EC mapping) of IMP cyclohydrolase activity.
      This is the same core catalytic function established experimentally for
      human ATIC.
    action: ACCEPT
    reason: >-
      The IEA (EC 3.5.4.10 / RHEA:18445) correctly maps to ATIC's experimentally
      confirmed IMP cyclohydrolase activity.
    supported_by:
    - reference_id: PMID:14756554
      supporting_text: >-
        transformylase/inosine monophosphate cyclohydrolase (ATIC) is responsible
        for catalysis of the last two steps in the de novo purine pathway
- term:
    id: GO:0004643
    label: phosphoribosylaminoimidazolecarboxamide formyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assertion (RHEA:22192 / EC 2.1.2.3) of AICAR transformylase
      activity, matching the experimentally confirmed core function of ATIC.
    action: ACCEPT
    reason: >-
      The IEA correctly maps EC 2.1.2.3 to ATIC's experimentally confirmed AICAR
      transformylase activity.
    supported_by:
    - reference_id: PMID:10985775
      supporting_text: >-
        It is proposed that the conformation of the carboxamide moiety
        required for binding to AICAR Tfase is different than the conformation
        required for binding to IMP CHase
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic assertion of cytosol localization from UniProt Subcellular
      Location mapping (SL-0091). Consistent with the established cytosolic
      localization of ATIC.
    action: ACCEPT
    reason: >-
      Matches the curated UniProt subcellular location (Cytoplasm, cytosol) and
      the IBA cytosol annotation.
    supported_by:
    - reference_id: file:human/ATIC/ATIC-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0006164
    label: purine nucleotide biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO mapping (IPR002695, PurH-like) to the general process of purine
      nucleotide biosynthesis. Correct but less specific than the de novo IMP
      biosynthetic process annotation.
    action: ACCEPT
    reason: >-
      Biologically correct; ATIC functions in purine nucleotide biosynthesis.
      This is a broader parent of the more specific de novo IMP biosynthetic
      process annotation, and acceptable as an IEA that is deliberately
      conservative.
    supported_by:
    - reference_id: PMID:11948179
      supporting_text: >-
        sequentially catalyze the last two steps in the pathway for de novo
        synthesis of inosine 5'-monophosphate
- term:
    id: GO:0003360
    label: brainstem development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic transfer of a rat/mouse ortholog annotation (Ensembl Compara)
      asserting involvement in brainstem development. There is no direct evidence
      that ATIC has a dedicated developmental role in the brainstem; any
      neurodevelopmental phenotype is a downstream consequence of impaired purine
      supply (AICA-ribosiduria), not a distinct molecular process ATIC
      participates in.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This is an over-propagated ortholog-transfer IEA. ATIC's neurological
      involvement is indirect, via its housekeeping purine-biosynthesis function;
      a specific brainstem developmental process annotation over-interprets an
      electronic ortholog transfer and is not a core function.
- term:
    id: GO:0006177
    label: GMP biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic assertion that ATIC is involved in GMP biosynthesis. ATIC
      produces IMP, the common precursor from which GMP (and AMP) are
      subsequently derived; ATIC itself does not catalyze any GMP-specific step.
    action: KEEP_AS_NON_CORE
    reason: >-
      ATIC acts upstream of GMP biosynthesis by generating the shared IMP
      precursor, so an acts-upstream-of style relationship is defensible, but GMP
      biosynthesis is not a core function of ATIC (its core outputs are the two
      enzymatic steps that make IMP). Keep as non-core rather than remove.
    supported_by:
    - reference_id: PMID:11948179
      supporting_text: >-
        sequentially catalyze the last two steps in the pathway for de novo
        synthesis of inosine 5'-monophosphate
- term:
    id: GO:0006189
    label: '''de novo'' IMP biosynthetic process'
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic assertion (ARBA / UniPathway UPA00074) of involvement in de novo
      IMP biosynthesis, matching the core biological process of ATIC.
    action: ACCEPT
    reason: >-
      Correct core process, redundant with the IBA/IDA de novo IMP biosynthesis
      annotations.
    supported_by:
    - reference_id: PMID:11948179
      supporting_text: >-
        sequentially catalyze the last two steps in the pathway for de novo
        synthesis of inosine 5'-monophosphate
- term:
    id: GO:0021549
    label: cerebellum development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ortholog-transfer IEA (Ensembl Compara) asserting cerebellum development.
      As with brainstem development, there is no evidence for a dedicated ATIC
      role in cerebellar development beyond its general housekeeping
      purine-biosynthesis function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-propagated developmental IEA; neurodevelopmental effects of ATIC
      deficiency are indirect consequences of purine insufficiency, not a
      distinct cerebellum-development function.
- term:
    id: GO:0021987
    label: cerebral cortex development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ortholog-transfer IEA (Ensembl Compara) asserting cerebral cortex
      development. No direct evidence for a specific cortical developmental role
      of ATIC distinct from its metabolic housekeeping function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-propagated developmental IEA; not a core function of ATIC.
- term:
    id: GO:0031100
    label: animal organ regeneration
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ortholog-transfer IEA (Ensembl Compara) asserting involvement in organ
      regeneration, likely reflecting increased purine demand in regenerating
      rodent tissue rather than a specific regenerative function of ATIC.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-propagated IEA; any association with regeneration is an indirect
      consequence of proliferation-driven purine demand, not a dedicated
      molecular role of ATIC.
- term:
    id: GO:0044208
    label: '''de novo'' AMP biosynthetic process'
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic assertion of involvement in de novo AMP biosynthesis. ATIC
      produces IMP, from which AMP is subsequently synthesized; ATIC does not
      catalyze an AMP-specific step.
    action: KEEP_AS_NON_CORE
    reason: >-
      ATIC acts upstream of AMP biosynthesis via the shared IMP precursor.
      Defensible as an upstream involvement but not a core function; keep as
      non-core.
    supported_by:
    - reference_id: PMID:11948179
      supporting_text: >-
        sequentially catalyze the last two steps in the pathway for de novo
        synthesis of inosine 5'-monophosphate
- term:
    id: GO:0046452
    label: dihydrofolate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ortholog-transfer IEA (Ensembl Compara) asserting dihydrofolate metabolic
      process. ATIC's transformylase reaction consumes 10-formyltetrahydrofolate
      (and can use 10-formyldihydrofolate) and releases tetrahydrofolate (or
      dihydrofolate), so it participates in folate one-carbon metabolism, but it
      is not a canonical enzyme of dihydrofolate metabolism.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      ATIC consumes a formyl-folate cofactor rather than performing dedicated
      dihydrofolate metabolism; the term over-interprets the cofactor usage. Its
      folate link is that its AICAR-transformylase step depends on 10-formyl-THF,
      making it an antifolate target, not a dihydrofolate-metabolizing enzyme.
    supported_by:
    - reference_id: file:human/ATIC/ATIC-uniprot.txt
      supporting_text: >-
        Can use both 10-formyldihydrofolate
- term:
    id: GO:0046654
    label: tetrahydrofolate biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ortholog-transfer IEA (Ensembl Compara) asserting tetrahydrofolate
      biosynthesis. ATIC releases tetrahydrofolate as a product of the
      transformylase reaction (from 10-formyl-THF) but does not synthesize the
      tetrahydrofolate scaffold; this is not a biosynthetic role for THF.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Regenerating THF from a formyl-THF donor during formyl transfer is not
      tetrahydrofolate biosynthesis. Over-propagated cofactor-based IEA.
    supported_by:
    - reference_id: file:human/ATIC/ATIC-uniprot.txt
      supporting_text: >-
        and 10-formyltetrahydrofolate as the formyl donor in this reaction
- term:
    id: GO:0097294
    label: '''de novo'' XMP biosynthetic process'
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic assertion of involvement in de novo XMP biosynthesis. XMP is
      derived from IMP (via IMP dehydrogenase) downstream of ATIC; ATIC does not
      catalyze an XMP-specific step.
    action: KEEP_AS_NON_CORE
    reason: >-
      ATIC acts upstream of XMP biosynthesis through the shared IMP precursor.
      Not a core function; keep as non-core.
    supported_by:
    - reference_id: PMID:11948179
      supporting_text: >-
        sequentially catalyze the last two steps in the pathway for de novo
        synthesis of inosine 5'-monophosphate
- term:
    id: GO:0003937
    label: IMP cyclohydrolase activity
  evidence_type: EXP
  original_reference_id: PMID:11948179
  qualifier: enables
  review:
    summary: >-
      Direct kinetic characterization of the human bifunctional enzyme
      established the IMP cyclohydrolase activity (cyclization of FAICAR to IMP),
      which is essentially unidirectional and draws the overall reaction toward
      IMP.
    action: ACCEPT
    reason: >-
      Experimental (EXP) evidence directly demonstrating the core IMP
      cyclohydrolase function of human ATIC via complete kinetic analysis.
    supported_by:
    - reference_id: PMID:11948179
      supporting_text: >-
        the cyclohydrolase reaction is essentially unidirectional in the forward
        sense. The cyclohydrolase reaction thus draws the overall bifunctional
        reaction toward the production of inosine monophosphate.
- term:
    id: GO:0003937
    label: IMP cyclohydrolase activity
  evidence_type: EXP
  original_reference_id: PMID:14756554
  qualifier: enables
  review:
    summary: >-
      Site-directed mutagenesis and steady-state kinetics of the human enzyme
      dissected the catalytic mechanism of the IMP cyclohydrolase activity,
      directly confirming this core function.
    action: ACCEPT
    reason: >-
      Experimental evidence directly characterizing ATIC's IMP cyclohydrolase
      catalytic mechanism in the human enzyme.
    supported_by:
    - reference_id: PMID:14756554
      supporting_text: >-
        four candidate residues, Lys66, Tyr104, Asp125, and Lys137, were
        identified for site-directed mutagenesis to study the cyclohydrolase
        activity of this bifunctional enzyme
- term:
    id: GO:0004643
    label: phosphoribosylaminoimidazolecarboxamide formyltransferase activity
  evidence_type: EXP
  original_reference_id: PMID:10985775
  qualifier: enables
  review:
    summary: >-
      Mechanistic study of human AICAR transformylase using AICAR analogues,
      establishing the specificity and catalytic role of the 4-carboxamide and
      directly confirming AICAR transformylase (formyltransferase) activity.
    action: ACCEPT
    reason: >-
      Experimental evidence directly characterizing the human AICAR
      transformylase catalytic activity.
    supported_by:
    - reference_id: PMID:10985775
      supporting_text: >-
        The results show that the 4-carboxamide of AICAR is essential
        for catalysis, and it is proposed to assist in mediating proton transfer
- term:
    id: GO:0004643
    label: phosphoribosylaminoimidazolecarboxamide formyltransferase activity
  evidence_type: EXP
  original_reference_id: PMID:11948179
  qualifier: enables
  review:
    summary: >-
      The complete kinetic mechanism study of human ATIC directly measured the
      AICAR transformylase reaction (forward/reverse rates, rate-limiting THF
      release), confirming formyltransferase activity.
    action: ACCEPT
    reason: >-
      Experimental evidence directly demonstrating human ATIC AICAR
      transformylase activity within the bifunctional enzyme.
    supported_by:
    - reference_id: PMID:11948179
      supporting_text: >-
        The rate-limiting step in the overall reaction (2.9
        +/- 0.4 s(-1)) is likely the release of tetrahydrofolate from the
        formyltransferase active site
- term:
    id: GO:0004643
    label: phosphoribosylaminoimidazolecarboxamide formyltransferase activity
  evidence_type: EXP
  original_reference_id: PMID:9378707
  qualifier: enables
  review:
    summary: >-
      Molecular cloning and expression of human AICAR transformylase with
      mutagenesis identifying His213 and His267 as essential for activity,
      directly confirming the formyltransferase function.
    action: ACCEPT
    reason: >-
      Experimental evidence: recombinant human enzyme with demonstrated AICAR
      transformylase activity and essential catalytic residues identified.
    supported_by:
    - reference_id: PMID:9378707
      supporting_text: >-
        Mutational analysis, utilizing this
        expression system, showed that His213 and His267 were essential for AICAR
        transformylase activity.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9700181
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol localization annotation. Consistent with the established
      cytosolic localization of ATIC, though attached to an ALK-fusion signaling
      event module (see reference).
    action: ACCEPT
    reason: >-
      Cytosol is the correct location for ATIC; TAS from Reactome is consistent
      with curated UniProt subcellular location.
    supported_by:
    - reference_id: file:human/ATIC/ATIC-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9700190
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol localization annotation (ALK-fusion module). Consistent
      with ATIC's cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct location for ATIC.
    supported_by:
    - reference_id: file:human/ATIC/ATIC-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9700193
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol localization annotation (ALK-fusion module). Consistent
      with ATIC's cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct location for ATIC.
    supported_by:
    - reference_id: file:human/ATIC/ATIC-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9710914
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol localization annotation (ALK-fusion module). Consistent
      with ATIC's cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct location for ATIC.
    supported_by:
    - reference_id: file:human/ATIC/ATIC-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9710917
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol localization annotation (ALK-fusion module). Consistent
      with ATIC's cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct location for ATIC.
    supported_by:
    - reference_id: file:human/ATIC/ATIC-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9712086
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol localization annotation (ALK-fusion module). Consistent
      with ATIC's cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct location for ATIC.
    supported_by:
    - reference_id: file:human/ATIC/ATIC-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9724099
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol localization annotation (ALK-fusion module). Consistent
      with ATIC's cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct location for ATIC.
    supported_by:
    - reference_id: file:human/ATIC/ATIC-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0003937
    label: IMP cyclohydrolase activity
  evidence_type: IDA
  original_reference_id: PMID:26588576
  qualifier: enables
  review:
    summary: >-
      In this study ATIC (with ASL) was used as a de novo purine pathway enzyme
      to study sequential enzyme colocalization; ATIC catalyzes steps 9 and 10
      (AICAR transformylase then IMP cyclohydrolase). Supports IMP cyclohydrolase
      activity.
    action: ACCEPT
    reason: >-
      Direct assay context confirming ATIC's IMP cyclohydrolase (step 10)
      activity; redundant with the EXP annotations but consistent and correct.
    supported_by:
    - reference_id: PMID:26588576
      supporting_text: >-
        ATIC (5-aminoimidazole-4-carboxamide
        ribonucleotide transformylase/inosine monophosphate cyclohydrolase, Steps
        9 and
        10)
- term:
    id: GO:0006177
    label: GMP biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:26588576
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      ATIC acts upstream of GMP biosynthesis by producing IMP, the common
      precursor of GMP and AMP. The acts_upstream_of_or_within qualifier captures
      this indirect relationship.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct upstream relationship (IMP is the precursor of GMP) but GMP
      biosynthesis is not a core function of ATIC. Keep as non-core.
    supported_by:
    - reference_id: PMID:26588576
      supporting_text: >-
        Two proteins of the de novo purine biosynthesis pathway, ASL
        (adenylosuccinate lyase, Step 8) and ATIC
- term:
    id: GO:0006189
    label: '''de novo'' IMP biosynthetic process'
  evidence_type: IDA
  original_reference_id: PMID:26588576
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      ATIC catalyzes the final two steps (9 and 10) of de novo IMP biosynthesis;
      the acts_upstream_of_or_within relation is consistent with its
      participation in this pathway.
    action: ACCEPT
    reason: >-
      Core biological process; ATIC produces IMP, the end product of de novo
      purine biosynthesis.
    supported_by:
    - reference_id: PMID:26588576
      supporting_text: >-
        Two proteins of the de novo purine biosynthesis pathway, ASL
        (adenylosuccinate lyase, Step 8) and ATIC
- term:
    id: GO:0044208
    label: '''de novo'' AMP biosynthetic process'
  evidence_type: IDA
  original_reference_id: PMID:26588576
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      ATIC acts upstream of AMP biosynthesis by producing IMP, the precursor of
      AMP. The acts_upstream_of_or_within qualifier captures this indirect
      relationship.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct upstream relationship but not a core function of ATIC; keep as
      non-core.
    supported_by:
    - reference_id: PMID:26588576
      supporting_text: >-
        Two proteins of the de novo purine biosynthesis pathway, ASL
        (adenylosuccinate lyase, Step 8) and ATIC
- term:
    id: GO:0097294
    label: '''de novo'' XMP biosynthetic process'
  evidence_type: IDA
  original_reference_id: PMID:26588576
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      ATIC acts upstream of XMP biosynthesis by producing IMP, the precursor from
      which XMP is made (via IMP dehydrogenase).
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct upstream relationship but not a core function of ATIC; keep as
      non-core.
    supported_by:
    - reference_id: PMID:26588576
      supporting_text: >-
        Two proteins of the de novo purine biosynthesis pathway, ASL
        (adenylosuccinate lyase, Step 8) and ATIC
- term:
    id: GO:0097294
    label: '''de novo'' XMP biosynthetic process'
  evidence_type: IDA
  original_reference_id: PMID:26588576
  qualifier: involved_in
  review:
    summary: >-
      involved_in variant of the XMP biosynthesis annotation from the same study.
      ATIC provides the IMP precursor upstream of XMP synthesis but does not
      itself catalyze XMP formation.
    action: KEEP_AS_NON_CORE
    reason: >-
      ATIC's contribution to XMP biosynthesis is indirect (via IMP); not a core
      function. Keep as non-core rather than accept as core process.
    supported_by:
    - reference_id: PMID:26588576
      supporting_text: >-
        Two proteins of the de novo purine biosynthesis pathway, ASL
        (adenylosuccinate lyase, Step 8) and ATIC
- term:
    id: GO:0006177
    label: GMP biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:26588576
  qualifier: involved_in
  review:
    summary: >-
      involved_in variant of the GMP biosynthesis annotation. ATIC provides the
      IMP precursor upstream of GMP synthesis but does not itself catalyze a
      GMP-specific step.
    action: KEEP_AS_NON_CORE
    reason: >-
      Indirect (upstream) relationship; not a core function of ATIC. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:26588576
      supporting_text: >-
        Two proteins of the de novo purine biosynthesis pathway, ASL
        (adenylosuccinate lyase, Step 8) and ATIC
- term:
    id: GO:0006189
    label: '''de novo'' IMP biosynthetic process'
  evidence_type: IDA
  original_reference_id: PMID:26588576
  qualifier: involved_in
  review:
    summary: >-
      involved_in variant of the de novo IMP biosynthesis annotation. ATIC
      catalyzes the last two steps of this pathway, making this a core biological
      process.
    action: ACCEPT
    reason: >-
      Core biological process for ATIC (production of IMP), directly supported.
    supported_by:
    - reference_id: PMID:26588576
      supporting_text: >-
        Two proteins of the de novo purine biosynthesis pathway, ASL
        (adenylosuccinate lyase, Step 8) and ATIC
- term:
    id: GO:0044208
    label: '''de novo'' AMP biosynthetic process'
  evidence_type: IDA
  original_reference_id: PMID:26588576
  qualifier: involved_in
  review:
    summary: >-
      involved_in variant of the AMP biosynthesis annotation. ATIC provides the
      IMP precursor upstream of AMP synthesis but does not catalyze an
      AMP-specific step.
    action: KEEP_AS_NON_CORE
    reason: >-
      Indirect (upstream) relationship; not a core function. Keep as non-core.
    supported_by:
    - reference_id: PMID:26588576
      supporting_text: >-
        Two proteins of the de novo purine biosynthesis pathway, ASL
        (adenylosuccinate lyase, Step 8) and ATIC
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9700179
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol localization annotation (ALK-fusion module). Consistent
      with ATIC's cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct location for ATIC.
    supported_by:
    - reference_id: file:human/ATIC/ATIC-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0045296
    label: cadherin binding
  evidence_type: HDA
  original_reference_id: PMID:25468996
  qualifier: enables
  review:
    summary: >-
      ATIC was identified among the proteins in the vicinity of the E-cadherin
      cytoplasmic tail in a high-throughput BioID proximity-biotinylation
      proteomic screen. This is a proximity-labeling co-detection, not evidence
      of a specific, functionally meaningful cadherin-binding activity of ATIC.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The authors themselves note the screen captured many proteins that do not
      localize to junctions and are found elsewhere in the cell; ATIC is a soluble
      cytosolic metabolic enzyme with no independent evidence of a
      cadherin-binding function. This is a non-specific proximity-proteomics hit,
      not a core molecular function. Per policy, an HDA is not removed outright.
    supported_by:
    - reference_id: PMID:25468996
      supporting_text: >-
        employed proximity biotinylation and quantitative proteomics to
        isolate and identify 612 proteins in the vicinity of E-cadherin’s
        cytoplasmic tail
    - reference_id: PMID:25468996
      supporting_text: >-
        the expression of GFP-tagged candidates clearly showed that many of the
        E-cad-BirA* interactome proteins are found in other locations in the cell
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: >-
      ATIC was detected among ~900 proteins in a shotgun proteomic survey of
      exosomes from expressed prostatic secretions in urine. This is a
      bulk-proteomics co-detection typical for abundant cytosolic housekeeping
      enzymes and does not reflect ATIC's genuine functional localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Detection in an exosome proteome is a common non-specific finding for
      abundant cytosolic enzymes and does not indicate a functional
      extracellular/exosomal role for ATIC, whose established localization is
      cytosol. Not a core function.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: >-
        In pooled EPS-urine exosome
        samples, ~900 proteins were detected.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: >-
      ATIC was identified in a mass-spectrometry membrane-proteome survey of an
      NK-like cell line; the authors explicitly note that many identified species
      are not integral membrane proteins but are transiently or peripherally
      associated. ATIC is a soluble cytosolic enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Non-specific co-purification in a membrane fraction; the study itself flags
      that a large fraction of hits are not genuine membrane proteins. ATIC is
      cytosolic; not a core membrane localization.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: >-
        The remaining species were largely involved in cellular processes and
        molecular functions that could be predicted to be transiently associated
        with membranes.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: >-
      ATIC was detected among 1132 proteins in a large-scale proteomic profile of
      human urinary exosomes. As above, this is a bulk-proteomics co-detection of
      an abundant cytosolic enzyme, not evidence of a functional exosomal role.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Non-specific exosome-proteome detection; ATIC's established localization is
      cytosol. Not a core function.
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: >-
        the
        analysis identified 1132 proteins unambiguously
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  qualifier: located_in
  review:
    summary: >-
      ATIC was detected among 539 proteins in a proteomic analysis of purified
      B-cell-derived exosomes. Again a bulk-proteomics co-detection, not a
      functional exosomal localization for this cytosolic enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Non-specific exosome-proteome detection; ATIC is cytosolic. Not a core
      function.
    supported_by:
    - reference_id: PMID:20458337
      supporting_text: >-
        we first analyzed the total
        proteome of highly purified B cell-derived exosomes using sensitive and
        accurate mass spectrometry (MS), and identified 539 proteins
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73797
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol localization for the reaction "FAICAR => IMP + H2O" (the
      IMP cyclohydrolase step). This correctly places ATIC's catalytic activity
      in the cytosol.
    action: ACCEPT
    reason: >-
      Cytosol is the correct location for ATIC, and this Reactome event
      corresponds directly to ATIC's IMP cyclohydrolase reaction.
    supported_by:
    - reference_id: file:human/ATIC/ATIC-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73798
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol localization for the reaction "AICAR + 10-Formyl-THF =>
      FAICAR + THF" (the AICAR transformylase step). Correctly places ATIC's
      catalytic activity in the cytosol.
    action: ACCEPT
    reason: >-
      Cytosol is the correct location for ATIC, and this Reactome event
      corresponds directly to ATIC's AICAR transformylase reaction.
    supported_by:
    - reference_id: file:human/ATIC/ATIC-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:14756553
  qualifier: enables
  review:
    summary: >-
      Crystal structures of human ATIC establish that the enzyme is a homodimer,
      with the AICAR transformylase active site formed at the dimer interface
      (substrate shared between dimeric partners). Homodimerization is
      functionally important because the dimeric form has enhanced cyclohydrolase
      activity.
    action: ACCEPT
    reason: >-
      ATIC functions as an obligate homodimer; structural evidence (PDB 1PKX)
      confirms the homodimeric assembly. This is a genuine, functionally relevant
      quaternary-structure activity, not a bare protein-binding annotation.
    supported_by:
    - reference_id: PMID:14756553
      supporting_text: >-
        crystal structures of XMP inhibitor complexes of human ATIC at 1.9 A
        resolution
    - reference_id: file:human/ATIC/ATIC-uniprot.txt
      supporting_text: 'SUBUNIT: Homodimer (PubMed:14756553, PubMed:14966129)'
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:14966129
  qualifier: enables
  review:
    summary: >-
      Crystal structures of human ATIC in complex with AICAR and sulfonyl-
      containing antifolates confirm the homodimeric assembly, with the
      transformylase active site (Lys266, His267, Asn431') built at the dimer
      interface.
    action: ACCEPT
    reason: >-
      Structural confirmation of the functionally required homodimer. This is a
      meaningful quaternary-structure annotation, not a vague protein-binding
      term.
    supported_by:
    - reference_id: PMID:14966129
      supporting_text: >-
        now
        implicate Asn(431') in the reaction mechanism along with previously
        identified
        key catalytic residues Lys(266) and His(267)
    - reference_id: file:human/ATIC/ATIC-uniprot.txt
      supporting_text: 'SUBUNIT: Homodimer (PubMed:14756553, PubMed:14966129)'
- term:
    id: GO:0003937
    label: IMP cyclohydrolase activity
  evidence_type: TAS
  original_reference_id: PMID:8567683
  qualifier: enables
  review:
    summary: >-
      Cloning, purification, kinetic analysis and domain mapping of the human
      purH (ATIC) gene product established both enzymatic activities, localizing
      IMP cyclohydrolase (IMPCHase) to the N-terminal region.
    action: ACCEPT
    reason: >-
      Author-asserted (TAS) and directly supported by the same paper's
      domain-mapping and kinetic data; core IMP cyclohydrolase function.
    supported_by:
    - reference_id: PMID:8567683
      supporting_text: >-
        IMPCHase and AICARFT activities are located within the NH2-terminal
        223 and COOH-terminal 406 amino acids, respectively.
- term:
    id: GO:0004643
    label: phosphoribosylaminoimidazolecarboxamide formyltransferase activity
  evidence_type: TAS
  original_reference_id: PMID:8567683
  qualifier: enables
  review:
    summary: >-
      The same cloning/domain-mapping study established the AICAR formyltransferase
      (AICARFT) activity of human ATIC and localized it to the C-terminal region.
    action: ACCEPT
    reason: >-
      Author-asserted and directly supported; core AICAR transformylase function.
    supported_by:
    - reference_id: PMID:8567683
      supporting_text: >-
        IMPCHase and AICARFT activities are located within the NH2-terminal
        223 and COOH-terminal 406 amino acids, respectively.
- term:
    id: GO:0006139
    label: nucleobase-containing compound metabolic process
  evidence_type: TAS
  original_reference_id: PMID:8567683
  qualifier: involved_in
  review:
    summary: >-
      Author-asserted involvement in nucleobase-containing compound metabolism.
      This is a very general parent term; ATIC's specific role is in de novo
      IMP/purine nucleotide biosynthesis.
    action: MODIFY
    reason: >-
      The term is correct but far too general given that ATIC's specific process
      is de novo IMP biosynthesis (and, more broadly, purine nucleotide
      biosynthesis). Replace with the more informative specific process term.
    proposed_replacement_terms:
    - id: GO:0006189
      label: "'de novo' IMP biosynthetic process"
    supported_by:
    - reference_id: PMID:8567683
      supporting_text: >-
        These steps of de novo purine biosynthesis, respectively.
core_functions:
- description: >-
    AICAR transformylase (phosphoribosylaminoimidazolecarboxamide
    formyltransferase, EC 2.1.2.3) that transfers a formyl group from
    10-formyltetrahydrofolate to AICAR to form FAICAR -- the penultimate step of
    de novo IMP biosynthesis. Acts as a cytosolic homodimer.
  molecular_function:
    id: GO:0004643
    label: phosphoribosylaminoimidazolecarboxamide formyltransferase activity
  directly_involved_in:
  - id: GO:0006189
    label: "'de novo' IMP biosynthetic process"
  - id: GO:0006164
    label: purine nucleotide biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:9378707
    supporting_text: >-
      Mutational analysis, utilizing this
      expression system, showed that His213 and His267 were essential for AICAR
      transformylase activity.
  - reference_id: PMID:11948179
    supporting_text: >-
      sequentially catalyze the last two steps in the pathway for de novo
      synthesis of inosine 5'-monophosphate
- description: >-
    IMP cyclohydrolase (EC 3.5.4.10) that cyclizes FAICAR to inosine
    5'-monophosphate (IMP) plus water -- the final, essentially irreversible step
    of de novo IMP biosynthesis, which drives the overall AICAR-to-IMP conversion
    forward. Resides in the N-terminal MGS-like domain; acts as a cytosolic
    homodimer.
  molecular_function:
    id: GO:0003937
    label: IMP cyclohydrolase activity
  directly_involved_in:
  - id: GO:0006189
    label: "'de novo' IMP biosynthetic process"
  - id: GO:0006164
    label: purine nucleotide biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:11948179
    supporting_text: >-
      the cyclohydrolase reaction is essentially unidirectional in the forward
      sense. The cyclohydrolase reaction thus draws the overall bifunctional
      reaction toward the production of inosine monophosphate.
  - reference_id: PMID:14756554
    supporting_text: >-
      The bifunctional enzyme aminoimidazole carboxamide ribonucleotide
      transformylase/inosine monophosphate cyclohydrolase (ATIC) is responsible
      for catalysis of the last two steps in the de novo purine pathway.
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: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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/ATIC/ATIC-uniprot.txt
  title: UniProtKB entry P31939 (ATIC / PUR9_HUMAN)
  findings: []
- id: PMID:10985775
  title: 'Human AICAR transformylase: role of the 4-carboxamide of AICAR in binding
    and catalysis.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Directly characterizes human AICAR transformylase catalytic activity and
      specificity; supports the GO:0004643 EXP annotation.
- id: PMID:11948179
  title: The kinetic mechanism of the human bifunctional enzyme ATIC (5-amino-4-imidazolecarboxamide
    ribonucleotide transformylase/inosine 5'-monophosphate cyclohydrolase). A surprising
    lack of substrate channeling.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Complete kinetic mechanism of human ATIC establishing both transformylase
      and cyclohydrolase activities and that the cyclohydrolase step drives IMP
      formation.
- id: PMID:14756553
  title: Structural insights into the human and avian IMP cyclohydrolase mechanism
    via crystal structures with the bound XMP inhibitor.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Human ATIC crystal structure (PDB 1PKX); supports homodimer and IMP
      cyclohydrolase mechanism.
- id: PMID:14756554
  title: Catalytic mechanism of the cyclohydrolase activity of human aminoimidazole
    carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Mutagenesis/kinetics of human ATIC cyclohydrolase mechanism; supports
      GO:0003937 EXP annotation.
- id: PMID:14966129
  title: Crystal structures of human bifunctional enzyme aminoimidazole-4-carboxamide
    ribonucleotide transformylase/IMP cyclohydrolase in complex with potent sulfonyl-containing
    antifolates.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Human ATIC structures (PDB 1P4R/1PL0) with AICAR and antifolates; supports
      homodimer, transformylase active site, and antifolate targeting.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale urinary exosome proteome; ATIC is a non-specific bulk-proteomics
      detection, not evidence of a functional exosomal role.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Membrane-proteome survey; study notes many hits are transiently/peripherally
      associated. ATIC membrane localization is non-specific.
- id: PMID:20458337
  title: MHC class II-associated proteins in B-cell exosomes and potential functional
    implications for exosome biogenesis.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      B-cell exosome proteome; ATIC is a bulk-proteomics co-detection, not a
      functional exosomal localization.
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Prostatic-secretion exosome proteome (~900 proteins); ATIC detection is
      non-specific.
- id: PMID:25468996
  title: E-cadherin interactome complexity and robustness resolved by quantitative
    proteomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      BioID proximity-proteomics of the E-cadherin tail; authors note many hits
      localize elsewhere in the cell. ATIC "cadherin binding" is a non-specific
      proximity hit.
- id: PMID:26588576
  title: 'Colocalization and Sequential Enzyme Activity in Aqueous Biphasic Systems:
    Experiments and Modeling.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Uses ATIC (steps 9-10 of de novo purine synthesis) as a model enzyme;
      confirms its catalytic activities and pathway position but the biophysical
      focus is on compartmentalization, not ATIC biology per se.
- id: PMID:8567683
  title: The human purH gene product, 5-aminoimidazole-4-carboxamide ribonucleotide
    formyltransferase/IMP cyclohydrolase. Cloning, sequencing, expression, purification,
    kinetic analysis, and domain mapping.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Foundational cloning/domain-mapping of human ATIC establishing both
      activities and their domain locations.
- id: PMID:9378707
  title: Characterization of molecularly cloned human 5-aminoimidazole-4-carboxamide
    ribonucleotide transformylase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Human AICAR transformylase cloning/expression; His213/His267 essential for
      activity. Supports GO:0004643.
- id: Reactome:R-HSA-73797
  title: FAICAR => IMP + H2O
  findings: []
- id: Reactome:R-HSA-73798
  title: AICAR + 10-Formyl-THF => FAICAR + THF
  findings: []
- id: Reactome:R-HSA-9700179
  title: Ligand-independent dimerization of ALK fusions
  findings: []
- id: Reactome:R-HSA-9700181
  title: Autophosphorylation of ALK fusions
  findings: []
- id: Reactome:R-HSA-9700190
  title: ALK mutants bind SHC
  findings: []
- id: Reactome:R-HSA-9700193
  title: ALK mutants phosphorylate SHC1
  findings: []
- id: Reactome:R-HSA-9710914
  title: ALK fusions bind GRB2
  findings: []
- id: Reactome:R-HSA-9710917
  title: ALK fusion proteins bind PLCG1
  findings: []
- id: Reactome:R-HSA-9712086
  title: ALK fusions phosphorylate PLCG1
  findings: []
- id: Reactome:R-HSA-9724099
  title: ALK mutants:p-3Y SHC binds GRB2
  findings: []