id: P30566
gene_symbol: ADSL
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Adenylosuccinate lyase (ADSL; adenylosuccinase; EC 4.3.2.2) is a cytosolic
  homotetrameric enzyme of purine metabolism that catalyses two distinct beta-elimination
  (fumarate-releasing) reactions in the same active site. In de novo purine synthesis
  it cleaves SAICAR ((S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido)succinate)
  to AICAR plus fumarate, completing the step 2/2 that converts SAICAR toward IMP;
  and at the IMP-to-AMP branch it cleaves adenylosuccinate (S-AMP) to AMP plus fumarate.
  The enzyme therefore contributes to both de novo IMP biosynthesis and de novo AMP
  biosynthesis. It assembles as a homotetramer in which three subunits contribute
  residues to each of the four active sites, and can associate with other de novo
  purine synthesis enzymes in the purinosome. Loss-of-function variants cause adenylosuccinate
  lyase deficiency (ADSLD), an autosomal-recessive neurodevelopmental disorder marked
  by psychomotor/mental retardation, epilepsy and autistic features, with accumulation
  of the dephosphorylated substrates SAICA-riboside and succinyladenosine in body
  fluids.
alternative_products:
- name: '1'
  id: P30566-1
- name: 2 (Delta-ADSL)
  id: P30566-2
  sequence_note: VSP_000318
existing_annotations:
- term:
    id: GO:0070626
    label: (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido) succinate
      lyase (fumarate-forming) activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: SAICAR-lyase (fumarate-forming) activity, one of the two core catalytic
      functions of ADSL. This IBA is fully consistent with the human experimental
      data and the enzyme's role in de novo IMP synthesis.
    action: ACCEPT
    reason: This is a core molecular function of ADSL, cleaving SAICAR to AICAR plus
      fumarate as step 2/2 of the de novo IMP pathway. The phylogenetic inference
      matches the human IDA (PMID:27590927) and UniProt.
    supported_by:
    - reference_id: file:human/ADSL/ADSL-uniprot.txt
      supporting_text: Catalyzes two non-sequential steps in de novo AMP synthesis
    - reference_id: PMID:19405474
      supporting_text: the conversion of 5-aminoimidazole-4-(N-succinylocarboxamide
        ribonucleotide) (SAICAR) to 5-aminoimidazole-4-carboxamide ribonucleotide
        (AICAR) and fumarate
- term:
    id: GO:0004018
    label: N6-(1,2-dicarboxyethyl)AMP AMP-lyase (fumarate-forming) activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Adenylosuccinate (S-AMP) lyase (fumarate-forming) activity, the second
      core catalytic function of ADSL, cleaving S-AMP to AMP plus fumarate at the
      IMP-to-AMP branch.
    action: ACCEPT
    reason: Core molecular function, corroborated by human IDA data (PMID:19405474,
      PMID:16973378) and UniProt catalytic-activity annotation (EC 4.3.2.2, Rhea RHEA:16853).
    supported_by:
    - reference_id: PMID:19405474
      supporting_text: the cleavage of adenylosuccinate (SAMP)1 to AMP and fumarate
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: ADSL is a cytosolic enzyme; its active form is a cytosolic tetramer.
      This localization is supported by IBA, IDA (HPA) and TAS (Reactome).
    action: ACCEPT
    reason: Cytosolic localization is well established and consistent across phylogenetic,
      immunofluorescence and Reactome evidence.
    supported_by:
    - reference_id: Reactome:R-HSA-73800
      supporting_text: The active form of this enzyme is a cytosolic tetramer
- term:
    id: GO:0044208
    label: '''de novo'' AMP biosynthetic process'
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: ADSL catalyses the final step (S-AMP to AMP) of de novo AMP biosynthesis
      from IMP. This is a core biological process for the gene.
    action: ACCEPT
    reason: The SAMP-to-AMP reaction is AMP-from-IMP step 2/2 of the de novo AMP pathway,
      as stated in the UniProt PATHWAY annotation. IBA is at the correct level.
    supported_by:
    - reference_id: file:human/ADSL/ADSL-uniprot.txt
      supporting_text: 'AMP biosynthesis via de novo pathway; AMP'
- term:
    id: GO:0003824
    label: catalytic activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Root-level catalytic activity term from InterPro2GO. Not wrong, but far
      too general given the two specific lyase activities (GO:0004018, GO:0070626)
      are already annotated with experimental evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: This is an uninformative parent of the specific molecular functions ADSL
      is already annotated to. It adds no information beyond the specific lyase terms.
    supported_by:
    - reference_id: file:human/ADSL/ADSL-uniprot.txt
      supporting_text: Catalyzes two non-sequential steps in de novo AMP synthesis
- term:
    id: GO:0004018
    label: N6-(1,2-dicarboxyethyl)AMP AMP-lyase (fumarate-forming) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic annotation (ARBA/RHEA:16853) of the S-AMP lyase activity,
      redundant with and corroborated by the experimental IDA annotations.
    action: ACCEPT
    reason: Correct molecular function derived from the EC/Rhea mapping; matches the
      human experimental data.
    supported_by:
    - reference_id: PMID:19405474
      supporting_text: the cleavage of adenylosuccinate (SAMP)1 to AMP and fumarate
- term:
    id: GO:0009152
    label: purine ribonucleotide biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: General purine ribonucleotide biosynthesis process, correctly capturing
      ADSL's role in de novo IMP/AMP synthesis, though broader than the specific de
      novo terms.
    action: ACCEPT
    reason: A correct, if general, biological-process parent. ADSL participates in
      purine ribonucleotide biosynthesis via de novo IMP and AMP synthesis.
    supported_by:
    - reference_id: file:human/ADSL/ADSL-uniprot.txt
      supporting_text: Catalyzes two non-sequential steps in de novo AMP synthesis
- term:
    id: GO:0001666
    label: response to hypoxia
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Stimulus-response process transferred electronically from a rat ortholog
      via Ensembl Compara. There is no evidence that human ADSL functions as an effector
      in the hypoxia response; this is an over-propagated ortholog IEA.
    action: REMOVE
    reason: ADSL is a cytosolic purine-biosynthesis lyase. "Response to hypoxia" is
      a stimulus-response biological process not supported by any experimental data
      for ADSL, and is a classic Ensembl-Compara over-propagation from an ortholog.
- term:
    id: GO:0006167
    label: AMP biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: AMP biosynthetic process (general parent of de novo AMP biosynthesis),
      correctly capturing ADSL's production of AMP from S-AMP.
    action: ACCEPT
    reason: ADSL produces AMP as the second step of AMP-from-IMP; this general term
      is correct and is also supported by the human IDA (PMID:11428554).
    supported_by:
    - reference_id: PMID:19405474
      supporting_text: the cleavage of adenylosuccinate (SAMP)1 to AMP and fumarate
- term:
    id: GO:0006177
    label: GMP biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: GMP biosynthesis is not catalysed or supported by ADSL. GMP is produced
      from IMP by IMP dehydrogenase and GMP synthase; ADSL acts on the AMP branch,
      not the GMP branch.
    action: REMOVE
    reason: Biochemically incorrect. ADSL has no role in GMP synthesis; this is an
      erroneous Ensembl-Compara ortholog transfer. The enzyme's reactions (SAICAR
      to AICAR, and S-AMP to AMP) lie on the IMP and AMP branches only.
- term:
    id: GO:0006189
    label: '''de novo'' IMP biosynthetic process'
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: ADSL contributes to de novo IMP biosynthesis via its SAICAR-lyase step
      (SAICAR to AICAR + fumarate), which is step 2/2 in the conversion of SAICAR
      toward IMP. Core biological process.
    action: ACCEPT
    reason: Correct core process. The UniProt PATHWAY annotation places this SAICAR-lyase
      reaction within de novo IMP biosynthesis.
    supported_by:
    - reference_id: file:human/ADSL/ADSL-uniprot.txt
      supporting_text: 'IMP biosynthesis via de novo pathway'
- term:
    id: GO:0007584
    label: response to nutrient
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Stimulus-response process transferred electronically from a rat ortholog.
      No experimental support for human ADSL acting as a nutrient-response effector.
    action: REMOVE
    reason: Over-propagated Ensembl-Compara ortholog IEA; not a supportable molecular
      role for human ADSL, which is a constitutive purine-biosynthesis enzyme.
- term:
    id: GO:0009060
    label: aerobic respiration
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Aerobic respiration is a mitochondrial process; ADSL is a cytosolic purine-biosynthesis
      lyase. Fumarate release by ADSL does not constitute participation in aerobic
      respiration.
    action: REMOVE
    reason: Biologically incorrect over-propagation via Ensembl Compara. ADSL is not
      part of the respiratory chain or TCA cycle; its product fumarate feeds general
      metabolism but that does not make ADSL a participant in aerobic respiration.
- term:
    id: GO:0014850
    label: response to muscle activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Although ADSL is highly expressed in skeletal muscle and participates
      in the purine nucleotide cycle there, "response to muscle activity" is a stimulus-response
      biological process electronically transferred from a rat ortholog, without experimental
      support for human ADSL as an effector of this response.
    action: REMOVE
    reason: Over-propagated Ensembl-Compara ortholog IEA. Muscle expression does not
      justify a stimulus-response BP annotation; ADSL's role in muscle is its constitutive
      purine-cycle catalysis.
- term:
    id: GO:0042594
    label: response to starvation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Stimulus-response process transferred electronically from a rat ortholog.
      No experimental support for human ADSL as a starvation-response effector.
    action: REMOVE
    reason: Over-propagated Ensembl-Compara ortholog IEA, not supportable for human
      ADSL.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Self-association is real (ADSL is a homotetramer), but "identical protein
      binding" is an uninformative molecular-function term compared with the enzyme's
      catalytic activities and its "protein-containing complex" annotation. This IEA
      duplicates the IDA below.
    action: KEEP_AS_NON_CORE
    reason: The homotetrameric assembly makes identical-protein binding technically
      correct, but it is non-core relative to the catalytic MFs. Retain as non-core;
      the homotetramer is better captured by GO:0032991 and the SUBUNIT annotation.
    supported_by:
    - reference_id: PMID:19405474
      supporting_text: ASL, a catalyst of key reactions in purine biosynthesis, is
        normally a homotetramer in which three subunits contribute to each of four
        active sites
- 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 annotation of de novo AMP biosynthesis (UniPathway UPA00075),
      redundant with the IBA and consistent with the S-AMP-to-AMP reaction.
    action: ACCEPT
    reason: Correct core process, matching the UniProt de novo AMP biosynthesis pathway
      annotation.
    supported_by:
    - reference_id: file:human/ADSL/ADSL-uniprot.txt
      supporting_text: 'AMP biosynthesis via de novo pathway; AMP'
- term:
    id: GO:0044209
    label: AMP salvage
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: ADSL produces AMP as part of DE NOVO purine synthesis (and the purine
      nucleotide cycle), not the salvage pathway. AMP salvage refers to recovery of
      AMP from adenine/adenosine via APRT and adenosine kinase, in which ADSL plays
      no part.
    action: MARK_AS_OVER_ANNOTATED
    reason: Misleading Ensembl-Compara ortholog IEA. ADSL's S-AMP-to-AMP reaction
      is de novo AMP biosynthesis, correctly captured by GO:0044208/GO:0006167; annotating
      it to AMP salvage misassigns the pathway context.
- term:
    id: GO:0070626
    label: (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido) succinate
      lyase (fumarate-forming) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic annotation (ARBA/RHEA:23920) of the SAICAR-lyase activity,
      redundant with and corroborated by the human IDA and IBA annotations.
    action: ACCEPT
    reason: Correct core molecular function from the EC/Rhea mapping; matches the human
      experimental data (PMID:27590927).
    supported_by:
    - reference_id: PMID:19405474
      supporting_text: the conversion of 5-aminoimidazole-4-(N-succinylocarboxamide
        ribonucleotide) (SAICAR) to 5-aminoimidazole-4-carboxamide ribonucleotide
        (AICAR) and fumarate
- term:
    id: GO:0097294
    label: '''de novo'' XMP biosynthetic process'
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: XMP is synthesized from IMP by IMP dehydrogenase; ADSL is not involved
      in the XMP branch. This is an erroneous Ensembl-Compara ortholog transfer.
    action: REMOVE
    reason: Biochemically incorrect. ADSL acts on the SAICAR-to-IMP and IMP-to-AMP
      branches, not on the IMP-to-XMP branch. No support for XMP biosynthesis.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence (HPA) localizes ADSL to the cytosol, consistent with
      the enzyme's cytosolic tetrameric active form.
    action: ACCEPT
    reason: Direct experimental (HPA immunofluorescence) evidence for cytosolic localization,
      concordant with IBA and Reactome TAS.
    supported_by:
    - reference_id: Reactome:R-HSA-73800
      supporting_text: The active form of this enzyme is a cytosolic tetramer
- term:
    id: GO:0004018
    label: N6-(1,2-dicarboxyethyl)AMP AMP-lyase (fumarate-forming) activity
  evidence_type: IDA
  original_reference_id: PMID:19405474
  qualifier: enables
  review:
    summary: Direct assay of the S-AMP-to-AMP + fumarate reaction on purified recombinant
      human ADSL and disease-associated mutants. Core molecular function.
    action: ACCEPT
    reason: Strong direct experimental evidence for the adenylosuccinate (S-AMP) lyase
      activity, measured continuously as SAMP is converted to AMP and fumarate.
    supported_by:
    - reference_id: PMID:19405474
      supporting_text: as 60 μM SAMP is converted to AMP and fumarate
- term:
    id: GO:0070626
    label: (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido) succinate
      lyase (fumarate-forming) activity
  evidence_type: IDA
  original_reference_id: PMID:27590927
  qualifier: enables
  review:
    summary: SAICAR-lyase activity demonstrated in the context of de novo purine synthesis;
      CRISPR knockout of ADSL in HeLa cells leads to accumulation of its substrate,
      confirming the in vivo lyase step. Core molecular function.
    action: ACCEPT
    reason: Direct experimental evidence supporting the SAICAR-lyase activity; substrate
      accumulation on knockout confirms the enzyme performs this step in cells.
    supported_by:
    - reference_id: PMID:27590927
      supporting_text: an accumulation of the substrate(s) for the knocked out enzyme
        was identified
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:16973378
  qualifier: part_of
  review:
    summary: ADSL is a homotetramer, i.e. a protein-containing complex. Direct evidence
      from analytical ultracentrifugation of the purified recombinant enzyme (tetramer,
      ~220 kDa). Correct but very general.
    action: KEEP_AS_NON_CORE
    reason: The homotetrameric assembly is real and experimentally demonstrated, but
      "protein-containing complex" is an uninformative CC parent; the specific homotetramer
      state is better described in the SUBUNIT annotation. Retain as non-core.
    supported_by:
    - reference_id: PMID:16973378
      supporting_text: the histidine-tagged enzyme is in tetrameric form with a molecular
        weight of 220 kDa
    - reference_id: file:human/ADSL/ADSL-uniprot.txt
      supporting_text: Homotetramer. Residues from neighboring subunits contribute
        catalytic and substrate-binding residues to each active site.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IDA
  original_reference_id: PMID:16973378
  qualifier: enables
  review:
    summary: Self-association into a homotetramer is experimentally demonstrated (analytical
      ultracentrifugation). "Identical protein binding" is technically correct but
      uninformative relative to the catalytic MFs and the complex annotation.
    action: KEEP_AS_NON_CORE
    reason: Homo-oligomerization is real (homotetramer), so the term is not wrong,
      but per curation guidelines bare binding terms are non-core; the functionally
      informative annotations are the two lyase MFs and GO:0032991. Retain as non-core.
    supported_by:
    - reference_id: PMID:16973378
      supporting_text: the histidine-tagged enzyme is in tetrameric form with a molecular
        weight of 220 kDa
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73800
  qualifier: located_in
  review:
    summary: Reactome (SAICAR => AICAR + Fumarate) places ADSL in the cytosol; the
      active enzyme is a cytosolic tetramer. Concordant with IDA and IBA.
    action: ACCEPT
    reason: Traceable author statement supporting cytosolic localization, consistent
      with all other localization evidence.
    supported_by:
    - reference_id: Reactome:R-HSA-73800
      supporting_text: The active form of this enzyme is a cytosolic tetramer
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73828
  qualifier: located_in
  review:
    summary: Reactome (adenylosuccinate => AMP + fumarate) places ADSL in the cytosol;
      the active enzyme is a cytosolic tetramer.
    action: ACCEPT
    reason: Traceable author statement supporting cytosolic localization, consistent
      with all other localization evidence.
    supported_by:
    - reference_id: Reactome:R-HSA-73828
      supporting_text: The active form of this enzyme is a cytosolic tetramer
- term:
    id: GO:0006164
    label: purine nucleotide biosynthetic process
  evidence_type: IC
  original_reference_id: PMID:10888601
  qualifier: involved_in
  review:
    summary: Curator inference (from the SAMP-lyase activity, GO:0004018) that ADSL
      is involved in purine nucleotide biosynthesis. Correct general biological process.
    action: ACCEPT
    reason: ADSL is a bifunctional enzyme of de novo purine synthesis and purine nucleotide
      recycling; the general purine nucleotide biosynthetic process term is appropriate.
    supported_by:
    - reference_id: PMID:10888601
      supporting_text: Adenylosuccinate lyase (ADSL) is a bifunctional enzyme acting
        in de novo purine synthesis and purine nucleotide recycling
- term:
    id: GO:0006167
    label: AMP biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:11428554
  qualifier: involved_in
  review:
    summary: ADSL activity measured in blood cells, with the study discussing its
      role in regulating cellular AMP levels. Supports involvement in AMP biosynthesis.
    action: ACCEPT
    reason: Direct measurement of ADSL activity and its role in cellular AMP regulation;
      consistent with the enzyme's S-AMP-to-AMP reaction in de novo AMP synthesis.
    supported_by:
    - reference_id: PMID:11428554
      supporting_text: The biological role of adenylosuccinate lyase and its importance
        in regulating cellular levels of AMP is discussed
- term:
    id: GO:0004018
    label: N6-(1,2-dicarboxyethyl)AMP AMP-lyase (fumarate-forming) activity
  evidence_type: IDA
  original_reference_id: PMID:16973378
  qualifier: enables
  review:
    summary: Recombinant human ADSL was characterized for its S-AMP lyase activity,
      with kinetic parameters (Vmax, Km) determined for S-AMP. Core molecular function.
    action: ACCEPT
    reason: Direct experimental characterization of the adenylosuccinate (S-AMP) lyase
      activity of purified human ADSL, defining EC 4.3.2.2 for the human enzyme.
    supported_by:
    - reference_id: PMID:16973378
      supporting_text: The histidine-tagged and non-tagged adenylosuccinate lyases
        exhibit similar values of Vmax and Km for S-AMP
core_functions:
- description: Adenylosuccinate (S-AMP) lyase activity - cleaves N6-(1,2-dicarboxyethyl)-AMP
    (S-AMP) to AMP and fumarate, the second step of de novo AMP biosynthesis from
    IMP.
  molecular_function:
    id: GO:0004018
    label: N6-(1,2-dicarboxyethyl)AMP AMP-lyase (fumarate-forming) activity
  directly_involved_in:
  - id: GO:0044208
    label: '''de novo'' AMP biosynthetic process'
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:19405474
    supporting_text: the cleavage of adenylosuccinate (SAMP)1 to AMP and fumarate
  - reference_id: PMID:16973378
    supporting_text: The histidine-tagged and non-tagged adenylosuccinate lyases exhibit
      similar values of Vmax and Km for S-AMP
- description: SAICAR-lyase activity - cleaves SAICAR to AICAR and fumarate, step 2/2
    of de novo IMP biosynthesis, contributing to purine nucleotide biosynthesis.
  molecular_function:
    id: GO:0070626
    label: (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido) succinate
      lyase (fumarate-forming) activity
  directly_involved_in:
  - id: GO:0006189
    label: '''de novo'' IMP biosynthetic process'
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:19405474
    supporting_text: the conversion of 5-aminoimidazole-4-(N-succinylocarboxamide
      ribonucleotide) (SAICAR) to 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)
      and fumarate
  - reference_id: PMID:27590927
    supporting_text: an accumulation of the substrate(s) for the knocked out enzyme
      was identified
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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: Source of a block of stimulus-response and off-pathway biosynthesis
      IEAs (hypoxia, nutrient, starvation, muscle activity, aerobic respiration, GMP,
      XMP, AMP salvage) transferred from rodent orthologs. Several are biologically
      unsupportable for human ADSL and are flagged for REMOVE / MARK_AS_OVER_ANNOTATED.
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10888601
  title: Human adenylosuccinate lyase (ADSL), cloning and characterization of full-length
    cDNA and its isoform, gene structure and molecular basis for ADSL deficiency in
    six patients.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes ADSL as a bifunctional de novo purine synthesis/recycling
      enzyme, characterizes the enzymatically inactive isoform 2, and defines the
      molecular basis of ADSL deficiency in six patients (abstract verified against
      cached record).
- id: PMID:11428554
  title: Determination, activity and biological role of adenylosuccinate lyase in
    blood cells.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Measures ADSL activity in human blood cells and discusses its role
      in regulating cellular AMP levels; supports the AMP biosynthetic process annotation.
- id: PMID:16973378
  title: Expression, purification, and characterization of stable, recombinant human
    adenylosuccinate lyase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Defines the recombinant human enzyme's S-AMP lyase kinetics (Vmax/Km)
      and demonstrates the homotetramer (~220 kDa) by analytical ultracentrifugation;
      basis for the MF, identical-protein-binding, and protein-complex annotations.
- id: PMID:19405474
  title: Biochemical and biophysical analysis of five disease-associated human adenylosuccinate
    lyase mutants.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; explicitly states the two beta-elimination
      reactions (SAMP->AMP+fumarate; SAICAR->AICAR+fumarate) and the homotetramer
      with three subunits per active site. Primary support for both core MFs.
- id: PMID:27590927
  title: CRISPR-Cas9 induced mutations along de novo purine synthesis in HeLa cells
    result in accumulation of individual enzyme substrates and affect purinosome formation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: CRISPR knockout of de novo purine synthesis enzymes (including ADSL)
      in HeLa cells causes accumulation of the knocked-out enzyme's substrate and
      impairs purinosome assembly; supports the in vivo SAICAR-lyase step.
- id: Reactome:R-HSA-73800
  title: SAICAR => AICAR + Fumarate
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome reaction for the SAICAR-lyase step; states the active enzyme
      is a cytosolic tetramer and mediates both reactions in vivo.
- id: Reactome:R-HSA-73828
  title: adenylosuccinate => adenosine 5'-monophosphate + fumarate
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome reaction for the S-AMP lyase step; states the active enzyme
      is a cytosolic tetramer.
- id: file:human/ADSL/ADSL-uniprot.txt
  title: UniProtKB P30566 (PUR8_HUMAN) adenylosuccinate lyase record
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Curated UniProt record; source of the dual catalytic-activity, de
      novo IMP/AMP pathway, homotetramer subunit, and ADSLD disease annotations.