id: P23109
gene_symbol: AMPD1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  AMPD1 is the skeletal-muscle ("M") isoform of AMP deaminase, a cytosolic
  zinc metalloenzyme that catalyses the hydrolytic deamination of AMP to IMP
  and ammonia (AMP + H2O -> IMP + NH4+; EC 3.5.4.6). It is a homotetramer of
  the metallo-dependent hydrolase superfamily (adenosine and AMP deaminase
  family). In skeletal muscle AMPD1 performs the committed step of the purine
  nucleotide cycle (AMP -> IMP by AMP deaminase; IMP -> adenylosuccinate by
  adenylosuccinate synthase; adenylosuccinate -> AMP + fumarate by
  adenylosuccinate lyase). By deaminating AMP, the enzyme pulls the adenylate
  kinase equilibrium toward ATP regeneration and thereby buffers the cellular
  energy charge during intense exercise, while the cycle also releases
  fumarate for TCA-cycle anaplerosis and ammonia. It is the most highly
  expressed AMP deaminase isoform in skeletal muscle (also expressed in
  tongue). Loss-of-function of AMPD1 causes myoadenylate deaminase deficiency
  (AMP deaminase deficiency; MMDD, MIM:615511), one of the most common
  inherited metabolic muscle defects, which is frequently benign or
  asymptomatic but can present with exercise-induced myalgia, cramps and
  early fatigue.
alternative_products:
- name: '1'
  id: P23109-1
- name: '2'
  id: P23109-2
  sequence_note: VSP_042638
existing_annotations:
- term:
    id: GO:0003876
    label: AMP deaminase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Core molecular function. AMPD1 hydrolytically deaminates AMP to IMP plus
      ammonia (EC 3.5.4.6), the defining and experimentally established
      activity of this enzyme. The phylogenetic (IBA) call is well supported
      and consistent with direct human evidence.
    action: ACCEPT
    reason: >-
      AMP deaminase activity is the primary, catalytically demonstrated
      function of AMPD1. UniProt records the reaction and EC number with
      experimental evidence, and disease-causing mutations abolish this
      activity.
    supported_by:
    - reference_id: file:human/AMPD1/AMPD1-uniprot.txt
      supporting_text: "Reaction=AMP + H2O + H(+) = IMP + NH4(+)"
    - reference_id: PMID:11102975
      supporting_text: "undetectable AMPD activity in the"
- term:
    id: GO:0006188
    label: IMP biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      IMP is the direct product of AMPD1-catalysed AMP deamination, so
      participation in IMP biosynthesis is correct. UniProt frames the pathway
      as "IMP biosynthesis via salvage pathway; IMP from AMP: step 1/1", which
      is captured more precisely by GO:0032264 IMP salvage.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate but less precise than the salvage-specific term; retained as a
      correct broader process annotation rather than the core process framing.
    supported_by:
    - reference_id: file:human/AMPD1/AMPD1-uniprot.txt
      supporting_text: "Purine metabolism; IMP biosynthesis via salvage pathway"
- term:
    id: GO:0046033
    label: AMP metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      AMPD1 acts directly on AMP (its substrate), so participation in AMP
      metabolic process is accurate and reflects the enzyme's role in the
      purine nucleotide cycle and adenylate energy-charge regulation.
    action: ACCEPT
    reason: >-
      Directly describes the metabolism of the enzyme's substrate; well
      supported by the catalytic activity and by the phylogenetic inference.
    supported_by:
    - reference_id: file:human/AMPD1/AMPD1-uniprot.txt
      supporting_text: "Reaction=AMP + H2O + H(+) = IMP + NH4(+)"
- term:
    id: GO:0003876
    label: AMP deaminase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assertion of the core AMP deaminase activity (via mouse
      ortholog, InterPro AMPD signature, RHEA:14777 and EC 3.5.4.6). Consistent
      with the experimental human evidence.
    action: ACCEPT
    reason: >-
      Correct molecular function; redundant with the experimental and IBA calls
      but appropriately mapped.
    supported_by:
    - reference_id: file:human/AMPD1/AMPD1-uniprot.txt
      supporting_text: "Reaction=AMP + H2O + H(+) = IMP + NH4(+)"
- term:
    id: GO:0006753
    label: nucleoside phosphate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      Very general parent process (AMP and IMP are nucleoside phosphates), so
      the annotation is correct but uninformative relative to the specific
      AMP/IMP terms already present.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but high-level ARBA electronic annotation; superseded in
      specificity by GO:0046033 (AMP metabolic process) and GO:0032264 (IMP
      salvage).
    supported_by:
    - reference_id: file:human/AMPD1/AMPD1-uniprot.txt
      supporting_text: "Reaction=AMP + H2O + H(+) = IMP + NH4(+)"
- term:
    id: GO:0009168
    label: purine ribonucleoside monophosphate biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO electronic mapping. AMPD1 produces the purine ribonucleoside
      monophosphate IMP from AMP, so the biosynthetic framing is broadly
      correct, but AMP salvage/catabolism to IMP (GO:0032264) captures the
      enzyme's role more precisely.
    action: KEEP_AS_NON_CORE
    reason: >-
      Broadly correct generic IEA; the enzyme's actual step is better described
      by IMP salvage / AMP metabolism, which are already annotated.
    supported_by:
    - reference_id: file:human/AMPD1/AMPD1-uniprot.txt
      supporting_text: "Purine metabolism; IMP biosynthesis via salvage pathway"
- term:
    id: GO:0019239
    label: deaminase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO mapping to the generic parent term. The specific and correct
      molecular function is AMP deaminase activity (GO:0003876), already
      annotated with experimental support.
    action: MODIFY
    reason: >-
      Too general; AMPD1 specifically deaminates AMP. Replace with the child
      term AMP deaminase activity.
    proposed_replacement_terms:
    - id: GO:0003876
      label: AMP deaminase activity
    supported_by:
    - reference_id: file:human/AMPD1/AMPD1-uniprot.txt
      supporting_text: "Reaction=AMP + H2O + H(+) = IMP + NH4(+)"
- term:
    id: GO:0032264
    label: IMP salvage
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      AMPD1 forms IMP directly from AMP; UniProt/UniPathway annotate this as
      "IMP biosynthesis via salvage pathway; IMP from AMP: step 1/1"
      (UPA00591). This is the precise process for the enzyme's product-forming
      reaction.
    action: ACCEPT
    reason: >-
      Directly matches the enzyme's committed step (AMP -> IMP), the most
      informative process term for AMPD1.
    supported_by:
    - reference_id: file:human/AMPD1/AMPD1-uniprot.txt
      supporting_text: "Purine metabolism; IMP biosynthesis via salvage pathway"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" from the human binary interactome (HuRI, IntAct).
      The captured interactions are AMPD1 with the paralogs AMPD2 (Q01433-2)
      and AMPD3 (Q01432-4). The term itself is uninformative about molecular
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Experimental IPI, retained per curation policy (not removed), but the
      generic "protein binding" term conveys no specific function. The
      biologically meaningful oligomerisation is captured by GO:0042802
      (identical protein binding), matching the documented homotetramer.
    supported_by:
    - reference_id: file:human/AMPD1/AMPD1-uniprot.txt
      supporting_text: "AMPD3; NbExp=3"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      AMPD1 self-interaction detected in the human binary interactome, matching
      the well-established homotetrameric quaternary structure of AMP deaminase.
    action: ACCEPT
    reason: >-
      Consistent with the documented homotetramer; a biologically meaningful
      self-association annotation.
    supported_by:
    - reference_id: file:human/AMPD1/AMPD1-uniprot.txt
      supporting_text: "Homotetramer."
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-76590
  qualifier: located_in
  review:
    summary: >-
      AMP deaminase is a cytosolic enzyme. Reactome curates the AMPD reaction
      (AMP + H2O => IMP + NH4+) in the cytosol; in skeletal muscle AMPD1 is
      classically associated with the myofibrillar/contractile apparatus.
    action: ACCEPT
    reason: >-
      Correct subcellular localisation, consistent with Reactome and the
      enzyme's role in cytosolic purine nucleotide metabolism.
    supported_by:
    - reference_id: Reactome:R-HSA-76590
      supporting_text: "Cytosolic AMP deaminase (AMPD) catalyzes the hydrolysis of AMP to yield IMP and ammonia."
- term:
    id: GO:0003876
    label: AMP deaminase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Sequence-similarity transfer of AMP deaminase activity from the rat
      ortholog (P10759). Correct and concordant with the experimental human
      evidence.
    action: ACCEPT
    reason: >-
      Correct core molecular function; ISS transfer is appropriate for this
      well-conserved enzyme.
    supported_by:
    - reference_id: file:human/AMPD1/AMPD1-uniprot.txt
      supporting_text: "Reaction=AMP + H2O + H(+) = IMP + NH4(+)"
- term:
    id: GO:0003876
    label: AMP deaminase activity
  evidence_type: IMP
  original_reference_id: PMID:11102975
  qualifier: enables
  review:
    summary: >-
      Direct human functional evidence. The MMDD missense variants R388W and
      R425H, expressed recombinantly, produced comparable amounts of AMPD1
      protein but had undetectable AMP deaminase activity, confirming that
      AMPD1 enables AMP deaminase activity and that its loss causes myopathy.
    action: ACCEPT
    reason: >-
      Loss-of-function mutations abolishing AMPD activity provide strong
      experimental support for this being the enzyme's core molecular function.
    supported_by:
    - reference_id: PMID:11102975
      supporting_text: "undetectable AMPD activity in the"
    - reference_id: PMID:11102975
      supporting_text: "AMPD1 indeed has a key role in muscle metabolism"
- term:
    id: GO:0032263
    label: GMP salvage
  evidence_type: IDA
  original_reference_id: PMID:29079593
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      This annotation derives from a red-blood-cell storage metabolomics study
      of the purine salvage/deamination pathway. AMP deaminase acts on AMP to
      make IMP + ammonia and does not act on guanine nucleotides, so "GMP
      salvage" is a pathway-level co-annotation rather than a direct function
      of AMPD1.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Experimental IDA, retained per curation policy (not removed), but GMP
      salvage is not the direct biochemistry of AMP deaminase; the enzyme's
      role is in the AMP -> IMP branch, better captured by GO:0032264 IMP
      salvage and GO:0046033 AMP metabolic process.
    supported_by:
    - reference_id: PMID:29079593
      supporting_text: "purine salvage pathway"
- term:
    id: GO:0032263
    label: GMP salvage
  evidence_type: IDA
  original_reference_id: PMID:29079593
  qualifier: involved_in
  review:
    summary: >-
      Duplicate GMP salvage annotation (involved_in qualifier) from the same
      RBC storage metabolomics study. As above, AMP deaminase does not act on
      guanine nucleotides; this is a pathway-level co-annotation, not AMPD1's
      direct function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Experimental IDA retained per policy, but not the enzyme's direct process;
      the AMP -> IMP step is captured by IMP salvage and AMP metabolic process.
    supported_by:
    - reference_id: PMID:29079593
      supporting_text: "purine salvage pathway"
- term:
    id: GO:0003876
    label: AMP deaminase activity
  evidence_type: TAS
  original_reference_id: PMID:644316
  qualifier: enables
  review:
    summary: >-
      Author statement supporting AMP deaminase (adenylate deaminase) activity
      as the muscle enzyme whose deficiency defines myoadenylate deaminase
      deficiency. Fishbein et al. showed patient muscle biopsies lacked
      adenylate deaminase by stain and solution assay.
    action: ACCEPT
    reason: >-
      Consistent with the core molecular function; the foundational clinical
      description linking loss of muscle AMP deaminase activity to disease.
    supported_by:
    - reference_id: PMID:644316
      supporting_text: "lacked adenylate deaminase by"
core_functions:
- description: >-
    Cytosolic AMP deaminase catalysing the hydrolytic deamination of AMP to IMP
    and ammonia (EC 3.5.4.6), the committed step of the skeletal-muscle purine
    nucleotide cycle.
  molecular_function:
    id: GO:0003876
    label: AMP deaminase activity
  directly_involved_in:
  - id: GO:0032264
    label: IMP salvage
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:11102975
    supporting_text: "undetectable AMPD activity in the"
  - reference_id: file:human/AMPD1/AMPD1-uniprot.txt
    supporting_text: "Purine metabolism; IMP biosynthesis via salvage pathway"
- description: >-
    By deaminating AMP, AMPD1 drives adenine-nucleotide (AMP) metabolism in
    muscle, pulling the adenylate kinase equilibrium toward ATP regeneration
    and buffering the cellular energy charge during intense exercise.
  molecular_function:
    id: GO:0003876
    label: AMP deaminase activity
  directly_involved_in:
  - id: GO:0046033
    label: AMP metabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/AMPD1/AMPD1-uniprot.txt
    supporting_text: "AMP deaminase plays a critical role in energy metabolism."
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11102975
  title: First missense mutations (R388W and R425H) of AMPD1 accompanied with myopathy
    found in a Japanese patient.
  findings:
  - statement: >-
      The MMDD missense variants R388W and R425H produced comparable amounts of
      AMPD1 protein on recombinant expression but had undetectable AMP deaminase
      activity, establishing AMPD1's core catalytic function and its role in
      muscle metabolism.
    supporting_text: "undetectable AMPD activity in the"
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache; title and abstract match PubMed 11102975. Directly
      establishes AMPD1 AMP deaminase activity and disease link via
      loss-of-function variants.
- id: PMID:29079593
  title: Hypoxia modulates the purine salvage pathway and decreases red blood cell
    and supernatant levels of hypoxanthine during refrigerated storage.
  findings:
  - statement: >-
      Study of hypoxia and refrigerated storage effects on the red-blood-cell
      purine salvage/deamination pathway; source of an MGI GMP salvage
      annotation that is a pathway-level co-annotation rather than a direct AMP
      deaminase function.
    supporting_text: "purine salvage pathway"
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: >-
      Full-text available. The paper concerns erythrocyte purine
      salvage/deamination during RBC storage; AMP deaminase acts on AMP (not
      guanine nucleotides), so the derived "GMP salvage" annotation does not
      reflect AMPD1's direct biochemistry (marked over-annotated, not removed
      per policy on experimental annotations).
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: >-
      Human binary interactome (HuRI) map; source of AMPD1 protein-protein
      interaction annotations, including self-association consistent with the
      homotetramer and interactions with paralogs AMPD2 and AMPD3.
    supporting_text: "reference map of the human binary protein interactome"
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Large-scale interactome resource. Supports identical protein binding
      (homotetramer); the bare "protein binding" rows are uninformative and
      marked over-annotated.
- id: PMID:644316
  title: 'Myoadenylate deaminase deficiency: a new disease of muscle.'
  findings:
  - statement: >-
      Foundational clinical description of myoadenylate deaminase deficiency:
      patients with exercise-induced muscle weakness/cramping whose biopsies
      lacked adenylate deaminase activity, defining loss of muscle AMP deaminase
      as a distinct muscle disease.
    supporting_text: "lacked adenylate deaminase by"
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache; title/abstract match PubMed 644316. Establishes the
      disease phenotype associated with loss of muscle AMP deaminase activity.
- id: Reactome:R-HSA-76590
  title: AMP + H2O => IMP + NH4+ (AMPD)
  findings:
  - statement: >-
      Reactome reaction placing cytosolic AMP deaminase (AMPD) catalysis of
      AMP + H2O => IMP + NH4+ in the cytosol.
    supporting_text: "Cytosolic AMP deaminase (AMPD) catalyzes the hydrolysis of AMP to yield IMP and ammonia."