id: P43304
gene_symbol: GPD2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  GPD2 (mGPDH) is the mitochondrial FAD-dependent glycerol-3-phosphate
  dehydrogenase, a flavoenzyme of the mitochondrial inner membrane that faces
  the intermembrane-space side. It oxidises sn-glycerol-3-phosphate to
  dihydroxyacetone phosphate (DHAP) and passes the electrons through its bound
  FAD cofactor to ubiquinone in the respiratory chain (EC 1.1.5.3). Together
  with the cytosolic NAD-linked isozyme GPD1, it forms the glycerol-phosphate
  shuttle, which delivers cytosolic reducing equivalents to the mitochondrial
  ubiquinone pool and thereby bypasses Complex I. The enzyme carries two
  C-terminal EF-hand motifs and binds calcium, which enhances its activity; this
  calcium responsiveness makes GPD2 an important component of the pancreatic
  beta-cell glucose-sensing apparatus. The protein is synthesised as a precursor
  with an N-terminal mitochondrial transit peptide and exists as two
  alternatively spliced isoforms.
alternative_products:
- name: '1'
  id: P43304-1
- name: '2'
  id: P43304-2
  sequence_note: VSP_017134
existing_annotations:
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      GPD2 is a mitochondrial enzyme; this phylogenetic annotation is correct
      but non-specific. UniProt gives the location as Mitochondrion, and the
      protein is more precisely an inner-membrane enzyme (GO:0005743), which is
      the location captured in the core functions.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: file:human/GPD2/GPD2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion.'
      reference_section_type: OTHER
- term:
    id: GO:0006127
    label: glycerol-3-phosphate shuttle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Core biological process. With cytosolic GPD1, GPD2 constitutes the
      glycerol-phosphate shuttle that transfers reducing equivalents from the
      cytosol into the mitochondrial respiratory chain via glycerol-3-phosphate.
      Well supported phylogenetically and by Reactome.
    action: ACCEPT
    supported_by:
    - reference_id: Reactome:R-HSA-188467
      supporting_text: >-
        FAD-linked mitochondrial glycerol 3-phosphate dehydrogenase (GPD2,
        alias: mGPDH) and its NAD-linked  cytosolic isoform (GPD1, alias:cGPDH)
        constitute glycerol phosphate shuttle.
      reference_section_type: OTHER
- term:
    id: GO:0004368
    label: glycerol-3-phosphate dehydrogenase (quinone) activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Core molecular function. This is the catalytic activity of GPD2 (EC
      1.1.5.3): oxidation of sn-glycerol 3-phosphate to DHAP with electron
      transfer to a quinone. Phylogenetic call is consistent with the
      experimental IDA (PMID:9070847) and the UniProt catalytic activity.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/GPD2/GPD2-uniprot.txt
      supporting_text: >-
        Reaction=a quinone + sn-glycerol 3-phosphate = dihydroxyacetone
      reference_section_type: OTHER
- term:
    id: GO:0006072
    label: glycerol-3-phosphate metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Correct but general parent process. GPD2 does participate in
      glycerol-3-phosphate metabolism, but the specific biological roles are
      better captured by the glycerol-3-phosphate shuttle (GO:0006127) and
      glycerol catabolic pathway; retain as non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0004368
    label: glycerol-3-phosphate dehydrogenase (quinone) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic prediction (ARBA/InterPro/RHEA/EC 1.1.5.3) of the same core
      catalytic activity that is experimentally supported by PMID:9070847 and by
      the UniProt catalytic-activity annotation. Correct; duplicate of the IDA
      and IBA calls for this term.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/GPD2/GPD2-uniprot.txt
      supporting_text: >-
        Reaction=a quinone + sn-glycerol 3-phosphate = dihydroxyacetone
      reference_section_type: OTHER
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      GPD2 has two C-terminal EF-hand domains and binds calcium; this InterPro
      EF-hand prediction is biologically correct. Calcium binding is regulatory
      (it enhances catalytic activity) rather than the core catalytic function,
      so retain as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: file:human/GPD2/GPD2-uniprot.txt
      supporting_text: Calcium-binding enhance the activity of the
      reference_section_type: OTHER
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Correct but non-specific location derived from the UniProt subcellular
      location vocabulary. The more informative location is mitochondrial inner
      membrane (GO:0005743); retain as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: file:human/GPD2/GPD2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion.'
      reference_section_type: OTHER
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: >-
      Correct and specific location. GPD2 is an integral inner-membrane
      flavoenzyme facing the intermembrane space, where it feeds electrons to
      the ubiquinone pool. This ARBA electronic call agrees with the Reactome
      TAS annotation to the same term and is the core location.
    action: ACCEPT
- term:
    id: GO:0006072
    label: glycerol-3-phosphate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro electronic annotation to the general glycerol-3-phosphate
      metabolic process; same term as the IBA call above. Correct but general;
      retain as non-core in favour of the specific shuttle/catabolic terms.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0006127
    label: glycerol-3-phosphate shuttle
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-188467
  qualifier: involved_in
  review:
    summary: >-
      Reactome traceable-author annotation to the glycerol-phosphate shuttle,
      the core biological process of GPD2. Agrees with the IBA call for this
      term.
    action: ACCEPT
    supported_by:
    - reference_id: Reactome:R-HSA-188467
      supporting_text: >-
        FAD-linked mitochondrial glycerol 3-phosphate dehydrogenase (GPD2,
        alias: mGPDH) and its NAD-linked  cytosolic isoform (GPD1, alias:cGPDH)
        constitute glycerol phosphate shuttle.
      reference_section_type: OTHER
- term:
    id: GO:0019563
    label: glycerol catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway-derived pathway annotation. GPD2 catalyses the final step of
      glycerol degradation via the glycerol kinase pathway (glycerol ->
      glycerol-3-phosphate -> DHAP), so participation in glycerol catabolism is
      pathway-appropriate. However, GPD2 acts on glycerol-3-phosphate rather
      than free glycerol, and this is a broad pathway-level process; retain as
      non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: file:human/GPD2/GPD2-uniprot.txt
      supporting_text: >-
        Polyol metabolism; glycerol degradation via glycerol kinase
      reference_section_type: OTHER
- term:
    id: GO:0004368
    label: glycerol-3-phosphate dehydrogenase (quinone) activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-188467
  qualifier: enables
  review:
    summary: >-
      Reactome traceable-author annotation of the core catalytic activity,
      consistent with the experimental IDA and the UniProt catalytic activity.
    action: ACCEPT
    supported_by:
    - reference_id: Reactome:R-HSA-188467
      supporting_text: >-
        GPD2 catalyzes the unidirectional conversion of glycerol-3-phosphate
        (G-3-P) to dihydroxyacetone phosphate (DHAP) with concomitant reduction
        of the enzyme-bound FAD.
      reference_section_type: OTHER
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Human Protein Atlas immunofluorescence localisation to mitochondrion.
      Correct but non-specific relative to the inner-membrane location; retain
      as non-core supporting evidence.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput mitochondrial-proteome evidence: GPD2/P43304 is a member
      of the high-confidence human mitochondrial proteome (MitoCoP). Corroborates
      mitochondrial localisation; non-specific relative to the inner membrane, so
      retain as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: high-confidence mitochondrial proteome MitoCoP
      reference_section_type: RESULTS
- term:
    id: GO:0004368
    label: glycerol-3-phosphate dehydrogenase (quinone) activity
  evidence_type: IDA
  original_reference_id: PMID:9070847
  qualifier: enables
  review:
    summary: >-
      Experimental (IDA) support for the core catalytic activity. Novials et al.
      assayed FAD-linked (m-GDH) glycerophosphate dehydrogenase activity and its
      calcium-dependent regulation in cells from diabetic subjects; this is the
      experimental basis for the EC 1.1.5.3 catalytic-activity annotation in
      UniProt. Accept as the core molecular function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:9070847
      supporting_text: >-
        The Ca(2+)-sensitive and mitochondrial enzyme FAD-linked glycerophosphate
      reference_section_type: ABSTRACT
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-188467
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author annotation to the mitochondrial inner membrane,
      the specific and correct location for this inner-membrane flavoenzyme.
      Core location.
    action: ACCEPT
- term:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      GPD2 binds FAD as its redox cofactor (InterPro FAD-binding domain; UniProt
      COFACTOR Name=FAD), which accepts the electrons abstracted from
      glycerol-3-phosphate and passes them to ubiquinone. This core cofactor molecular
      function is absent from the current GOA snapshot.
    action: NEW
    reason: >-
      FAD binding is an essential, well-supported cofactor MF for this FAD-dependent
      glycerol-3-phosphate dehydrogenase but is missing from GOA; added as NEW to make
      the proposed annotation explicit (mirrors its use in core_functions).
    supported_by:
    - reference_id: file:human/GPD2/GPD2-uniprot.txt
      supporting_text: Name=FAD
core_functions:
- description: >-
    GPD2 is the mitochondrial FAD-dependent glycerol-3-phosphate dehydrogenase
    (EC 1.1.5.3). Bound FAD accepts electrons as sn-glycerol 3-phosphate is
    oxidised to dihydroxyacetone phosphate, and the reduced flavin transfers the
    electrons to ubiquinone in the respiratory chain. Acting at the mitochondrial
    inner membrane, this activity forms the mitochondrial arm of the
    glycerol-phosphate shuttle together with cytosolic GPD1.
  molecular_function:
    id: GO:0004368
    label: glycerol-3-phosphate dehydrogenase (quinone) activity
  directly_involved_in:
  - id: GO:0006127
    label: glycerol-3-phosphate shuttle
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:9070847
    supporting_text: >-
      The Ca(2+)-sensitive and mitochondrial enzyme FAD-linked glycerophosphate
    reference_section_type: ABSTRACT
  - reference_id: file:human/GPD2/GPD2-uniprot.txt
    supporting_text: >-
      Reaction=a quinone + sn-glycerol 3-phosphate = dihydroxyacetone
    reference_section_type: OTHER
  - reference_id: Reactome:R-HSA-188467
    supporting_text: >-
      GPD2 catalyzes the unidirectional conversion of glycerol-3-phosphate
      (G-3-P) to dihydroxyacetone phosphate (DHAP) with concomitant reduction of
      the enzyme-bound FAD.
    reference_section_type: OTHER
- description: >-
    GPD2 binds FAD as an essential redox cofactor. The flavin prosthetic group
    is required for the enzyme's oxidoreductase activity, accepting hydride from
    glycerol-3-phosphate before passing electrons to ubiquinone.
  molecular_function:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: file:human/GPD2/GPD2-uniprot.txt
    supporting_text: 'Name=FAD; Xref=ChEBI:CHEBI:57692'
    reference_section_type: OTHER
proposed_new_terms: []
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  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:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      High-confidence human mitochondrial proteome (MitoCoP) study; GPD2/P43304
      is a MitoCoP member. Corroborates mitochondrial localisation (HTP) but does
      not resolve sub-mitochondrial location or function.
- id: PMID:9070847
  title: Mutation in the calcium-binding domain of the mitochondrial glycerophosphate
    dehydrogenase gene in a family of diabetic subjects.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Abstract-only (full_text_available: false). Source of the
      UniProt catalytic-activity, activity-regulation (calcium enhances activity),
      and beta-cell glucose-sensing FUNCTION statements, and of the GOA IDA on
      GO:0004368. Establishes GPD2 as the Ca2+-sensitive FAD-linked mitochondrial
      glycerophosphate dehydrogenase.
- id: Reactome:R-HSA-188467
  title: Gly-3-P+FAD->DHAP+FADH2 (catalyzed by mitochondrial Gly-Phos dehydrogenase)
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction for GPD2 catalysis; supports the core catalytic activity,
      the glycerol-phosphate shuttle role, and inner-membrane localisation.