id: P21695
gene_symbol: GPD1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  GPD1 encodes the cytosolic NAD-dependent glycerol-3-phosphate dehydrogenase
  (alpha-glycerophosphate dehydrogenase; GPD-C/GPDH-C; EC 1.1.1.8), a homodimeric
  enzyme that reversibly interconverts dihydroxyacetone phosphate (DHAP) and
  sn-glycerol 3-phosphate (G3P) coupled to the NAD+/NADH redox pair. In its
  physiological (reductive) direction it converts DHAP plus NADH to G3P plus NAD+,
  regenerating cytosolic NAD+ and providing the glycerol-3-phosphate backbone for
  glycerolipid, glycerophospholipid and triacylglycerol biosynthesis. It is the
  cytosolic component of the glycerol-3-phosphate (glycerophosphate) shuttle: acting
  with the mitochondrial FAD-dependent glycerol-3-phosphate dehydrogenase (GPD2), it
  transfers reducing equivalents from cytosolic NADH into the mitochondrial
  ubiquinone pool. The enzyme is strongly NAD+-preferring (its affinity for NADP is
  negligible) and adopts an N-terminal NAD-binding Rossmann fold together with a
  C-terminal substrate/catalytic domain, with the catalytic proton acceptor in the
  C-terminal domain. GPD1 is a soluble cytoplasmic protein, expressed prominently in
  liver, adipose tissue and skeletal muscle. Biallelic loss-of-function variants
  cause transient infantile hypertriglyceridemia with hepatomegaly, fatty liver and
  hepatic fibrosis.
alternative_products:
- name: '1'
  id: P21695-1
- name: '2'
  id: P21695-2
  sequence_note: VSP_045999
existing_annotations:
- term:
    id: GO:0006072
    label: glycerol-3-phosphate metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation to the core biological process of GPD1: metabolism
      of glycerol-3-phosphate. GPD1 interconverts DHAP and sn-glycerol 3-phosphate,
      so this is the central process the enzyme participates in.
    action: ACCEPT
    reason: >-
      This is a well-supported, correctly-scoped core BP for a cytosolic
      glycerol-3-phosphate dehydrogenase. Corroborated by the enzyme's catalytic
      activity and by InterPro and Reactome evidence.
    supported_by:
    - reference_id: file:human/GPD1/GPD1-uniprot.txt
      supporting_text: >-
        Reaction=sn-glycerol 3-phosphate + NAD(+) = dihydroxyacetone phosphate
- term:
    id: GO:0047952
    label: glycerol-3-phosphate dehydrogenase [NAD(P)+] activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) annotation to the dual-cofactor [NAD(P)+] dehydrogenase
      activity. The human enzyme is essentially NAD+-specific: KM for NAD is 140 uM
      whereas KM for NADP is 1070 mM (roughly 10,000-fold weaker), so the NADP arm of
      the [NAD(P)+] term is not physiologically relevant.
    action: MODIFY
    reason: >-
      The [NAD(P)+] term overstates cofactor breadth. The precise, current catalytic
      term GO:0141152 (glycerol-3-phosphate dehydrogenase (NAD+) activity) matches the
      UniProt/Rhea reaction (RHEA:11092) and EC 1.1.1.8 and is the term GOA already
      applies from other sources.
    proposed_replacement_terms:
    - id: GO:0141152
      label: glycerol-3-phosphate dehydrogenase (NAD+) activity
    supported_by:
    - reference_id: file:human/GPD1/GPD1-uniprot.txt
      supporting_text: 'KM=140 uM for NAD'
    - reference_id: file:human/GPD1/GPD1-uniprot.txt
      supporting_text: 'KM=1070 mM for NADP'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation placing the active enzyme in the cytosol. GPD1 is
      a soluble cytoplasmic protein and the cytosolic half of the glycerol-3-phosphate
      shuttle; cytosol is the correct, specific compartment.
    action: ACCEPT
    reason: >-
      Consistent with the experimentally-supported cytoplasmic localization and with
      the enzyme's role as the cytosolic partner of the mitochondrial GPD2. Cytosol is
      the appropriate specific CC term.
    supported_by:
    - reference_id: file:human/GPD1/GPD1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation from the UniProt Subcellular Location keyword mapping
      (SL-0086, Cytoplasm). Correct but less specific than the cytosol term also
      annotated to this gene.
    action: KEEP_AS_NON_CORE
    reason: >-
      Not wrong, but 'cytoplasm' is a broad parent of the more informative 'cytosol'
      annotation. Retained as non-core to avoid loss of the SubCell-derived location
      while cytosol carries the core CC.
    supported_by:
    - reference_id: file:human/GPD1/GPD1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO electronic annotation mapping the G3P-dehydrogenase domain to the
      very general 'carbohydrate metabolic process'. GPD1 acts on the phosphorylated
      three-carbon metabolites DHAP/G3P at the interface of glycolysis and lipid
      metabolism; the specific process is glycerol-3-phosphate metabolism, which is
      also annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Too general and not the most informative description of GPD1's role. The specific
      glycerol-3-phosphate metabolic/biosynthetic processes better capture the biology;
      this broad carbohydrate-metabolism term adds little.
    supported_by:
    - reference_id: file:human/GPD1/GPD1-uniprot.txt
      supporting_text: >-
        Reaction=sn-glycerol 3-phosphate + NAD(+) = dihydroxyacetone phosphate
- term:
    id: GO:0006072
    label: glycerol-3-phosphate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO electronic annotation to glycerol-3-phosphate metabolic process,
      duplicating the IBA annotation to the same term. This is the correct core BP for
      GPD1.
    action: ACCEPT
    reason: >-
      Correctly-scoped core biological process, independently supported by the
      phylogenetic annotation and by the catalytic activity.
    supported_by:
    - reference_id: file:human/GPD1/GPD1-uniprot.txt
      supporting_text: >-
        Reaction=sn-glycerol 3-phosphate + NAD(+) = dihydroxyacetone phosphate
- term:
    id: GO:0016616
    label: oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP
      as acceptor
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO electronic annotation to the parent oxidoreductase class (CH-OH
      donor, NAD/NADP acceptor). This is a true but non-specific ancestor of the
      precise catalytic term GO:0141152.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Correct as a grouping class but less informative than the specific
      glycerol-3-phosphate dehydrogenase (NAD+) activity term that is also annotated.
      The specific MF should carry the core annotation.
    supported_by:
    - reference_id: file:human/GPD1/GPD1-uniprot.txt
      supporting_text: >-
        Reaction=sn-glycerol 3-phosphate + NAD(+) = dihydroxyacetone phosphate
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO electronic annotation to protein homodimerization. GPD1 is indeed a
      homodimer, confirmed by X-ray crystallography and stated in the UniProt SUBUNIT
      line, so the annotation reflects real structural biology.
    action: KEEP_AS_NON_CORE
    reason: >-
      Homodimerization is a genuine, structurally-verified property of the active
      enzyme but describes its quaternary structure rather than its catalytic function.
      Kept as non-core supporting information.
    supported_by:
    - reference_id: file:human/GPD1/GPD1-uniprot.txt
      supporting_text: 'SUBUNIT: Homodimer'
    - reference_id: Reactome:R-HSA-75889
      supporting_text: The active forms of both enzymes are homodimers.
- term:
    id: GO:0046168
    label: glycerol-3-phosphate catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO annotation to glycerol-3-phosphate catabolic process, i.e. the
      oxidative direction G3P + NAD+ -> DHAP + NADH. This is in fact the direction that
      UniProt's PhysiologicalDirection=left-to-right annotates (the reaction is written
      G3P + NAD+ = DHAP + NADH), but the dominant cellular role of cytosolic GPD1 is the
      reductive (biosynthetic/shuttle) DHAP -> G3P direction.
    action: KEEP_AS_NON_CORE
    reason: >-
      Captures a chemically valid direction of the reversible reaction; however the
      predominant physiological role of cytosolic GPD1 is reductive (glycerolipid
      biosynthesis and the glycerol-phosphate shuttle, per Reactome R-HSA-75889). Kept
      as non-core rather than core.
    supported_by:
    - reference_id: file:human/GPD1/GPD1-uniprot.txt
      supporting_text: PhysiologicalDirection=left-to-right
- term:
    id: GO:0051287
    label: NAD binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO annotation to NAD binding. GPD1 has a defined NAD-binding Rossmann
      fold with multiple crystallographically-mapped NAD(+) contact residues, so this
      molecular-function detail is well supported.
    action: ACCEPT
    reason: >-
      Directly supported by the UniProt NAD(+) BINDING features and the NAD-complex
      crystal structures. An accurate cofactor-binding MF that underlies the catalytic
      activity.
    supported_by:
    - reference_id: file:human/GPD1/GPD1-uniprot.txt
      supporting_text: /ligand="NAD(+)"
- term:
    id: GO:0141152
    label: glycerol-3-phosphate dehydrogenase (NAD+) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated (Rhea/EC-based) annotation to the precise NAD+-specific catalytic
      activity. This matches the UniProt CATALYTIC ACTIVITY (RHEA:11092) and EC 1.1.1.8
      and is the core molecular function of GPD1.
    action: ACCEPT
    reason: >-
      This is the correct, current, precise catalytic term for GPD1 and represents its
      defining molecular function. Also independently supported by experimental TAS
      annotation (PMID:7772607).
    supported_by:
    - reference_id: file:human/GPD1/GPD1-uniprot.txt
      supporting_text: EC=1.1.1.8
    - reference_id: file:human/GPD1/GPD1-uniprot.txt
      supporting_text: >-
        Reaction=sn-glycerol 3-phosphate + NAD(+) = dihydroxyacetone phosphate
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare 'protein binding' IPI from the human binary protein interactome (HuRI)
      yeast two-hybrid screen, recording a GPD1-FAM25A interaction (UniProt INTERACTION
      line lists FAM25A, B3EWG3). FAM25A is a small uncharacterised protein and the
      interaction has no established functional consequence for GPD1.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      'Protein binding' is uninformative about molecular function, and this
      high-throughput binary interaction has not been shown to be functionally
      meaningful for GPD1. Per policy the IPI is retained (not removed) but flagged as
      over-annotated; no specific MF can be substituted.
    supported_by:
    - reference_id: file:human/GPD1/GPD1-uniprot.txt
      supporting_text: 'P21695; B3EWG3: FAM25A'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-75889
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation placing GPD1 in the cytosol, where it catalyses the
      DHAP -> G3P reaction. Consistent with the enzyme's soluble cytoplasmic
      localization and its role as the cytosolic arm of the glycerol-3-phosphate
      shuttle.
    action: ACCEPT
    reason: >-
      Author-traceable statement corroborating the core cytosolic localization.
    supported_by:
    - reference_id: Reactome:R-HSA-75889
      supporting_text: DHAP is converted to G3P by GPD1/GPD1L
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:7772607
  qualifier: located_in
  review:
    summary: >-
      Experimental (EXP) annotation of cytoplasmic localization from the original human
      liver GPD1 cloning/expression study, the basis for the UniProt SUBCELLULAR
      LOCATION 'Cytoplasm' statement. Correct but less specific than the cytosol term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported and not removed, but 'cytoplasm' is a broad parent of
      the more informative 'cytosol' annotation that carries the core localization.
    supported_by:
    - reference_id: file:human/GPD1/GPD1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:7772607}'
- term:
    id: GO:0141152
    label: glycerol-3-phosphate dehydrogenase (NAD+) activity
  evidence_type: TAS
  original_reference_id: PMID:7772607
  qualifier: enables
  review:
    summary: >-
      TAS annotation to the NAD+-specific glycerol-3-phosphate dehydrogenase activity
      from the paper that cloned and expressed human liver GPD1 and defined it as an
      NAD-dependent alpha-glycerol-3-phosphate dehydrogenase (EC 1.1.1.8). Core
      molecular function.
    action: ACCEPT
    reason: >-
      Precise, current catalytic term backed by the primary characterization of the
      human enzyme; this is the defining molecular function of GPD1.
    supported_by:
    - reference_id: file:human/GPD1/GPD1-uniprot.txt
      supporting_text: EC=1.1.1.8 {ECO:0000269|PubMed:7772607}
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: >-
      High-throughput mass-spectrometry detection of GPD1 among 1132 proteins in a
      proteomic survey of human urinary exosomes. This reflects presence in a secreted
      vesicle proteome, not a site where GPD1 performs its catalytic function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GPD1 is a soluble cytosolic enzyme; its detection in urinary exosomes is a
      common feature of abundant cytoplasmic proteins in large-scale exosome proteomes
      and does not indicate a functional extracellular/exosomal localization. Flagged
      as over-annotated rather than removed (experimental HDA detection is real).
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: >-
        we used LC-MS/MS to profile the proteome of human urinary exosomes
- term:
    id: GO:0046167
    label: glycerol-3-phosphate biosynthetic process
  evidence_type: IEA
  original_reference_id: file:human/GPD1/GPD1-uniprot.txt
  qualifier: involved_in
  review:
    summary: >-
      Proposed core BP not currently in GOA. The physiological direction of the GPD1
      reaction is reductive (DHAP + NADH -> G3P + NAD+), i.e. biosynthesis of
      glycerol-3-phosphate, which supplies the glycerol backbone for glycerolipid
      synthesis.
    action: NEW
    reason: >-
      The predominant physiological role of cytosolic GPD1 is reductive
      (DHAP + NADH -> G3P + NAD+), supplying the glycerol-3-phosphate backbone for
      glycerolipid biosynthesis; this direction is directly modelled by Reactome
      R-HSA-75889. (UniProt's PhysiologicalDirection=left-to-right annotates the
      oxidative direction, as its reaction is written G3P + NAD+ = DHAP + NADH, so it is
      not cited here as support for biosynthesis.) The biosynthetic term is more
      specific than the general metabolic-process term.
    supported_by:
    - reference_id: Reactome:R-HSA-75889
      supporting_text: GPD1/GPD1L reduces dihydroxyacetone phosphate with NADH donating electrons to this reduction
    - reference_id: Reactome:R-HSA-75889
      supporting_text: DHAP is converted to G3P by GPD1/GPD1L
- term:
    id: GO:0006127
    label: glycerol-3-phosphate shuttle
  evidence_type: IEA
  original_reference_id: file:human/GPD1/GPD1-uniprot.txt
  qualifier: involved_in
  review:
    summary: >-
      Proposed core BP not currently in GOA. GPD1 is the cytosolic half of the
      glycerol-3-phosphate (glycerophosphate) shuttle: it reduces DHAP to G3P using
      cytosolic NADH, and the mitochondrial FAD-dependent GPD2 re-oxidises G3P, so the
      pair transfers reducing equivalents from cytosol to the mitochondrial ubiquinone
      pool.
    action: NEW
    reason: >-
      The glycerol-3-phosphate shuttle is a well-established role of cytosolic
      NAD-dependent glycerol-3-phosphate dehydrogenase acting with mitochondrial GPD2;
      this specific process is missing from the current GOA set.
    supported_by:
    - reference_id: file:human/GPD1/GPD1-uniprot.txt
      supporting_text: >-
        Reaction=sn-glycerol 3-phosphate + NAD(+) = dihydroxyacetone phosphate
core_functions:
- description: >-
    Cytosolic NAD-dependent glycerol-3-phosphate dehydrogenase: reversibly interconverts
    dihydroxyacetone phosphate (DHAP) and sn-glycerol 3-phosphate (G3P) using the
    NAD+/NADH couple (EC 1.1.1.8). Physiologically it runs the reductive direction
    (DHAP + NADH -> G3P + NAD+), providing the glycerol-3-phosphate backbone for
    glycerolipid biosynthesis while regenerating cytosolic NAD+.
  molecular_function:
    id: GO:0141152
    label: glycerol-3-phosphate dehydrogenase (NAD+) activity
  directly_involved_in:
  - id: GO:0006072
    label: glycerol-3-phosphate metabolic process
  - id: GO:0046167
    label: glycerol-3-phosphate biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/GPD1/GPD1-uniprot.txt
    supporting_text: >-
      Reaction=sn-glycerol 3-phosphate + NAD(+) = dihydroxyacetone phosphate
  - reference_id: Reactome:R-HSA-75889
    supporting_text: GPD1/GPD1L reduces dihydroxyacetone phosphate with NADH donating electrons to this reduction
- description: >-
    Cytosolic component of the glycerol-3-phosphate (glycerophosphate) shuttle: by
    reducing DHAP to G3P at the expense of cytosolic NADH, GPD1 works with the
    mitochondrial FAD-dependent glycerol-3-phosphate dehydrogenase (GPD2) to transfer
    reducing equivalents from the cytosol into the mitochondrial ubiquinone pool and
    regenerate cytosolic NAD+.
  molecular_function:
    id: GO:0141152
    label: glycerol-3-phosphate dehydrogenase (NAD+) activity
  directly_involved_in:
  - id: GO:0006127
    label: glycerol-3-phosphate shuttle
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: Reactome:R-HSA-75889
    supporting_text: >-
      GPD1/GPD1L reduces dihydroxyacetone phosphate with NADH donating electrons to
      this reduction.
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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Abstract-verified urinary-exosome proteome (1132 proteins by LC-MS/MS). GPD1 is
      detected but no function is assigned; supports only the extracellular-exosome
      HDA location, which is a proteome-detection artefact rather than functional
      localization for this soluble cytosolic enzyme.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI reference binary interactome (yeast two-hybrid). Basis for the bare
      GPD1-FAM25A 'protein binding' IPI. Correctly cited but the interaction is
      high-throughput with no established functional consequence for GPD1.
- id: PMID:7772607
  title: Molecular cloning, sequencing and expression of a cDNA encoding a human liver
    NAD-dependent alpha-glycerol-3-phosphate dehydrogenase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary characterization of human liver GPD1: cloning, sequencing and expression
      of the NAD-dependent alpha-glycerol-3-phosphate dehydrogenase (EC 1.1.1.8). Basis
      for the core catalytic-activity and cytoplasmic-localization annotations. Abstract
      only in cache (full_text_available: false).
- id: Reactome:R-HSA-75889
  title: DHAP is converted to G3P by GPD1/GPD1L
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction modelling the physiological DHAP -> G3P step catalysed by the
      GPD1 homodimer with NADH as electron donor; supports the core catalytic activity,
      biosynthetic direction and cytosolic localization.
- id: file:human/GPD1/GPD1-uniprot.txt
  title: UniProtKB P21695 (GPDA_HUMAN) record
  findings: []