id: Q9UBQ7
gene_symbol: GRHPR
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: GRHPR encodes glyoxylate reductase/hydroxypyruvate reductase, a cytosolic
  NADPH-dependent D-2-hydroxyacid dehydrogenase (D-isomer specific 2-hydroxyacid dehydrogenase
  family) that is most abundantly expressed in the liver. It reduces glyoxylate to
  glycolate (EC 1.1.1.79) and hydroxypyruvate to D-glycerate (EC 1.1.1.81), and can
  oxidize D-glycerate back to hydroxypyruvate; it prefers glyoxylate and hydroxypyruvate
  over pyruvate. By reducing glyoxylate to glycolate it limits the oxidation of glyoxylate
  to oxalate, providing a key route for cytosolic glyoxylate detoxification and
  constraining endogenous oxalate synthesis. The enzyme is a homodimer with a Rossmann
  NAD(P)-binding fold. Loss-of-function variants cause primary hyperoxaluria type 2
  (PH2), characterized by elevated urinary excretion of oxalate and L-glycerate,
  calcium-oxalate nephrolithiasis, nephrocalcinosis, and progressive renal disease.
alternative_products:
- name: '1'
  id: Q9UBQ7-1
- name: '2'
  id: Q9UBQ7-2
  sequence_note: VSP_057016, VSP_057017, VSP_057018
existing_annotations:
- term:
    id: GO:0030267
    label: glyoxylate reductase (NADPH) activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) assignment of the enzyme's central molecular function,
      glyoxylate reductase (NADPH) activity. This is the core catalytic activity of
      GRHPR, directly demonstrated for the human enzyme and confirmed by structure.
    action: ACCEPT
    reason: Glyoxylate reductase (NADPH) activity is the defining, experimentally
      established function of GRHPR and is well conserved across the D-2-hydroxyacid
      dehydrogenase family, so the IBA assignment is fully appropriate.
    supported_by:
    - reference_id: PMID:16756993
      supporting_text: Human glyoxylate reductase/hydroxypyruvate reductase (GRHPR)
        is a D-2-hydroxy-acid dehydrogenase that plays a critical role in the removal
        of the metabolic by-product glyoxylate from within the liver.
    - reference_id: file:human/GRHPR/GRHPR-uniprot.txt
      supporting_text: hydroxypyruvate to D-glycerate, glyoxylate to glycolate
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) assignment placing the active enzyme in the cytosol,
      consistent with independent IDA cytoplasm localization and the absence of any
      targeting signal in the 328-residue sequence.
    action: ACCEPT
    reason: GRHPR is a soluble cytosolic enzyme; the cytosol is the principal site
      where it acts to reduce glyoxylate. This is supported by IDA cytoplasm
      localization and is the appropriate core cellular component.
    supported_by:
    - reference_id: PMID:16756993
      supporting_text: plays a critical role in the removal of the metabolic by-product
        glyoxylate from within the liver
- term:
    id: GO:0008465
    label: hydroxypyruvate reductase (NADH) activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) assignment of hydroxypyruvate reductase activity with
      NADH. GRHPR reduces hydroxypyruvate to D-glycerate; UniProt records EC 1.1.1.81
      with both NAD(H) and NADP(H) cofactor reactions.
    action: ACCEPT
    reason: Hydroxypyruvate reductase activity is an experimentally verified activity
      of GRHPR, and the enzyme can use NAD(H) as well as NADP(H); the IBA is consistent
      with the literature.
    supported_by:
    - reference_id: file:human/GRHPR/GRHPR-uniprot.txt
      supporting_text: hydroxypyruvate to D-glycerate, glyoxylate to glycolate
    - reference_id: PMID:10484776
      supporting_text: verified that it encoded an enzyme with hydroxy-pyruvate reductase,
        glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities
- 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 mapping (IPR006139, D-isomer 2-hydroxyacid dehydrogenase
      catalytic domain) to the parent oxidoreductase activity acting on CH-OH groups
      with NAD/NADP as acceptor.
    action: ACCEPT
    reason: This is a correct but general parent of the specific reductase activities.
      It is not wrong; it is simply less informative than the specific glyoxylate/hydroxypyruvate
      reductase terms captured elsewhere. Acceptable as a broad IEA.
    supported_by:
    - reference_id: file:human/GRHPR/GRHPR-uniprot.txt
      supporting_text: Belongs to the D-isomer specific 2-hydroxyacid
- term:
    id: GO:0016618
    label: hydroxypyruvate reductase [NAD(P)H] activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated (multiple-method IEA) assignment of hydroxypyruvate reductase
      [NAD(P)H] activity, matching EC 1.1.1.81 and the enzyme's demonstrated reduction
      of hydroxypyruvate to D-glycerate with either cofactor.
    action: ACCEPT
    reason: Consistent with experimental IDA annotations to the same term; a correct
      electronic inference of a genuine GRHPR activity.
    supported_by:
    - reference_id: file:human/GRHPR/GRHPR-uniprot.txt
      supporting_text: hydroxypyruvate to D-glycerate, glyoxylate to glycolate
- term:
    id: GO:0030267
    label: glyoxylate reductase (NADPH) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated (multiple-method IEA) assignment of glyoxylate reductase (NADPH)
      activity (EC 1.1.1.79, RHEA:10992), the core catalytic function of GRHPR.
    action: ACCEPT
    reason: Duplicates the experimentally supported core MF; a correct electronic
      inference.
    supported_by:
    - reference_id: file:human/GRHPR/GRHPR-uniprot.txt
      supporting_text: hydroxypyruvate to D-glycerate, glyoxylate to glycolate
- term:
    id: GO:0051287
    label: NAD binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated assignment of NAD binding, reflecting the NAD(H)-utilizing
      hydroxypyruvate reductase/D-glycerate dehydrogenase reaction (EC 1.1.1.81) and
      the Rossmann NAD(P)-binding fold.
    action: KEEP_AS_NON_CORE
    reason: Cofactor binding is a molecular detail supporting the catalytic activity
      rather than a core function in itself. The enzyme's crystallographically defined
      cofactor is NADP(H); NAD binding is inferred from the NAD-dependent glycerate
      reaction. Retain as non-core supporting detail.
    supported_by:
    - reference_id: file:human/GRHPR/GRHPR-uniprot.txt
      supporting_text: Belongs to the D-isomer specific 2-hydroxyacid
- term:
    id: GO:0106345
    label: glyoxylate reductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: ARBA machine-learning assignment of the general glyoxylate reductase
      activity term (cofactor-agnostic parent of the NADPH-specific term).
    action: ACCEPT
    reason: A correct but more general parent of GO:0030267 glyoxylate reductase (NADPH)
      activity, which is the enzyme's characterized activity. Acceptable as a broad IEA.
    supported_by:
    - reference_id: PMID:10484776
      supporting_text: verified that it encoded an enzyme with hydroxy-pyruvate reductase,
        glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities
- term:
    id: GO:0120509
    label: hydroxypyruvate reductase (NADPH) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: RHEA-based automated assignment (RHEA:18657) of hydroxypyruvate reductase
      (NADPH) activity, i.e. NADPH-dependent reduction of 3-hydroxypyruvate to
      (R)-glycerate.
    action: ACCEPT
    reason: Matches an experimentally supported activity (see EXP/IDA annotations to
      the same term) and the UniProt catalytic-activity record. Correct electronic
      inference.
    supported_by:
    - reference_id: file:human/GRHPR/GRHPR-uniprot.txt
      supporting_text: hydroxypyruvate to D-glycerate, glyoxylate to glycolate
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23599041
  qualifier: enables
  review:
    summary: IPI annotation from a yeast two-hybrid/co-IP study reporting that GRHPR
      (hGR/HPR) physically interacts with the sodium-dependent vitamin C transporter
      SLC23A1 (hSVCT1) to modulate ascorbate uptake and local oxalate production.
    action: MARK_AS_OVER_ANNOTATED
    reason: The interaction with SLC23A1 is genuine and functionally interesting, but
      the bare "protein binding" term is uninformative about GRHPR's molecular function.
      Per curation guidance this generic term is marked as over-annotated rather than
      removed; the specific SLC23A1 interaction is retained in the record.
    supported_by:
    - reference_id: PMID:23599041
      supporting_text: we identify the enzyme human glyoxalate reductase/hydroxypyruvate
        reductase (hGR/HPR) as an hSVCT1 associated protein by yeast two-hybrid (Y2H)
        screening of a human liver cDNA library
- term:
    id: GO:0008465
    label: hydroxypyruvate reductase (NADH) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated (multiple-method IEA) assignment of NADH-dependent hydroxypyruvate
      reductase activity, matching EC 1.1.1.81 and duplicating the experimental IDA/IBA
      annotations to the same term.
    action: ACCEPT
    reason: Correct electronic inference of a genuine GRHPR activity, consistent with
      the experimentally supported reduction of hydroxypyruvate to D-glycerate.
    supported_by:
    - reference_id: file:human/GRHPR/GRHPR-uniprot.txt
      supporting_text: hydroxypyruvate to D-glycerate, glyoxylate to glycolate
- term:
    id: GO:0031406
    label: carboxylic acid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ensembl orthology-based (IEA) assignment of carboxylic acid binding,
      reflecting that the substrates (glyoxylate, hydroxypyruvate, glycerate) are
      carboxylic acids bound in the active site.
    action: KEEP_AS_NON_CORE
    reason: Substrate binding is a molecular detail entailed by the catalytic activity
      rather than an independent core function; retain as non-core supporting detail.
    supported_by:
    - reference_id: PMID:16756993
      supporting_text: the relationship of substrate and catalytic residues within
        the active site
- term:
    id: GO:0043648
    label: dicarboxylic acid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl orthology-based (IEA) assignment to dicarboxylic acid metabolic
      process. Glyoxylate (HOC-COOH) is a monocarboxylate, and the more precise
      process is glyoxylate metabolism captured by the IDA annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific and experimentally supported process is glyoxylate metabolic
      process (GO:0046487), annotated by IDA. Dicarboxylic acid metabolic process is
      a broad, orthology-transferred term that is less accurate for this enzyme's
      characterized chemistry, so it is marked as over-annotated in favor of the
      glyoxylate-specific term.
    supported_by:
    - reference_id: PMID:16756993
      supporting_text: plays a critical role in the removal of the metabolic by-product
        glyoxylate from within the liver
- term:
    id: GO:0050661
    label: NADP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ensembl orthology-based (IEA) assignment of NADP binding, consistent with
      the crystallographically defined NADP(H) cofactor site of GRHPR.
    action: KEEP_AS_NON_CORE
    reason: NADP(H) is the physiological cofactor and is well supported (see IDA NADPH
      binding, PMID:16756993), but cofactor binding is a supporting molecular detail
      rather than a standalone core function.
    supported_by:
    - reference_id: PMID:16756993
      supporting_text: one subunit forms a ternary (enzyme+NADPH+reduced substrate)
        complex, and the other a binary (enzyme+NADPH) form
- term:
    id: GO:0030267
    label: glyoxylate reductase (NADPH) activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-389826
  qualifier: enables
  review:
    summary: Reactome TAS annotation of glyoxylate reductase (NADPH) activity for the
      reaction glyoxylate + NADPH + H+ => glycolate + NADP+, the enzyme's core
      catalytic step.
    action: ACCEPT
    reason: This is the defining reaction of GRHPR and is experimentally established;
      the Reactome traceable-author-statement annotation is appropriate.
    supported_by:
    - reference_id: Reactome:R-HSA-389826
      supporting_text: Peroxisomal GRHPR catalyzes the reaction of glyoxylate and NADPH
        + H+ to form glycolate and NADP+.
- term:
    id: GO:0120509
    label: hydroxypyruvate reductase (NADPH) activity
  evidence_type: EXP
  original_reference_id: PMID:10484776
  qualifier: enables
  review:
    summary: Experimental (EXP) assignment of NADPH-dependent hydroxypyruvate reductase
      activity from expression of the human GRHPR cDNA, which conferred hydroxypyruvate
      reductase, glyoxylate reductase and D-glycerate dehydrogenase activities.
    action: ACCEPT
    reason: Directly supported by expression assays of the human enzyme; a core
      catalytic activity of GRHPR.
    supported_by:
    - reference_id: PMID:10484776
      supporting_text: verified that it encoded an enzyme with hydroxy-pyruvate reductase,
        glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities
- term:
    id: GO:0120509
    label: hydroxypyruvate reductase (NADPH) activity
  evidence_type: EXP
  original_reference_id: PMID:10524214
  qualifier: enables
  review:
    summary: Experimental (EXP) assignment of NADPH-dependent hydroxypyruvate reductase
      activity from cloning and expression of the human liver cDNA encoding a protein
      with glyoxylate and hydroxypyruvate reductase activities.
    action: ACCEPT
    reason: Directly supported by expression of the human cDNA; a core catalytic
      activity of GRHPR.
    supported_by:
    - reference_id: PMID:10524214
      supporting_text: a human liver cDNA encoding a 40-kDa protein with glyoxylate
        and hydroxypyruvate reductase activities
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput (HTP) mitochondrial-proteome localization. GRHPR is a
      soluble cytosolic enzyme; detection in a large-scale mitochondrial proteomics
      dataset likely reflects abundance/co-fractionation rather than a mitochondrial
      site of action.
    action: MARK_AS_OVER_ANNOTATED
    reason: GRHPR is established as a cytosolic (and reported peroxisomal) enzyme with
      no mitochondrial targeting signal; the mitochondrial assignment comes from a
      single high-throughput proteomic survey and is not the catalytic location.
      Marked as over-annotated rather than removed, per policy on high-throughput
      localization data.
    supported_by:
    - reference_id: PMID:16756993
      supporting_text: plays a critical role in the removal of the metabolic by-product
        glyoxylate from within the liver
- term:
    id: GO:0046487
    label: glyoxylate metabolic process
  evidence_type: IDA
  original_reference_id: PMID:10484776
  qualifier: involved_in
  review:
    summary: IDA annotation to glyoxylate metabolic process. GRHPR reduces glyoxylate
      to glycolate, a defining step of hepatic glyoxylate detoxification; its loss
      causes the glyoxylate/oxalate overproduction of primary hyperoxaluria type 2.
    action: ACCEPT
    reason: This is the core biological process for GRHPR, experimentally supported
      and consistent with the PH2 disease phenotype of glyoxylate/oxalate accumulation.
    supported_by:
    - reference_id: PMID:10484776
      supporting_text: the reduction of glyoxylate to glycolate
    - reference_id: PMID:16756993
      supporting_text: plays a critical role in the removal of the metabolic by-product
        glyoxylate from within the liver
- term:
    id: GO:1902494
    label: catalytic complex
  evidence_type: IDA
  original_reference_id: PMID:16756993
  qualifier: part_of
  review:
    summary: IDA annotation that GRHPR is part of a catalytic complex, based on the
      crystal structure showing the functional enzyme is a homodimer with the active
      site completed by a tryptophan from the neighbouring subunit.
    action: KEEP_AS_NON_CORE
    reason: The relevant "complex" is the catalytic homodimer, which is captured more
      informatively by the protein homodimerization activity annotation from the same
      study. The generic catalytic complex term is retained as non-core.
    supported_by:
    - reference_id: PMID:16756993
      supporting_text: A tryptophan residue (Trp141) from the neighbouring subunit
        of the dimer is projected into the active site region
- term:
    id: GO:0016618
    label: hydroxypyruvate reductase [NAD(P)H] activity
  evidence_type: IDA
  original_reference_id: PMID:10524214
  qualifier: enables
  review:
    summary: IDA annotation of hydroxypyruvate reductase [NAD(P)H] activity (EC 1.1.1.81)
      from expression of the human liver cDNA, which showed glyoxylate and hydroxypyruvate
      reductase activities.
    action: ACCEPT
    reason: Directly demonstrated core catalytic activity of GRHPR with NAD(P)H as
      cofactor.
    supported_by:
    - reference_id: PMID:10524214
      supporting_text: a human liver cDNA encoding a 40-kDa protein with glyoxylate
        and hydroxypyruvate reductase activities
- term:
    id: GO:0030267
    label: glyoxylate reductase (NADPH) activity
  evidence_type: IDA
  original_reference_id: PMID:10524214
  qualifier: enables
  review:
    summary: IDA annotation of glyoxylate reductase (NADPH) activity from expression
      of the human liver cDNA. This is the core catalytic function of GRHPR.
    action: ACCEPT
    reason: Directly demonstrated core catalytic activity; the defining reaction of
      the enzyme.
    supported_by:
    - reference_id: PMID:10524214
      supporting_text: a human liver cDNA encoding a 40-kDa protein with glyoxylate
        and hydroxypyruvate reductase activities
- term:
    id: GO:0046487
    label: glyoxylate metabolic process
  evidence_type: IDA
  original_reference_id: PMID:10524214
  qualifier: involved_in
  review:
    summary: IDA annotation to glyoxylate metabolic process, based on demonstration
      that the cloned human enzyme carries glyoxylate reductase activity that reduces
      glyoxylate to glycolate.
    action: ACCEPT
    reason: Core biological process for GRHPR, experimentally supported; duplicates
      the well-founded glyoxylate metabolism annotation.
    supported_by:
    - reference_id: PMID:10524214
      supporting_text: a human liver cDNA encoding a 40-kDa protein with glyoxylate
        and hydroxypyruvate reductase activities
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: High-throughput direct-assay (HDA) detection of GRHPR in urinary/exosome
      proteomics. GRHPR is a cytosolic enzyme; presence in exosome preparations is a
      common finding for abundant cytosolic proteins and does not reflect a functional
      extracellular localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Exosome detection is a proteomic-catalog observation, not the site where
      GRHPR performs glyoxylate detoxification. Marked as over-annotated rather than
      removed, consistent with treatment of high-throughput exosome localizations.
    supported_by:
    - reference_id: PMID:16756993
      supporting_text: plays a critical role in the removal of the metabolic by-product
        glyoxylate from within the liver
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: High-throughput direct-assay detection of GRHPR in urinary exosome
      proteomics/phosphoproteomics, duplicating the exosome catalog localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: As above, exosome presence is a proteomic-inventory finding rather than a
      functional extracellular site of action for this cytosolic enzyme.
    supported_by:
    - reference_id: PMID:16756993
      supporting_text: plays a critical role in the removal of the metabolic by-product
        glyoxylate from within the liver
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  qualifier: located_in
  review:
    summary: High-throughput direct-assay detection of GRHPR in B-cell exosome
      proteomics, duplicating the exosome catalog localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: As above, exosome detection reflects a proteomic inventory, not a functional
      extracellular localization of this cytosolic enzyme.
    supported_by:
    - reference_id: PMID:16756993
      supporting_text: plays a critical role in the removal of the metabolic by-product
        glyoxylate from within the liver
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-389826
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing GRHPR in the peroxisomal matrix (Reactome
      describes a "Peroxisomal GRHPR"). The enzyme is predominantly cytosolic; a minor
      peroxisomal pool has been proposed but the 328-residue sequence carries no PTS1/PTS2
      targeting signal.
    action: KEEP_AS_NON_CORE
    reason: The dominant and experimentally supported localization is cytosolic/cytoplasmic;
      the peroxisomal assignment is a Reactome pathway-context statement that is disputed
      and, at most, a minor pool. Retained as non-core rather than accepted as a core
      location.
    supported_by:
    - reference_id: Reactome:R-HSA-389826
      supporting_text: Peroxisomal GRHPR catalyzes the reaction of glyoxylate and NADPH
        + H+ to form glycolate and NADP+.
- term:
    id: GO:0016618
    label: hydroxypyruvate reductase [NAD(P)H] activity
  evidence_type: IDA
  original_reference_id: PMID:17510093
  qualifier: enables
  review:
    summary: IDA annotation of hydroxypyruvate reductase [NAD(P)H] activity in the
      context of a PH2 patient study characterizing a novel GRHPR mutation and its
      effect on enzyme function.
    action: ACCEPT
    reason: Consistent with the enzyme's established EC 1.1.1.81 activity; supports
      the core hydroxypyruvate reductase function. The full text (a PH2 case report)
      was read by the curator; deferring to the experimental annotation.
    supported_by:
    - reference_id: file:human/GRHPR/GRHPR-uniprot.txt
      supporting_text: hydroxypyruvate to D-glycerate, glyoxylate to glycolate
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:16756993
  qualifier: enables
  review:
    summary: IDA annotation of protein homodimerization activity based on the crystal
      structure, which shows GRHPR as a homodimer in which a Trp141 from the partner
      subunit projects into each active site.
    action: ACCEPT
    reason: The functional enzyme is an obligate homodimer, with the neighbouring
      subunit contributing to substrate specificity; homodimerization is a genuine,
      well-supported molecular activity.
    supported_by:
    - reference_id: PMID:16756993
      supporting_text: A tryptophan residue (Trp141) from the neighbouring subunit
        of the dimer is projected into the active site region
    - reference_id: file:human/GRHPR/GRHPR-uniprot.txt
      supporting_text: Homodimer
- term:
    id: GO:0070402
    label: NADPH binding
  evidence_type: IDA
  original_reference_id: PMID:16756993
  qualifier: enables
  review:
    summary: IDA annotation of NADPH binding from the crystal structure, which captured
      binary (enzyme+NADPH) and ternary (enzyme+NADPH+reduced substrate) complexes.
    action: KEEP_AS_NON_CORE
    reason: NADPH is the physiological cofactor and its binding is directly demonstrated,
      but cofactor binding is a supporting molecular detail underlying the catalytic
      activity rather than a standalone core function.
    supported_by:
    - reference_id: PMID:16756993
      supporting_text: one subunit forms a ternary (enzyme+NADPH+reduced substrate)
        complex, and the other a binary (enzyme+NADPH) form
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000054
  qualifier: located_in
  review:
    summary: IDA localization to the cytoplasm from imaging of expressed fusion proteins
      in living cells (LIFEdb), consistent with GRHPR being a soluble cytosolic enzyme.
    action: ACCEPT
    reason: Directly supports the cytoplasmic/cytosolic localization of GRHPR, its
      principal site of action. Cytoplasm is a correct (slightly more general) parent
      of the cytosol annotation.
    supported_by:
    - reference_id: file:human/GRHPR/GRHPR-uniprot.txt
      supporting_text: Most abundantly expressed in the liver
- term:
    id: GO:0008465
    label: hydroxypyruvate reductase (NADH) activity
  evidence_type: IDA
  original_reference_id: PMID:10484776
  qualifier: enables
  review:
    summary: IDA annotation of NADH-dependent hydroxypyruvate reductase activity from
      expression of the human GRHPR cDNA, which conferred hydroxypyruvate reductase,
      glyoxylate reductase and D-glycerate dehydrogenase activities.
    action: ACCEPT
    reason: Directly demonstrated activity of the human enzyme; supports the core
      hydroxypyruvate/glycerate branch of GRHPR function.
    supported_by:
    - reference_id: PMID:10484776
      supporting_text: verified that it encoded an enzyme with hydroxy-pyruvate reductase,
        glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities
- term:
    id: GO:0016618
    label: hydroxypyruvate reductase [NAD(P)H] activity
  evidence_type: IDA
  original_reference_id: PMID:10484776
  qualifier: enables
  review:
    summary: IDA annotation of hydroxypyruvate reductase [NAD(P)H] activity (EC 1.1.1.81)
      from expression of the human GRHPR cDNA.
    action: ACCEPT
    reason: Directly demonstrated core catalytic activity of GRHPR with NAD(P)H.
    supported_by:
    - reference_id: PMID:10484776
      supporting_text: verified that it encoded an enzyme with hydroxy-pyruvate reductase,
        glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities
- term:
    id: GO:0030267
    label: glyoxylate reductase (NADPH) activity
  evidence_type: IDA
  original_reference_id: PMID:10484776
  qualifier: enables
  review:
    summary: IDA annotation of glyoxylate reductase (NADPH) activity from expression
      of the human GRHPR cDNA. This is the core, disease-relevant catalytic function
      whose loss causes primary hyperoxaluria type 2.
    action: ACCEPT
    reason: Directly demonstrated core catalytic activity; the defining reaction of
      GRHPR and the basis of its role in limiting oxalate synthesis.
    supported_by:
    - reference_id: PMID:10484776
      supporting_text: verified that it encoded an enzyme with hydroxy-pyruvate reductase,
        glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities
core_functions:
- description: NADPH-dependent glyoxylate reductase that reduces glyoxylate to glycolate
    in the cytosol, providing the principal route for hepatic glyoxylate detoxification
    and limiting the oxidation of glyoxylate to oxalate.
  molecular_function:
    id: GO:0030267
    label: glyoxylate reductase (NADPH) activity
  directly_involved_in:
  - id: GO:0046487
    label: glyoxylate metabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:10484776
    supporting_text: verified that it encoded an enzyme with hydroxy-pyruvate reductase,
      glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities
  - reference_id: PMID:16756993
    supporting_text: plays a critical role in the removal of the metabolic by-product
      glyoxylate from within the liver
- description: Hydroxypyruvate reductase that reduces hydroxypyruvate to D-glycerate
    using NAD(P)H (and can oxidize D-glycerate to hydroxypyruvate), acting in the
    cytosol on the serine/glycerate branch of hydroxy-acid metabolism.
  molecular_function:
    id: GO:0016618
    label: hydroxypyruvate reductase [NAD(P)H] activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:10524214
    supporting_text: a human liver cDNA encoding a 40-kDa protein with glyoxylate and
      hydroxypyruvate reductase activities
  - reference_id: file:human/GRHPR/GRHPR-uniprot.txt
    supporting_text: hydroxypyruvate to D-glycerate, glyoxylate to glycolate
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:0000054
  title: Gene Ontology annotation based on curation of intracellular localizations
    of expressed fusion proteins in living cells
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  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:10484776
  title: The gene encoding hydroxypyruvate reductase (GRHPR) is mutated in patients
    with primary hyperoxaluria type II.
  findings:
  - statement: GRHPR encodes the enzyme that reduces hydroxypyruvate to D-glycerate,
      reduces glyoxylate to glycolate, and oxidizes D-glycerate; its deficiency causes
      primary hyperoxaluria type 2 with elevated urinary oxalate and L-glycerate.
    supporting_text: characterized by a lack of the enzyme that catalyzes the reduction
      of hydroxypyruvate to D-glycerate, the reduction of glyoxylate to glycolate and
      the oxidation of D-glycerate to hydroxypyruvate
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract-only cache; establishes GRHPR catalytic activities and the
      PH2 disease link. Consistent with UniProt FUNCTION and DISEASE records.
- id: PMID:10524214
  title: Identification and expression of a cDNA for human hydroxypyruvate/glyoxylate
    reductase.
  findings:
  - statement: Cloning and expression of the human liver GRHPR (GLXR) cDNA showed the
      328-residue protein has glyoxylate and hydroxypyruvate reductase activities.
    supporting_text: a human liver cDNA encoding a 40-kDa protein with glyoxylate and
      hydroxypyruvate reductase activities
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract-only cache; primary cloning/expression paper demonstrating
      the enzyme's dual reductase activities.
- id: PMID:16756993
  title: Structural basis of substrate specificity in human glyoxylate reductase/hydroxypyruvate
    reductase.
  findings:
  - statement: Crystal structure of human GRHPR shows a homodimer that binds NADPH and
      substrate; the enzyme prefers glyoxylate and hydroxypyruvate but not pyruvate,
      with Trp141 from the neighbouring subunit shaping specificity.
    supporting_text: A tryptophan residue (Trp141) from the neighbouring subunit of
      the dimer is projected into the active site region and appears to contribute to
      the selectivity for hydroxypyruvate.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract-only cache; defines fold, homodimer, NADPH cofactor,
      substrate specificity, and the hepatic glyoxylate-removal role.
- id: PMID:17510093
  title: A novel mutation in the GRHPR gene in a Japanese patient with primary hyperoxaluria
    type 2.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract-only cache (PH2 case report). Supports disease relevance;
      the IDA activity annotation reflects full-text data read by the curator.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput exosome proteomics; source of an exosome localization
      catalog entry, not a functional-localization study of GRHPR.
- 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: High-throughput exosome proteomics; catalog-level detection of GRHPR.
- 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: High-throughput exosome proteomics; catalog-level detection of GRHPR.
- id: PMID:23599041
  title: Glyoxalate reductase/hydroxypyruvate reductase interacts with the sodium-dependent
    vitamin C transporter-1 to regulate cellular vitamin C homeostasis.
  findings:
  - statement: GRHPR physically interacts with the sodium-dependent vitamin C transporter
      SLC23A1 (hSVCT1), and this interaction modulates ascorbate uptake, coupling
      vitamin C transport to control of cellular oxalate production.
    supporting_text: we identify the enzyme human glyoxalate reductase/hydroxypyruvate
      reductase (hGR/HPR) as an hSVCT1 associated protein by yeast two-hybrid (Y2H)
      screening of a human liver cDNA library
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract-only cache; source of the SLC23A1 IPI. Interaction is real
      but the GO term used (protein binding) is uninformative.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale mitochondrial proteomics; source of an HTP mitochondrion
      localization that is not the enzyme's catalytic site.
- id: Reactome:R-HSA-389826
  title: glyoxylate + NADPH + H+ => glycolate + NADP+
  findings:
  - statement: Reactome describes GRHPR catalyzing the NADPH-dependent reduction of
      glyoxylate to glycolate; it labels the enzyme peroxisomal and links its mutations
      to primary hyperoxaluria type II.
    supporting_text: Peroxisomal GRHPR catalyzes the reaction of glyoxylate and NADPH
      + H+ to form glycolate and NADP+.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome reaction for the core glyoxylate reductase step. Title left
      exactly as fetched. Peroxisomal localization claim is disputed (enzyme is mainly
      cytosolic).
- id: file:human/GRHPR/GRHPR-uniprot.txt
  title: UniProt entry GRHPR_HUMAN (Q9UBQ7)
  findings:
  - statement: UniProt records GRHPR as a hydroxypyruvate reductase, glyoxylate reductase
      and D-glycerate dehydrogenase (EC 1.1.1.79, EC 1.1.1.81), a homodimer of the
      D-isomer specific 2-hydroxyacid dehydrogenase family, most abundant in liver,
      whose deficiency causes primary hyperoxaluria type 2.
    supporting_text: hydroxypyruvate to D-glycerate, glyoxylate to glycolate
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Curated UniProt record; primary source for FUNCTION, catalytic
      activities, subunit, family, tissue specificity, and disease.