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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0030267 glyoxylate reductase (NADPH) activity | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:16756993 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. file:human/GRHPR/GRHPR-uniprot.txt hydroxypyruvate to D-glycerate, glyoxylate to glycolate |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:16756993 plays a critical role in the removal of the metabolic by-product glyoxylate from within the liver |
| GO:0008465 hydroxypyruvate reductase (NADH) activity | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: file:human/GRHPR/GRHPR-uniprot.txt hydroxypyruvate to D-glycerate, glyoxylate to glycolate PMID:10484776 verified that it encoded an enzyme with hydroxy-pyruvate reductase, glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities |
| GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor | IEA GO_REF:0000002 | ACCEPT | 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. 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. Supporting Evidence: file:human/GRHPR/GRHPR-uniprot.txt Belongs to the D-isomer specific 2-hydroxyacid |
| GO:0016618 hydroxypyruvate reductase [NAD(P)H] activity | IEA GO_REF:0000120 | ACCEPT | 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. Reason: Consistent with experimental IDA annotations to the same term; a correct electronic inference of a genuine GRHPR activity. Supporting Evidence: file:human/GRHPR/GRHPR-uniprot.txt hydroxypyruvate to D-glycerate, glyoxylate to glycolate |
| GO:0030267 glyoxylate reductase (NADPH) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (multiple-method IEA) assignment of glyoxylate reductase (NADPH) activity (EC 1.1.1.79, RHEA:10992), the core catalytic function of GRHPR. Reason: Duplicates the experimentally supported core MF; a correct electronic inference. Supporting Evidence: file:human/GRHPR/GRHPR-uniprot.txt hydroxypyruvate to D-glycerate, glyoxylate to glycolate |
| GO:0051287 NAD binding | IEA GO_REF:0000120 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/GRHPR/GRHPR-uniprot.txt Belongs to the D-isomer specific 2-hydroxyacid |
| GO:0106345 glyoxylate reductase activity | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning assignment of the general glyoxylate reductase activity term (cofactor-agnostic parent of the NADPH-specific term). 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. Supporting Evidence: PMID:10484776 verified that it encoded an enzyme with hydroxy-pyruvate reductase, glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities |
| GO:0120509 hydroxypyruvate reductase (NADPH) activity | IEA GO_REF:0000116 | ACCEPT | Summary: RHEA-based automated assignment (RHEA:18657) of hydroxypyruvate reductase (NADPH) activity, i.e. NADPH-dependent reduction of 3-hydroxypyruvate to (R)-glycerate. Reason: Matches an experimentally supported activity (see EXP/IDA annotations to the same term) and the UniProt catalytic-activity record. Correct electronic inference. Supporting Evidence: file:human/GRHPR/GRHPR-uniprot.txt hydroxypyruvate to D-glycerate, glyoxylate to glycolate |
| GO:0005515 protein binding | IPI PMID:23599041 Glyoxalate reductase/hydroxypyruvate reductase interacts wit... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:23599041 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 |
| GO:0008465 hydroxypyruvate reductase (NADH) activity | IEA GO_REF:0000120 | ACCEPT | 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. Reason: Correct electronic inference of a genuine GRHPR activity, consistent with the experimentally supported reduction of hydroxypyruvate to D-glycerate. Supporting Evidence: file:human/GRHPR/GRHPR-uniprot.txt hydroxypyruvate to D-glycerate, glyoxylate to glycolate |
| GO:0031406 carboxylic acid binding | IEA GO_REF:0000107 | KEEP AS NON CORE | 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. Reason: Substrate binding is a molecular detail entailed by the catalytic activity rather than an independent core function; retain as non-core supporting detail. Supporting Evidence: PMID:16756993 the relationship of substrate and catalytic residues within the active site |
| GO:0043648 dicarboxylic acid metabolic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:16756993 plays a critical role in the removal of the metabolic by-product glyoxylate from within the liver |
| GO:0050661 NADP binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl orthology-based (IEA) assignment of NADP binding, consistent with the crystallographically defined NADP(H) cofactor site of GRHPR. 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. Supporting Evidence: PMID:16756993 one subunit forms a ternary (enzyme+NADPH+reduced substrate) complex, and the other a binary (enzyme+NADPH) form |
| GO:0030267 glyoxylate reductase (NADPH) activity | TAS Reactome:R-HSA-389826 | ACCEPT | Summary: Reactome TAS annotation of glyoxylate reductase (NADPH) activity for the reaction glyoxylate + NADPH + H+ => glycolate + NADP+, the enzyme's core catalytic step. Reason: This is the defining reaction of GRHPR and is experimentally established; the Reactome traceable-author-statement annotation is appropriate. Supporting Evidence: Reactome:R-HSA-389826 Peroxisomal GRHPR catalyzes the reaction of glyoxylate and NADPH + H+ to form glycolate and NADP+. |
| GO:0120509 hydroxypyruvate reductase (NADPH) activity | EXP PMID:10484776 The gene encoding hydroxypyruvate reductase (GRHPR) is mutat... | ACCEPT | 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. Reason: Directly supported by expression assays of the human enzyme; a core catalytic activity of GRHPR. Supporting Evidence: PMID:10484776 verified that it encoded an enzyme with hydroxy-pyruvate reductase, glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities |
| GO:0120509 hydroxypyruvate reductase (NADPH) activity | EXP PMID:10524214 Identification and expression of a cDNA for human hydroxypyr... | ACCEPT | 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. Reason: Directly supported by expression of the human cDNA; a core catalytic activity of GRHPR. Supporting Evidence: PMID:10524214 a human liver cDNA encoding a 40-kDa protein with glyoxylate and hydroxypyruvate reductase activities |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:16756993 plays a critical role in the removal of the metabolic by-product glyoxylate from within the liver |
| GO:0046487 glyoxylate metabolic process | IDA PMID:10484776 The gene encoding hydroxypyruvate reductase (GRHPR) is mutat... | ACCEPT | 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. Reason: This is the core biological process for GRHPR, experimentally supported and consistent with the PH2 disease phenotype of glyoxylate/oxalate accumulation. Supporting Evidence: PMID:10484776 the reduction of glyoxylate to glycolate PMID:16756993 plays a critical role in the removal of the metabolic by-product glyoxylate from within the liver |
| GO:1902494 catalytic complex | IDA PMID:16756993 Structural basis of substrate specificity in human glyoxylat... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:16756993 A tryptophan residue (Trp141) from the neighbouring subunit of the dimer is projected into the active site region |
| GO:0016618 hydroxypyruvate reductase [NAD(P)H] activity | IDA PMID:10524214 Identification and expression of a cDNA for human hydroxypyr... | ACCEPT | 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. Reason: Directly demonstrated core catalytic activity of GRHPR with NAD(P)H as cofactor. Supporting Evidence: PMID:10524214 a human liver cDNA encoding a 40-kDa protein with glyoxylate and hydroxypyruvate reductase activities |
| GO:0030267 glyoxylate reductase (NADPH) activity | IDA PMID:10524214 Identification and expression of a cDNA for human hydroxypyr... | ACCEPT | Summary: IDA annotation of glyoxylate reductase (NADPH) activity from expression of the human liver cDNA. This is the core catalytic function of GRHPR. Reason: Directly demonstrated core catalytic activity; the defining reaction of the enzyme. Supporting Evidence: PMID:10524214 a human liver cDNA encoding a 40-kDa protein with glyoxylate and hydroxypyruvate reductase activities |
| GO:0046487 glyoxylate metabolic process | IDA PMID:10524214 Identification and expression of a cDNA for human hydroxypyr... | ACCEPT | Summary: IDA annotation to glyoxylate metabolic process, based on demonstration that the cloned human enzyme carries glyoxylate reductase activity that reduces glyoxylate to glycolate. Reason: Core biological process for GRHPR, experimentally supported; duplicates the well-founded glyoxylate metabolism annotation. Supporting Evidence: PMID:10524214 a human liver cDNA encoding a 40-kDa protein with glyoxylate and hydroxypyruvate reductase activities |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:16756993 plays a critical role in the removal of the metabolic by-product glyoxylate from within the liver |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | MARK AS OVER ANNOTATED | Summary: High-throughput direct-assay detection of GRHPR in urinary exosome proteomics/phosphoproteomics, duplicating the exosome catalog localization. Reason: As above, exosome presence is a proteomic-inventory finding rather than a functional extracellular site of action for this cytosolic enzyme. Supporting Evidence: PMID:16756993 plays a critical role in the removal of the metabolic by-product glyoxylate from within the liver |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | MARK AS OVER ANNOTATED | Summary: High-throughput direct-assay detection of GRHPR in B-cell exosome proteomics, duplicating the exosome catalog localization. Reason: As above, exosome detection reflects a proteomic inventory, not a functional extracellular localization of this cytosolic enzyme. Supporting Evidence: PMID:16756993 plays a critical role in the removal of the metabolic by-product glyoxylate from within the liver |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-389826 | KEEP AS NON CORE | 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. 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. Supporting Evidence: Reactome:R-HSA-389826 Peroxisomal GRHPR catalyzes the reaction of glyoxylate and NADPH + H+ to form glycolate and NADP+. |
| GO:0016618 hydroxypyruvate reductase [NAD(P)H] activity | IDA PMID:17510093 A novel mutation in the GRHPR gene in a Japanese patient wit... | ACCEPT | 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. 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. Supporting Evidence: file:human/GRHPR/GRHPR-uniprot.txt hydroxypyruvate to D-glycerate, glyoxylate to glycolate |
| GO:0042803 protein homodimerization activity | IDA PMID:16756993 Structural basis of substrate specificity in human glyoxylat... | ACCEPT | 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. Reason: The functional enzyme is an obligate homodimer, with the neighbouring subunit contributing to substrate specificity; homodimerization is a genuine, well-supported molecular activity. Supporting Evidence: PMID:16756993 A tryptophan residue (Trp141) from the neighbouring subunit of the dimer is projected into the active site region file:human/GRHPR/GRHPR-uniprot.txt Homodimer |
| GO:0070402 NADPH binding | IDA PMID:16756993 Structural basis of substrate specificity in human glyoxylat... | KEEP AS NON CORE | Summary: IDA annotation of NADPH binding from the crystal structure, which captured binary (enzyme+NADPH) and ternary (enzyme+NADPH+reduced substrate) complexes. 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. Supporting Evidence: PMID:16756993 one subunit forms a ternary (enzyme+NADPH+reduced substrate) complex, and the other a binary (enzyme+NADPH) form |
| GO:0005737 cytoplasm | IDA GO_REF:0000054 | ACCEPT | Summary: IDA localization to the cytoplasm from imaging of expressed fusion proteins in living cells (LIFEdb), consistent with GRHPR being a soluble cytosolic enzyme. 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. Supporting Evidence: file:human/GRHPR/GRHPR-uniprot.txt Most abundantly expressed in the liver |
| GO:0008465 hydroxypyruvate reductase (NADH) activity | IDA PMID:10484776 The gene encoding hydroxypyruvate reductase (GRHPR) is mutat... | ACCEPT | 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. Reason: Directly demonstrated activity of the human enzyme; supports the core hydroxypyruvate/glycerate branch of GRHPR function. Supporting Evidence: PMID:10484776 verified that it encoded an enzyme with hydroxy-pyruvate reductase, glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities |
| GO:0016618 hydroxypyruvate reductase [NAD(P)H] activity | IDA PMID:10484776 The gene encoding hydroxypyruvate reductase (GRHPR) is mutat... | ACCEPT | Summary: IDA annotation of hydroxypyruvate reductase [NAD(P)H] activity (EC 1.1.1.81) from expression of the human GRHPR cDNA. Reason: Directly demonstrated core catalytic activity of GRHPR with NAD(P)H. Supporting Evidence: PMID:10484776 verified that it encoded an enzyme with hydroxy-pyruvate reductase, glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities |
| GO:0030267 glyoxylate reductase (NADPH) activity | IDA PMID:10484776 The gene encoding hydroxypyruvate reductase (GRHPR) is mutat... | ACCEPT | 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. Reason: Directly demonstrated core catalytic activity; the defining reaction of GRHPR and the basis of its role in limiting oxalate synthesis. Supporting Evidence: PMID:10484776 verified that it encoded an enzyme with hydroxy-pyruvate reductase, glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities |
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