id: Q16851
gene_symbol: UGP2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  UGP2 is the human UDP-glucose pyrophosphorylase (UTP:glucose-1-phosphate
  uridylyltransferase, EC 2.7.7.9), a cytosolic enzyme that reversibly converts
  glucose-1-phosphate plus UTP into UDP-glucose plus diphosphate
  (pyrophosphate). It is the only known mammalian enzyme that produces
  UDP-glucose, the universal activated glucosyl donor. UDP-glucose is the direct
  precursor for glycogen synthesis (via glycogenin/glycogen synthase) and also
  feeds protein and lipid glycosylation, UDP-glucuronic acid formation
  (glucuronidation and glycosaminoglycan/proteoglycan synthesis), and galactose
  (Leloir) metabolism. The enzyme is a magnesium-dependent homooctamer of the
  UDPGP type 1 family whose activity is modulated by a "latch loop" and by the
  octamerization state. UGP2 is broadly expressed, with high levels in liver and
  brain, and exists as two alternatively spliced isoforms differing in their
  first exon. Bi-allelic loss of the brain-relevant short isoform (an
  isoform-specific start-loss variant) causes developmental and epileptic
  encephalopathy 83 (DEE83), an autosomal recessive early-onset epileptic
  encephalopathy; complete loss in all cells is embryonic lethal.
alternative_products:
- name: 1 (Muscle-II {ECO:0000303|PubMed:8631325}, long)
  id: Q16851-1
- name: 2 (Muscle-I {ECO:0000303|PubMed:8631325}, short)
  id: Q16851-2
  sequence_note: VSP_012834
existing_annotations:
- term:
    id: GO:0003983
    label: UTP:glucose-1-phosphate uridylyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Core, well-supported molecular function. UGP2 is the UTP:glucose-1-phosphate
      uridylyltransferase (EC 2.7.7.9) that reversibly forms UDP-glucose from
      glucose-1-phosphate and UTP. The IBA phylogenetic inference is fully
      concordant with direct human biochemical/enzymatic evidence.
    action: ACCEPT
    reason: >-
      This is the defining molecular function of UGP2, confirmed by human enzyme
      assays and structural studies and consistent across orthologs.
    supported_by:
    - reference_id: PMID:31820119
      supporting_text: >-
        UGP2 is an essential octameric enzyme in nucleotide sugar metabolism [38, 39,
        121], as it is the only known enzyme capable of catalyzing the conversion of
        glucose-1-phosphate to UDP-glucose
    - reference_id: PMID:8631325
      supporting_text: >-
        UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP
        plus Glc1P and UDP-Glc plus MgPPi.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      UGP2 is a cytosolic enzyme. Phylogenetic (IBA) cytoplasmic localization is
      consistent with human experimental localization and with the Reactome
      cytosol assignment.
    action: ACCEPT
    reason: >-
      Cytoplasmic/cytosolic localization is well established; the more precise term
      cytosol (GO:0005829) is captured by a separate annotation and used in
      core_functions.
    supported_by:
    - reference_id: PMID:31820119
      supporting_text: >-
        immunocytochemistry confirmed a similar subcellular localization of UGP2 in
        mutant and wild-type cells
    - reference_id: file:human/UGP2/UGP2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0006011
    label: UDP-alpha-D-glucose metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Core biological process. As the enzyme that produces UDP-glucose, UGP2 is
      directly involved in UDP-alpha-D-glucose metabolism. IBA inference matches
      direct human evidence.
    action: ACCEPT
    reason: >-
      Directly follows from the catalytic activity; UDP-glucose is the product of
      the UGP2 reaction.
    supported_by:
    - reference_id: PMID:34330832
      supporting_text: >-
        The use of glucose in these pathways depends on its activation to uridine
        diphosphate (UDP)-glucose catalyzed by UDP-glucose pyrophosphorylase 2 (UGP2),
        the only enzyme capable of converting glucose 1-phosphate to UDP-glucose in
        mammalian cells (6).
- term:
    id: GO:0005977
    label: glycogen metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      UDP-glucose produced by UGP2 is the direct precursor for glycogen. UGP2 thus
      participates in glycogen metabolism; loss of UGP2 reduces cellular glycogen.
    action: ACCEPT
    reason: >-
      Supported by both the biochemistry (UDP-glucose is the glycogen synthase
      substrate) and by functional loss-of-UGP2 experiments showing decreased
      glycogen. The more specific child term glycogen biosynthetic process is also
      annotated.
    supported_by:
    - reference_id: PMID:31820119
      supporting_text: >-
        UDP-glucose is a crucial precursor for the production of glycogen by glycogen
        synthase (GYS)
    - reference_id: PMID:34330832
      supporting_text: >-
        An important cellular process that utilizes UDP-glucose as a direct precursor
        is glycogen synthesis (18).
- term:
    id: GO:0003983
    label: UTP:glucose-1-phosphate uridylyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assignment of the core catalytic activity, mapped from ARBA/EC
      2.7.7.9/RHEA:19889. Redundant with, and confirmed by, the experimental IDA/IMP
      annotations.
    action: ACCEPT
    reason: >-
      Correct and precise mapping of the enzyme's molecular function.
    supported_by:
    - reference_id: file:human/UGP2/UGP2-uniprot.txt
      supporting_text: >-
        EC=2.7.7.9
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic localization derived from the UniProt Subcellular Location
      (SL-0086, Cytoplasm). Concordant with experimental data.
    action: ACCEPT
    reason: >-
      Correct localization; UGP2 is a soluble cytosolic enzyme.
    supported_by:
    - reference_id: file:human/UGP2/UGP2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0006011
    label: UDP-alpha-D-glucose metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO mapping (IPR016267, UDPGP transferase) to UDP-alpha-D-glucose
      metabolic process. Correct and redundant with experimental annotations.
    action: ACCEPT
    reason: >-
      Domain-based inference matches the well-established process; UDP-glucose is the
      reaction product.
    supported_by:
    - reference_id: PMID:34330832
      supporting_text: >-
        UDP-glucose pyrophosphorylase 2 (UGP2), the enzyme that synthesizes uridine
        diphosphate (UDP)-glucose
- term:
    id: GO:0070569
    label: uridylyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Parent-level molecular function from InterPro domain IPR002618. The precise
      child term GO:0003983 (UTP:glucose-1-phosphate uridylyltransferase activity)
      is directly supported and should be preferred.
    action: MODIFY
    reason: >-
      "uridylyltransferase activity" is too general; UGP2's activity is specifically
      UTP:glucose-1-phosphate uridylyltransferase (EC 2.7.7.9). Replace with the
      more informative specific term.
    proposed_replacement_terms:
    - id: GO:0003983
      label: UTP:glucose-1-phosphate uridylyltransferase activity
    supported_by:
    - reference_id: PMID:8631325
      supporting_text: >-
        UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP
        plus Glc1P and UDP-Glc plus MgPPi.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: >-
      Binary interaction (with ARIH2, UniProtKB:O95376) from a large-scale
      yeast two-hybrid proteome map. "protein binding" is uninformative and does not
      describe a molecular function of the enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidelines, the generic protein binding term is not retained as a
      core function. The interaction may be genuine but does not add functional
      insight; the underlying IPI evidence is preserved.
    supported_by:
    - reference_id: PMID:16189514
      supporting_text: >-
        Towards a proteome-scale map of the human protein-protein interaction network.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17474147
  qualifier: enables
  review:
    summary: >-
      Interaction with GRB2 (UniProtKB:P62993) from an SH3-domain peptide-array
      screen. Uninformative generic binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding is not a core molecular function; retained only as
      supporting interaction evidence.
    supported_by:
    - reference_id: PMID:17474147
      supporting_text: >-
        Systematic identification of SH3 domain-mediated human protein-protein
        interactions by peptide array target screening.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: >-
      Binary interactions (GLRX3 O76003, ARIH2 O95376) from a human interactome map.
      Uninformative generic binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding is not retained as a core function; interaction
      evidence is preserved.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: >-
        A proteome-scale map of the human interactome network.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Binary interactions (ARIH2 O95376, PLEKHF2 Q9H8W4) from the HuRI reference
      interactome. Uninformative generic binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding is not retained as a core function; interaction
      evidence is preserved.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        A reference map of the human binary protein interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: >-
      Interaction with KLF11 (UniProtKB:O14901) reported in a neurodegenerative-disease
      interactome mapping study. Uninformative generic binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding is not retained as a core function; interaction
      evidence is preserved.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: >-
        Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: >-
      Self-interaction (UGP2-UGP2, Q16851-Q16851). This is biologically meaningful:
      UGP2 functions as a homooctamer, so self-association is a real structural
      feature rather than an over-annotation.
    action: ACCEPT
    reason: >-
      Consistent with the crystallographic homooctamer; captures the obligate
      self-association underlying enzyme assembly and activity regulation. Treated as
      non-core relative to the catalytic function.
    supported_by:
    - reference_id: PMID:22132858
      supporting_text: >-
        shown to form octamers through end-to-end and side-by-side interactions
    - reference_id: file:human/UGP2/UGP2-uniprot.txt
      supporting_text: "Homooctamer"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  qualifier: enables
  review:
    summary: >-
      UGP2-UGP2 self-interaction detected in a human liver protein interaction network
      study; consistent with homooctamer formation.
    action: ACCEPT
    reason: >-
      Real self-association underlying the octameric quaternary structure.
    supported_by:
    - reference_id: PMID:22132858
      supporting_text: >-
        shown to form octamers through end-to-end and side-by-side interactions
    - reference_id: file:human/UGP2/UGP2-uniprot.txt
      supporting_text: "Homooctamer"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: >-
      UGP2-UGP2 self-interaction from a human interactome map; consistent with the
      homooctameric assembly.
    action: ACCEPT
    reason: >-
      Supports the obligate self-association of the enzyme.
    supported_by:
    - reference_id: PMID:22132858
      supporting_text: >-
        shown to form octamers through end-to-end and side-by-side interactions
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      UGP2-UGP2 self-interaction from the HuRI reference interactome; consistent with
      homooctamer formation.
    action: ACCEPT
    reason: >-
      Supports the obligate self-association of the enzyme.
    supported_by:
    - reference_id: PMID:22132858
      supporting_text: >-
        shown to form octamers through end-to-end and side-by-side interactions
- term:
    id: GO:0005978
    label: glycogen biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation to glycogen biosynthesis (UniPathway UPA00164). UGP2
      provides UDP-glucose, the substrate for glycogen synthase, and is UniProt's
      assigned enzyme for the "glycogen biosynthesis" pathway.
    action: ACCEPT
    reason: >-
      Correct; concordant with experimental IMP annotations and the UniProt pathway
      assignment.
    supported_by:
    - reference_id: file:human/UGP2/UGP2-uniprot.txt
      supporting_text: "Glycan biosynthesis; glycogen biosynthesis"
    - reference_id: PMID:31820119
      supporting_text: >-
        UDP-glucose is a crucial precursor for the production of glycogen by glycogen
        synthase (GYS)
- term:
    id: GO:0051748
    label: UTP-monosaccharide-1-phosphate uridylyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Broader parent activity transferred by orthology from mouse (Q91ZJ5). UGP2's
      characterized activity is specifically the glucose-1-phosphate form (GO:0003983);
      this parent term is not wrong but is less precise.
    action: KEEP_AS_NON_CORE
    reason: >-
      The term is a correct superclass (glucose-1-phosphate is a monosaccharide
      1-phosphate) but the specific GO:0003983 term is the appropriate core function.
      Retained as a valid but non-core broader annotation rather than removed.
    supported_by:
    - reference_id: PMID:8631325
      supporting_text: >-
        UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP
        plus Glc1P and UDP-Glc plus MgPPi.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:31820119
  qualifier: located_in
  review:
    summary: >-
      Experimental cytoplasmic localization of UGP2 shown by immunocytochemistry and
      immunohistochemistry in the DEE83 study.
    action: ACCEPT
    reason: >-
      Direct experimental support for cytoplasmic localization.
    supported_by:
    - reference_id: PMID:31820119
      supporting_text: >-
        immunocytochemistry confirmed a similar subcellular localization of UGP2 in
        mutant and wild-type cells
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:8354390
  qualifier: located_in
  review:
    summary: >-
      Cytoplasmic localization supported by the founding human liver UGP2 cDNA/enzyme
      characterization (a cytosolic pyrophosphorylase).
    action: ACCEPT
    reason: >-
      Consistent with the enzyme being a soluble cytosolic protein; supported by
      UniProt subcellular location and other experimental data.
    supported_by:
    - reference_id: file:human/UGP2/UGP2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0003983
    label: UTP:glucose-1-phosphate uridylyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:22132858
  qualifier: enables
  review:
    summary: >-
      Direct assay of the human enzyme in the crystal-structure study, which measured
      UGPase activity and its dependence on octamerization and the latch loop.
    action: ACCEPT
    reason: >-
      Direct experimental confirmation of the core catalytic activity.
    supported_by:
    - reference_id: PMID:22132858
      supporting_text: >-
        both dissociation of octamers and mutations of the latch loop can significantly
        affect the UGPase activity
- term:
    id: GO:0006011
    label: UDP-alpha-D-glucose metabolic process
  evidence_type: IDA
  original_reference_id: PMID:22132858
  qualifier: involved_in
  review:
    summary: >-
      The enzyme reversibly forms UDP-glucose, placing it directly in UDP-alpha-D-glucose
      metabolism; demonstrated by direct activity assays.
    action: ACCEPT
    reason: >-
      Follows directly from the measured catalytic activity producing UDP-glucose.
    supported_by:
    - reference_id: PMID:22132858
      supporting_text: >-
        UGPase reversibly catalyses the formation of UDP-glucose and is critical in
        carbohydrate metabolism.
- term:
    id: GO:0003983
    label: UTP:glucose-1-phosphate uridylyltransferase activity
  evidence_type: IMP
  original_reference_id: PMID:31820119
  qualifier: enables
  review:
    summary: >-
      Enzyme activity assessed in patient/engineered cells: UGP2 activity (UDP-glucose
      formation from glucose-1-phosphate and UTP) was measured and shown to depend on
      UGP2 levels.
    action: ACCEPT
    reason: >-
      Human loss-of-function/mutation evidence directly ties UGP2 to UTP:glucose-1-phosphate
      uridylyltransferase activity.
    supported_by:
    - reference_id: PMID:31820119
      supporting_text: >-
        the only known enzyme capable of catalyzing the conversion of
        glucose-1-phosphate to UDP-glucose
- term:
    id: GO:0005978
    label: glycogen biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:34330832
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      Knockdown of UGP2 in pancreatic cancer cells decreased intracellular UDP-glucose
      and glycogen, demonstrating UGP2's role upstream of glycogen biosynthesis.
    action: ACCEPT
    reason: >-
      Direct loss-of-function evidence linking UGP2 to glycogen production; UGP2 supplies
      the UDP-glucose substrate for glycogen synthase.
    supported_by:
    - reference_id: PMID:34330832
      supporting_text: >-
        we found that knockdown of YAP, which decreases UGP2 expression, led to a
        decrease in intracellular UDP-glucose and glycogen levels in PDAC cells
    - reference_id: PMID:34330832
      supporting_text: >-
        An important cellular process that utilizes UDP-glucose as a direct precursor
        is glycogen synthesis (18).
- term:
    id: GO:0003983
    label: UTP:glucose-1-phosphate uridylyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:31820119
  qualifier: enables
  review:
    summary: >-
      Direct measurement of UGP2 enzymatic activity (UDP-glucose production) in the
      DEE83 study using a modified GALT assay with glucose-1-phosphate and UTP substrates.
    action: ACCEPT
    reason: >-
      Direct experimental confirmation of the core catalytic activity in human cells.
    supported_by:
    - reference_id: PMID:31820119
      supporting_text: >-
        the only known enzyme capable of catalyzing the conversion of
        glucose-1-phosphate to UDP-glucose
- term:
    id: GO:0005978
    label: glycogen biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:31820119
  qualifier: involved_in
  review:
    summary: >-
      Loss of UGP2 in neural stem cells reduced UDP-glucose synthesis and impaired
      glycogen production (reduced PAS/glycogen staining under hypoxia).
    action: ACCEPT
    reason: >-
      Direct loss-of-function evidence linking UGP2 to glycogen biosynthesis.
    supported_by:
    - reference_id: PMID:31820119
      supporting_text: >-
        reduced synthesis of UDP-glucose, leading to defects in glycogen synthesis and
        protein glycosylation and to the activation of UPR response.
- term:
    id: GO:0006011
    label: UDP-alpha-D-glucose metabolic process
  evidence_type: IMP
  original_reference_id: PMID:31820119
  qualifier: involved_in
  review:
    summary: >-
      Loss/reduction of UGP2 reduced cellular UDP-glucose, directly implicating UGP2
      in UDP-alpha-D-glucose metabolism in human cells.
    action: ACCEPT
    reason: >-
      Direct loss-of-function evidence for UGP2's role in producing UDP-glucose.
    supported_by:
    - reference_id: PMID:31820119
      supporting_text: >-
        reduced synthesis of UDP-glucose, leading to defects in glycogen synthesis and
        protein glycosylation and to the activation of UPR response.
- term:
    id: GO:0007420
    label: brain development
  evidence_type: IMP
  original_reference_id: PMID:31820119
  qualifier: involved_in
  review:
    summary: >-
      Brain-relevant loss of the short UGP2 isoform causes DEE83, and UGP2 is expressed
      throughout the developing human brain; zebrafish ugp2a/ugp2b double mutants show
      metabolic and behavioral phenotypes recapitulating a brain-development defect.
      This reflects the developmental/disease consequence of losing the enzyme in brain
      tissue rather than a distinct molecular role of UGP2 in a developmental pathway.
    action: KEEP_AS_NON_CORE
    reason: >-
      The link to brain development is real and clinically important but is downstream of
      the core metabolic function (UDP-glucose supply); retained as a non-core,
      tissue/disease-relevance annotation.
    supported_by:
    - reference_id: PMID:31820119
      supporting_text: >-
        UGP2 can be detected in a broad variety of cell types during brain development
    - reference_id: PMID:31820119
      supporting_text: >-
        a novel form of a severe DEE syndrome is caused by the brain-relevant loss of the
        essential gene UGP2
- term:
    id: GO:0006011
    label: UDP-alpha-D-glucose metabolic process
  evidence_type: IDA
  original_reference_id: PMID:8354390
  qualifier: involved_in
  review:
    summary: >-
      The founding human liver UGP2 cDNA was cloned by complementation of a bacterial
      galU (UDP-glucose pyrophosphorylase) mutant, directly demonstrating UDP-glucose-
      producing activity.
    action: ACCEPT
    reason: >-
      Functional complementation establishes UDP-glucose pyrophosphorylase activity and
      thus UDP-alpha-D-glucose metabolism.
    supported_by:
    - reference_id: PMID:8354390
      supporting_text: >-
        A human liver cDNA clone which encodes the UDP-glucose pyrophosphorylase was
        isolated by complementation of a bacterial galU mutant.
- term:
    id: GO:0006011
    label: UDP-alpha-D-glucose metabolic process
  evidence_type: IDA
  original_reference_id: PMID:8631325
  qualifier: involved_in
  review:
    summary: >-
      Recombinant human muscle/liver UGP2 enzymes were characterized kinetically for the
      interconversion of MgUTP + Glc1P and UDP-Glc + MgPPi, directly demonstrating
      UDP-alpha-D-glucose metabolism.
    action: ACCEPT
    reason: >-
      Direct biochemical characterization of the reaction producing/consuming UDP-glucose.
    supported_by:
    - reference_id: PMID:8631325
      supporting_text: >-
        UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP
        plus Glc1P and UDP-Glc plus MgPPi.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: >-
      Detection in exosome proteomes (prostatic-secretion exosomes) by high-throughput
      mass spectrometry. UGP2 is an abundant cytosolic enzyme frequently found as a
      passenger in such datasets; this is not a functional localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-throughput proteomic detection in exosomes reflects abundance/contamination
      rather than a biologically meaningful extracellular site of action for a cytosolic
      UDP-glucose pyrophosphorylase.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: >-
        In-depth proteomic analyses of exosomes isolated from expressed prostatic
        secretions in urine.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  qualifier: located_in
  review:
    summary: >-
      Detection in a sperm-nucleus proteome by high-throughput mass spectrometry. UGP2 is
      a cytosolic enzyme; nuclear detection in a single specialized proteomic dataset most
      likely reflects abundance/co-purification rather than a functional nuclear role.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      No functional evidence for a nuclear role; the HDA signal is consistent with an
      abundant cytosolic protein appearing in a bulk proteome and should not be treated as
      a site of action.
    supported_by:
    - reference_id: PMID:21630459
      supporting_text: >-
        Proteomic characterization of the human sperm nucleus.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: >-
      Detection in urinary-exosome proteomics by mass spectrometry; a passenger-detection
      of an abundant cytosolic enzyme, not a functional localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-throughput exosome proteomics does not establish a functional extracellular
      site for this cytosolic enzyme.
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: >-
        Large-scale proteomics and phosphoproteomics of urinary exosomes.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  qualifier: located_in
  review:
    summary: >-
      Detection in B-cell exosome proteomics; again a mass-spectrometry passenger detection
      of an abundant cytosolic protein rather than a functional localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Not a biologically meaningful site of action for UGP2; reflects proteomic abundance.
    supported_by:
    - reference_id: PMID:20458337
      supporting_text: >-
        MHC class II-associated proteins in B-cell exosomes and potential functional
        implications for exosome biogenesis.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70286
  qualifier: located_in
  review:
    summary: >-
      Reactome asserts cytosolic UGP2 catalyzing UTP + glucose-1-phosphate to UDP-glucose
      + pyrophosphate. Cytosol is the precise and correct localization for this enzyme.
    action: ACCEPT
    reason: >-
      Authoritative traceable assignment; cytosol (GO:0005829) is the specific localization
      used in core_functions.
    supported_by:
    - reference_id: Reactome:R-HSA-70286
      supporting_text: >-
        Cytosolic UDP-glucose pyrophosphorylase 2 (UGP2) catalyzes the reaction of UTP and
        glucose 1-phosphate to form UDP glucose and pyrophosphate
- term:
    id: GO:0003983
    label: UTP:glucose-1-phosphate uridylyltransferase activity
  evidence_type: TAS
  original_reference_id: PMID:8354390
  qualifier: enables
  review:
    summary: >-
      Traceable assertion of UDP-glucose pyrophosphorylase activity from the founding human
      liver cDNA cloning by galU complementation.
    action: ACCEPT
    reason: >-
      Correct core molecular function with traceable experimental support.
    supported_by:
    - reference_id: PMID:8354390
      supporting_text: >-
        A human liver cDNA clone which encodes the UDP-glucose pyrophosphorylase was
        isolated by complementation of a bacterial galU mutant.
- term:
    id: GO:0003983
    label: UTP:glucose-1-phosphate uridylyltransferase activity
  evidence_type: TAS
  original_reference_id: PMID:8631325
  qualifier: enables
  review:
    summary: >-
      Traceable assertion of the EC 2.7.7.9 activity from kinetic characterization of
      recombinant human UGP2 enzymes.
    action: ACCEPT
    reason: >-
      Correct core molecular function with traceable biochemical support.
    supported_by:
    - reference_id: PMID:8631325
      supporting_text: >-
        UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP
        plus Glc1P and UDP-Glc plus MgPPi.
- term:
    id: GO:0006011
    label: UDP-alpha-D-glucose metabolic process
  evidence_type: TAS
  original_reference_id: PMID:8631325
  qualifier: involved_in
  review:
    summary: >-
      Traceable assertion that UGP2 participates in UDP-glucose metabolism, from kinetic
      studies of the recombinant enzyme.
    action: ACCEPT
    reason: >-
      UDP-glucose is the direct product of the characterized reaction.
    supported_by:
    - reference_id: PMID:8631325
      supporting_text: >-
        UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP
        plus Glc1P and UDP-Glc plus MgPPi.
core_functions:
- description: >-
    UGP2 is the human UDP-glucose pyrophosphorylase (UTP:glucose-1-phosphate
    uridylyltransferase, EC 2.7.7.9): a cytosolic, Mg2+-dependent homooctamer that
    reversibly converts glucose-1-phosphate + UTP into UDP-glucose + diphosphate. It is
    the sole mammalian source of UDP-glucose, the activated glucosyl donor.
  molecular_function:
    id: GO:0003983
    label: UTP:glucose-1-phosphate uridylyltransferase activity
  directly_involved_in:
  - id: GO:0006011
    label: UDP-alpha-D-glucose metabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:31820119
    supporting_text: >-
      the only known enzyme capable of catalyzing the conversion of glucose-1-phosphate
      to UDP-glucose
  - reference_id: PMID:8631325
    supporting_text: >-
      UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus
      Glc1P and UDP-Glc plus MgPPi.
- description: >-
    By supplying UDP-glucose, UGP2 provides the direct precursor for glycogen synthesis
    (via glycogen synthase); loss of UGP2 depletes UDP-glucose and reduces cellular
    glycogen.
  molecular_function:
    id: GO:0003983
    label: UTP:glucose-1-phosphate uridylyltransferase activity
  directly_involved_in:
  - id: GO:0005978
    label: glycogen biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:34330832
    supporting_text: >-
      An important cellular process that utilizes UDP-glucose as a direct precursor is
      glycogen synthesis (18).
  - reference_id: PMID:31820119
    supporting_text: >-
      UDP-glucose is a crucial precursor for the production of glycogen by glycogen
      synthase (GYS)
proposed_new_terms: []
suggested_questions:
- question: >-
    Beyond glycogen synthesis, how quantitatively important is UGP2-derived UDP-glucose
    for protein N-glycosylation and UDP-glucuronic acid (glucuronidation) flux in
    different human tissues?
- question: >-
    Does the octamerization/latch-loop regulation of UGP2 activity respond to
    physiological signals (e.g. metabolic or redox state) in vivo?
suggested_experiments:
- description: >-
    Tissue-specific conditional Ugp2 knockout (or isoform-specific short-isoform
    ablation) in mouse brain to model DEE83 and dissect the metabolic basis of the
    neurological phenotype.
- description: >-
    Metabolic flux analysis (13C-glucose) in UGP2-depleted human cells to quantify
    partitioning of UDP-glucose between glycogen, glycosylation, and glucuronidation
    pathways.
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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale Y2H interactome; source of an ARIH2 binary interaction and a UGP2 self
      interaction. Supports generic and identical protein binding IPI evidence but not
      core function.
- id: PMID:17474147
  title: Systematic identification of SH3 domain-mediated human protein-protein interactions
    by peptide array target screening.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      SH3-domain peptide-array screen (GRB2 interaction). Uninformative generic protein
      binding for UGP2 function.
- 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; UGP2 detected as an abundant passenger, not a
      functional localization.
- 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: >-
      Exosome proteomics; passenger detection of an abundant cytosolic enzyme.
- id: PMID:21630459
  title: Proteomic characterization of the human sperm nucleus.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Sperm-nucleus proteome; nuclear detection of a cytosolic enzyme is most likely
      abundance/co-purification, not a functional nuclear role.
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Human liver interactome; source of a UGP2 self-interaction, consistent with the
      homooctamer.
- id: PMID:22132858
  title: The crystal structure of human UDP-glucose pyrophosphorylase reveals a latch
    effect that influences enzymatic activity.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Human UGP2 crystal structure; establishes the homooctamer and latch-loop regulation
      of enzymatic activity. Directly supports catalytic activity and identical protein
      binding.
- 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: >-
      Exosome proteomics; passenger detection, not a functional localization.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Human interactome map; provides binary interactions and a UGP2 self-interaction.
- id: PMID:31820119
  title: Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing
    that bi-allelic isoform-specific start-loss mutations of essential genes can cause
    genetic diseases.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Definitive disease/function study: establishes UGP2 as the only mammalian enzyme
      making UDP-glucose, its cytoplasmic localization, its role in glycogen synthesis and
      glycosylation, and causation of DEE83 by brain-relevant isoform loss.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI reference interactome; binary interactions and a UGP2 self-interaction.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Neurodegenerative-disease interactome (KLF11 interaction); generic protein binding,
      not core function.
- id: PMID:34330832
  title: UDP-glucose pyrophosphorylase 2, a regulator of glycogen synthesis and glycosylation,
    is critical for pancreatic cancer growth.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Loss-of-function in PDAC cells confirms UGP2 as the sole mammalian UDP-glucose
      producer feeding glycogen synthesis and N-glycosylation (e.g. EGFR).
- id: PMID:8354390
  title: Cloning of a human liver UDP-glucose pyrophosphorylase cDNA by complementation
    of the bacterial galU mutation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Founding cloning of human UGP2 by galU complementation; establishes UDP-glucose
      pyrophosphorylase activity and tissue expression.
- id: PMID:8631325
  title: Sequence differences between human muscle and liver cDNAs for UDPglucose
    pyrophosphorylase and kinetic properties of the recombinant enzymes expressed
    in Escherichia coli.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Kinetic characterization of recombinant human UGP2 isoforms; defines the EC 2.7.7.9
      reaction (MgUTP + Glc1P to UDP-Glc + MgPPi).
- id: Reactome:R-HSA-70286
  title: UTP + D-glucose 1-phosphate => pyrophosphate + UDP-glucose
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction placing cytosolic UGP2 as catalyst of UTP + glucose-1-phosphate
      to UDP-glucose + pyrophosphate.
- id: file:human/UGP2/UGP2-uniprot.txt
  title: UniProtKB entry Q16851 (UGPA_HUMAN)
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      UniProt record: function, EC 2.7.7.9 catalytic activity, cytoplasm subcellular
      location, homooctamer subunit, and glycogen biosynthesis pathway.