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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003983 UTP:glucose-1-phosphate uridylyltransferase activity | IBA GO_REF:0000033 | ACCEPT | 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. Reason: This is the defining molecular function of UGP2, confirmed by human enzyme assays and structural studies and consistent across orthologs. Supporting Evidence: PMID:31820119 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 PMID:8631325 UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: UGP2 is a cytosolic enzyme. Phylogenetic (IBA) cytoplasmic localization is consistent with human experimental localization and with the Reactome cytosol assignment. 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. Supporting Evidence: PMID:31820119 immunocytochemistry confirmed a similar subcellular localization of UGP2 in mutant and wild-type cells file:human/UGP2/UGP2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006011 UDP-alpha-D-glucose metabolic process | IBA GO_REF:0000033 | ACCEPT | 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. Reason: Directly follows from the catalytic activity; UDP-glucose is the product of the UGP2 reaction. Supporting Evidence: PMID:34330832 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). |
| GO:0005977 glycogen metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: UDP-glucose produced by UGP2 is the direct precursor for glycogen. UGP2 thus participates in glycogen metabolism; loss of UGP2 reduces cellular glycogen. 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. Supporting Evidence: PMID:31820119 UDP-glucose is a crucial precursor for the production of glycogen by glycogen synthase (GYS) PMID:34330832 An important cellular process that utilizes UDP-glucose as a direct precursor is glycogen synthesis (18). |
| GO:0003983 UTP:glucose-1-phosphate uridylyltransferase activity | IEA GO_REF:0000120 | ACCEPT | 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. Reason: Correct and precise mapping of the enzyme's molecular function. Supporting Evidence: file:human/UGP2/UGP2-uniprot.txt EC=2.7.7.9 |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic localization derived from the UniProt Subcellular Location (SL-0086, Cytoplasm). Concordant with experimental data. Reason: Correct localization; UGP2 is a soluble cytosolic enzyme. Supporting Evidence: file:human/UGP2/UGP2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006011 UDP-alpha-D-glucose metabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping (IPR016267, UDPGP transferase) to UDP-alpha-D-glucose metabolic process. Correct and redundant with experimental annotations. Reason: Domain-based inference matches the well-established process; UDP-glucose is the reaction product. Supporting Evidence: PMID:34330832 UDP-glucose pyrophosphorylase 2 (UGP2), the enzyme that synthesizes uridine diphosphate (UDP)-glucose |
| GO:0070569 uridylyltransferase activity | IEA GO_REF:0000002 | MODIFY | 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. 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 replacements: UTP:glucose-1-phosphate uridylyltransferase activity Supporting Evidence: PMID:8631325 UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi. |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network. |
| GO:0005515 protein binding | IPI PMID:17474147 Systematic identification of SH3 domain-mediated human prote... | MARK AS OVER ANNOTATED | Summary: Interaction with GRB2 (UniProtKB:P62993) from an SH3-domain peptide-array screen. Uninformative generic binding term. Reason: Generic protein binding is not a core molecular function; retained only as supporting interaction evidence. Supporting Evidence: PMID:17474147 Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Binary interactions (GLRX3 O76003, ARIH2 O95376) from a human interactome map. Uninformative generic binding term. Reason: Generic protein binding is not retained as a core function; interaction evidence is preserved. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Binary interactions (ARIH2 O95376, PLEKHF2 Q9H8W4) from the HuRI reference interactome. Uninformative generic binding term. Reason: Generic protein binding is not retained as a core function; interaction evidence is preserved. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: Interaction with KLF11 (UniProtKB:O14901) reported in a neurodegenerative-disease interactome mapping study. Uninformative generic binding term. Reason: Generic protein binding is not retained as a core function; interaction evidence is preserved. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins |
| GO:0042802 identical protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | ACCEPT | 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. 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. Supporting Evidence: PMID:22132858 shown to form octamers through end-to-end and side-by-side interactions file:human/UGP2/UGP2-uniprot.txt Homooctamer |
| GO:0042802 identical protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | ACCEPT | Summary: UGP2-UGP2 self-interaction detected in a human liver protein interaction network study; consistent with homooctamer formation. Reason: Real self-association underlying the octameric quaternary structure. Supporting Evidence: PMID:22132858 shown to form octamers through end-to-end and side-by-side interactions file:human/UGP2/UGP2-uniprot.txt Homooctamer |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | ACCEPT | Summary: UGP2-UGP2 self-interaction from a human interactome map; consistent with the homooctameric assembly. Reason: Supports the obligate self-association of the enzyme. Supporting Evidence: PMID:22132858 shown to form octamers through end-to-end and side-by-side interactions |
| GO:0042802 identical protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | ACCEPT | Summary: UGP2-UGP2 self-interaction from the HuRI reference interactome; consistent with homooctamer formation. Reason: Supports the obligate self-association of the enzyme. Supporting Evidence: PMID:22132858 shown to form octamers through end-to-end and side-by-side interactions |
| GO:0005978 glycogen biosynthetic process | IEA GO_REF:0000120 | ACCEPT | 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. Reason: Correct; concordant with experimental IMP annotations and the UniProt pathway assignment. Supporting Evidence: file:human/UGP2/UGP2-uniprot.txt Glycan biosynthesis; glycogen biosynthesis PMID:31820119 UDP-glucose is a crucial precursor for the production of glycogen by glycogen synthase (GYS) |
| GO:0051748 UTP-monosaccharide-1-phosphate uridylyltransferase activity | IEA GO_REF:0000107 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:8631325 UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi. |
| GO:0005737 cytoplasm | EXP PMID:31820119 Loss of UGP2 in brain leads to a severe epileptic encephalop... | ACCEPT | Summary: Experimental cytoplasmic localization of UGP2 shown by immunocytochemistry and immunohistochemistry in the DEE83 study. Reason: Direct experimental support for cytoplasmic localization. Supporting Evidence: PMID:31820119 immunocytochemistry confirmed a similar subcellular localization of UGP2 in mutant and wild-type cells |
| GO:0005737 cytoplasm | EXP PMID:8354390 Cloning of a human liver UDP-glucose pyrophosphorylase cDNA ... | ACCEPT | Summary: Cytoplasmic localization supported by the founding human liver UGP2 cDNA/enzyme characterization (a cytosolic pyrophosphorylase). Reason: Consistent with the enzyme being a soluble cytosolic protein; supported by UniProt subcellular location and other experimental data. Supporting Evidence: file:human/UGP2/UGP2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0003983 UTP:glucose-1-phosphate uridylyltransferase activity | IDA PMID:22132858 The crystal structure of human UDP-glucose pyrophosphorylase... | ACCEPT | 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. Reason: Direct experimental confirmation of the core catalytic activity. Supporting Evidence: PMID:22132858 both dissociation of octamers and mutations of the latch loop can significantly affect the UGPase activity |
| GO:0006011 UDP-alpha-D-glucose metabolic process | IDA PMID:22132858 The crystal structure of human UDP-glucose pyrophosphorylase... | ACCEPT | Summary: The enzyme reversibly forms UDP-glucose, placing it directly in UDP-alpha-D-glucose metabolism; demonstrated by direct activity assays. Reason: Follows directly from the measured catalytic activity producing UDP-glucose. Supporting Evidence: PMID:22132858 UGPase reversibly catalyses the formation of UDP-glucose and is critical in carbohydrate metabolism. |
| GO:0003983 UTP:glucose-1-phosphate uridylyltransferase activity | IMP PMID:31820119 Loss of UGP2 in brain leads to a severe epileptic encephalop... | ACCEPT | 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. Reason: Human loss-of-function/mutation evidence directly ties UGP2 to UTP:glucose-1-phosphate uridylyltransferase activity. Supporting Evidence: PMID:31820119 the only known enzyme capable of catalyzing the conversion of glucose-1-phosphate to UDP-glucose |
| GO:0005978 glycogen biosynthetic process | IMP PMID:34330832 UDP-glucose pyrophosphorylase 2, a regulator of glycogen syn... | ACCEPT | Summary: Knockdown of UGP2 in pancreatic cancer cells decreased intracellular UDP-glucose and glycogen, demonstrating UGP2's role upstream of glycogen biosynthesis. Reason: Direct loss-of-function evidence linking UGP2 to glycogen production; UGP2 supplies the UDP-glucose substrate for glycogen synthase. Supporting Evidence: PMID:34330832 we found that knockdown of YAP, which decreases UGP2 expression, led to a decrease in intracellular UDP-glucose and glycogen levels in PDAC cells PMID:34330832 An important cellular process that utilizes UDP-glucose as a direct precursor is glycogen synthesis (18). |
| GO:0003983 UTP:glucose-1-phosphate uridylyltransferase activity | IDA PMID:31820119 Loss of UGP2 in brain leads to a severe epileptic encephalop... | ACCEPT | 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. Reason: Direct experimental confirmation of the core catalytic activity in human cells. Supporting Evidence: PMID:31820119 the only known enzyme capable of catalyzing the conversion of glucose-1-phosphate to UDP-glucose |
| GO:0005978 glycogen biosynthetic process | IMP PMID:31820119 Loss of UGP2 in brain leads to a severe epileptic encephalop... | ACCEPT | Summary: Loss of UGP2 in neural stem cells reduced UDP-glucose synthesis and impaired glycogen production (reduced PAS/glycogen staining under hypoxia). Reason: Direct loss-of-function evidence linking UGP2 to glycogen biosynthesis. Supporting Evidence: PMID:31820119 reduced synthesis of UDP-glucose, leading to defects in glycogen synthesis and protein glycosylation and to the activation of UPR response. |
| GO:0006011 UDP-alpha-D-glucose metabolic process | IMP PMID:31820119 Loss of UGP2 in brain leads to a severe epileptic encephalop... | ACCEPT | Summary: Loss/reduction of UGP2 reduced cellular UDP-glucose, directly implicating UGP2 in UDP-alpha-D-glucose metabolism in human cells. Reason: Direct loss-of-function evidence for UGP2's role in producing UDP-glucose. Supporting Evidence: PMID:31820119 reduced synthesis of UDP-glucose, leading to defects in glycogen synthesis and protein glycosylation and to the activation of UPR response. |
| GO:0007420 brain development | IMP PMID:31820119 Loss of UGP2 in brain leads to a severe epileptic encephalop... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:31820119 UGP2 can be detected in a broad variety of cell types during brain development PMID:31820119 a novel form of a severe DEE syndrome is caused by the brain-relevant loss of the essential gene UGP2 |
| GO:0006011 UDP-alpha-D-glucose metabolic process | IDA PMID:8354390 Cloning of a human liver UDP-glucose pyrophosphorylase cDNA ... | ACCEPT | 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. Reason: Functional complementation establishes UDP-glucose pyrophosphorylase activity and thus UDP-alpha-D-glucose metabolism. Supporting Evidence: PMID:8354390 A human liver cDNA clone which encodes the UDP-glucose pyrophosphorylase was isolated by complementation of a bacterial galU mutant. |
| GO:0006011 UDP-alpha-D-glucose metabolic process | IDA PMID:8631325 Sequence differences between human muscle and liver cDNAs fo... | ACCEPT | 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. Reason: Direct biochemical characterization of the reaction producing/consuming UDP-glucose. Supporting Evidence: PMID:8631325 UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:23533145 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. |
| GO:0005634 nucleus | HDA PMID:21630459 Proteomic characterization of the human sperm nucleus. | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:21630459 Proteomic characterization of the human sperm nucleus. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | MARK AS OVER ANNOTATED | Summary: Detection in urinary-exosome proteomics by mass spectrometry; a passenger-detection of an abundant cytosolic enzyme, not a functional localization. Reason: High-throughput exosome proteomics does not establish a functional extracellular site for this cytosolic enzyme. Supporting Evidence: PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exosomes. |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | MARK AS OVER ANNOTATED | Summary: Detection in B-cell exosome proteomics; again a mass-spectrometry passenger detection of an abundant cytosolic protein rather than a functional localization. Reason: Not a biologically meaningful site of action for UGP2; reflects proteomic abundance. Supporting Evidence: PMID:20458337 MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-70286 | ACCEPT | Summary: Reactome asserts cytosolic UGP2 catalyzing UTP + glucose-1-phosphate to UDP-glucose + pyrophosphate. Cytosol is the precise and correct localization for this enzyme. Reason: Authoritative traceable assignment; cytosol (GO:0005829) is the specific localization used in core_functions. Supporting Evidence: Reactome:R-HSA-70286 Cytosolic UDP-glucose pyrophosphorylase 2 (UGP2) catalyzes the reaction of UTP and glucose 1-phosphate to form UDP glucose and pyrophosphate |
| GO:0003983 UTP:glucose-1-phosphate uridylyltransferase activity | TAS PMID:8354390 Cloning of a human liver UDP-glucose pyrophosphorylase cDNA ... | ACCEPT | Summary: Traceable assertion of UDP-glucose pyrophosphorylase activity from the founding human liver cDNA cloning by galU complementation. Reason: Correct core molecular function with traceable experimental support. Supporting Evidence: PMID:8354390 A human liver cDNA clone which encodes the UDP-glucose pyrophosphorylase was isolated by complementation of a bacterial galU mutant. |
| GO:0003983 UTP:glucose-1-phosphate uridylyltransferase activity | TAS PMID:8631325 Sequence differences between human muscle and liver cDNAs fo... | ACCEPT | Summary: Traceable assertion of the EC 2.7.7.9 activity from kinetic characterization of recombinant human UGP2 enzymes. Reason: Correct core molecular function with traceable biochemical support. Supporting Evidence: PMID:8631325 UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi. |
| GO:0006011 UDP-alpha-D-glucose metabolic process | TAS PMID:8631325 Sequence differences between human muscle and liver cDNAs fo... | ACCEPT | Summary: Traceable assertion that UGP2 participates in UDP-glucose metabolism, from kinetic studies of the recombinant enzyme. Reason: UDP-glucose is the direct product of the characterized reaction. Supporting Evidence: PMID:8631325 UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi. |
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Download this section (compressed HTML)Q: 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?
Q: Does the octamerization/latch-loop regulation of UGP2 activity respond to physiological signals (e.g. metabolic or redox state) in vivo?
Experiment: 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.
Experiment: Metabolic flux analysis (13C-glucose) in UGP2-depleted human cells to quantify partitioning of UDP-glucose between glycogen, glycosylation, and glucuronidation pathways.
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