UPP1 (uridine phosphorylase 1) is a cytosolic enzyme of the PNP/UDP phosphorylase family that catalyzes the reversible phosphorolysis of uridine, and to a lesser extent 2'-deoxyuridine, into uracil plus (2-deoxy)-alpha-D-ribose 1-phosphate (EC 2.4.2.3). This is a central reaction of pyrimidine nucleoside salvage and catabolism: the liberated uracil can be salvaged for pyrimidine nucleotide synthesis or degraded reductively (by DPYD, DPYS and UPB1), while the ribose 1-phosphate feeds the pentose/energy pool. The active enzyme is a homodimer. UPP1 activity is important pharmacologically because it activates fluoropyrimidine chemotherapeutics such as 5-fluorouracil and its prodrug capecitabine, and its expression is induced by vitamin D3 and inflammatory cytokines (TNF, IL1, IFNG). Unlike the mouse enzyme, human UPP1 does not cleave thymidine; thymidine phosphorolysis in human is performed by TYMP. Upp1-knockout mice show markedly raised plasma and tissue uridine and altered pyrimidine nucleotide pools, establishing the enzyme as the main regulator of uridine homeostasis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004850 uridine phosphorylase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function. Phylogenetic (IBA) assignment of the family-defining uridine phosphorylase activity, in agreement with the direct experimental IDA (PMID:7488099) and the UniProt catalytic-activity/EC:2.4.2.3 annotation. Supporting Evidence: file:human/UPP1/UPP1-uniprot.txt Catalyzes the reversible phosphorylytic cleavage of uridine |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Correct core cellular component. UPP1 is a soluble cytosolic enzyme (no signal/transmembrane features), consistent with the Reactome "Cytosolic uridine phosphorylase" description and the family-conserved localization. Supporting Evidence: Reactome:R-HSA-74372 Cytosolic uridine phosphorylase (isoforms UPP1 and UPP2) |
| GO:0006218 uridine catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process. Phosphorolysis of uridine to uracil and ribose-1-phosphate is the committed step of uridine catabolism; consistent with the direct experimental IDA (PMID:7488099). Supporting Evidence: file:human/UPP1/UPP1-uniprot.txt Catalyzes the reversible phosphorylytic cleavage of uridine |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Root-level catalytic activity term. Not informative given the specific GO:0004850 (uridine phosphorylase activity) annotation, which is experimentally supported. Over-general, superseded by the specific MF. |
| GO:0004850 uridine phosphorylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Redundant electronic (ARBA/Rhea/EC) support for the gene's own correct core molecular function, uridine phosphorylase activity (EC 2.4.2.3). Retained as core. Supporting Evidence: file:human/UPP1/UPP1-uniprot.txt Reaction=uridine + phosphate = alpha-D-ribose 1-phosphate + uracil |
| GO:0005737 cytoplasm | IEA GO_REF:0000002 | ACCEPT | Summary: Correct, if less specific than cytosol. UPP1 is a cytoplasmic/cytosolic enzyme; this is the gene's own correct localization, so retained rather than flagged. Supporting Evidence: Reactome:R-HSA-74372 Cytosolic uridine phosphorylase (isoforms UPP1 and UPP2) |
| GO:0009116 nucleoside metabolic process | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Correct but over-general ancestor of the specific and experimentally supported uridine catabolic process (GO:0006218). Adds no specific information beyond the more precise BP annotation. |
| GO:0009166 nucleotide catabolic process | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro (IPR010059, eukaryotic uridine phosphorylase) mapping to the general term nucleotide catabolic process. Reason: Revised from REMOVE on re-review. The earlier rationale ('acts on the nucleoside, not the nucleotide, so wrong branch') does not hold: UPP1 catalyses the uracil-releasing step of UMP, CMP, dCMP and dUMP degradation, and mouse Upp1 carries those specific nucleotide catabolic terms experimentally (now transferred to human by Ensembl and kept here as non-core). The problem with this row is only granularity: the root-level parent adds nothing beyond the specific UMP/CMP/dCMP/dUMP rows. Supporting Evidence: PMID:15772079 In the liver, gut, kidney, and lung of UPase-/- mice, total uridine ribonucleotide concentrations increased 2-3 times as compared with control mice. |
| GO:0016763 pentosyltransferase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Correct but over-general parent term (EC 2.4.2 pentosyltransferases). UPP1 is a pentosyltransferase, but the specific and experimentally supported GO:0004850 (uridine phosphorylase activity) is the appropriate MF; the parent adds no information. |
| GO:0006218 uridine catabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: Redundant electronic (ARBA) support for the gene's own correct core biological process, uridine catabolic process. Retained as core. Supporting Evidence: file:human/UPP1/UPP1-uniprot.txt Catalyzes the reversible phosphorylytic cleavage of uridine |
| GO:0042149 cellular response to glucose starvation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer from the rat ortholog (ENSRNOP00000006765) via Ensembl Compara. Plausible in the context of uridine as an alternative carbon/energy source under glucose limitation, but not verified for human UPP1 and not a core function; kept as non-core. Reason: Ensembl transfer from rat Upp1, whose own annotation is IEP: UPase mRNA and protein rise after glucose deprivation and after ischaemia, and a UPase inhibitor blocks uridine-mediated neuroprotection. Induction is not participation, and nothing equivalent is shown for human UPP1, so this stays non-core; the underlying idea (uridine as an alternative carbon source via ribose 1-phosphate) is coherent with the core activity. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK Sources checked: UniProtKB:F7F0D5 · Upp1 SOURCE WEAK OR INFERRED Rat row is IEP (expression response), PMID:18457515. Supporting Evidence: PMID:18457515 Similar to our in vivo data, UPase expression was up-regulated by glucose deprivation in mRNA as well as protein levels. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | MARK AS OVER ANNOTATED | Summary: HPA immunofluorescence localization. UPP1 is an established cytosolic enzyme with no known nuclear function; the family-conserved and physiologically supported location is the cytosol/cytoplasm. Treated as an over-annotation (localization noise) rather than removed, as it is an experimental IDA. |
| GO:0004850 uridine phosphorylase activity | IDA PMID:7488099 Cloning and expression of human uridine phosphorylase. | ACCEPT | Summary: Core molecular function with direct experimental evidence. Recombinant human UPP1 expressed in COS-7 cells showed specific enzyme activity with uridine as substrate, blocked by a competitive uridine-analogue inhibitor. Supporting Evidence: PMID:7488099 specific enzyme activity with uridine as the substrate |
| GO:0006218 uridine catabolic process | IDA PMID:7488099 Cloning and expression of human uridine phosphorylase. | ACCEPT | Summary: Core biological process, direct experimental evidence. Phosphorolysis of uridine assayed for the cloned human enzyme places UPP1 in uridine catabolism. Supporting Evidence: PMID:7488099 specific enzyme activity with uridine as the substrate |
| GO:0042802 identical protein binding | IPI PMID:19291308 Implications of the structure of human uridine phosphorylase... | ACCEPT | Summary: Informative self-association. Crystallography shows the active human enzyme is a homodimer, in contrast to the hexameric microbial UPPs; this IPI (WITH UniProtKB:Q16831) captures the homodimer interface and is more informative than bare protein binding. Consistent with UniProt SUBUNIT "Homodimer". Supporting Evidence: PMID:19291308 is dimeric in contrast to the hexameric assembly present in microbial UPPs |
| GO:0042802 identical protein binding | IPI PMID:20856879 Active site conformational dynamics in human uridine phospho... | ACCEPT | Summary: Independent structural confirmation of the homodimer (5-FU-bound structure); the enzyme forms strictly dimeric complexes in eukaryotes. Supports the identical protein binding (homodimer) annotation. Supporting Evidence: PMID:20856879 strictly dimeric complexes in eukaryotic organisms |
| GO:0005829 cytosol | TAS Reactome:R-HSA-74372 | ACCEPT | Summary: Correct core cellular component. Reactome describes UPP1 as a cytosolic uridine phosphorylase; consistent with the IBA cytosol annotation. Supporting Evidence: Reactome:R-HSA-74372 Cytosolic uridine phosphorylase (isoforms UPP1 and UPP2) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-74376 | ACCEPT | Summary: Correct core cellular component (reverse-direction Reactome reaction, same cytosolic localization). Consistent with the other cytosol annotations. Supporting Evidence: Reactome:R-HSA-74376 Cytosolic uridine phosphorylase (isoforms UPP1 and UPP2) |
| GO:0006139 nucleobase-containing compound metabolic process | TAS PMID:7488099 Cloning and expression of human uridine phosphorylase. | MARK AS OVER ANNOTATED | Summary: Correct but very general (high-level) BP ancestor. The specific, experimentally supported uridine catabolic process (GO:0006218) captures the function precisely; this broad term adds no specific information. |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: Cytosol, transferred by Ensembl Compara from mouse Upp1 (IDA in PMID:7744869, PMID:14154460). Agrees with the IBA and Reactome rows. Reason: Soluble cytosolic enzyme; consistent with every other localisation source except the HPA nucleoplasm row. Core location. Supporting Evidence: Reactome:R-HSA-74372 Cytosolic uridine phosphorylase (isoforms UPP1 and UPP2) |
| GO:0006248 CMP catabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CMP catabolic process transferred from mouse Upp1 (MGI IDA, PMID:14715930). CMP -> cytidine -> uridine -> uracil; UPP1 performs the last step. Reason: UPP1 does not act on the nucleotide itself; it catalyses the downstream nucleoside step (uridine or deoxyuridine + phosphate -> uracil + (deoxy)ribose 1-phosphate) after 5'-nucleotidase and, for cytidine nucleotides, cytidine deaminase. That is genuine participation in the catabolic pathway of the nucleotide, and the mouse donor annotations are experimental (IDA), so the transfer is sound. It is a pathway context of the single core activity rather than an additional function, hence non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P52624 · Upp1 SUPPORTS TRANSFER Mouse row is IDA from the L-UrdPase/Upp2 comparison paper; activity itself is conserved in human UPP1. Supporting Evidence: PMID:15772079 In the liver, gut, kidney, and lung of UPase-/- mice, total uridine ribonucleotide concentrations increased 2-3 times as compared with control mice. file:human/UPP1/UPP1-uniprot.txt Catalyzes the reversible phosphorylytic cleavage of uridine |
| GO:0006249 dCMP catabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: dCMP catabolic process transferred from mouse Upp1 (MGI IDA, PMID:7744869). dCMP -> deoxycytidine -> deoxyuridine -> uracil; UPP1 cleaves deoxyuridine. Reason: UPP1 does not act on the nucleotide itself; it catalyses the downstream nucleoside step (uridine or deoxyuridine + phosphate -> uracil + (deoxy)ribose 1-phosphate) after 5'-nucleotidase and, for cytidine nucleotides, cytidine deaminase. That is genuine participation in the catabolic pathway of the nucleotide, and the mouse donor annotations are experimental (IDA), so the transfer is sound. It is a pathway context of the single core activity rather than an additional function, hence non-core. Human UPP1 has the required deoxyuridine phosphorylase activity (RHEA:22824). Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P52624 · Upp1 SUPPORTS TRANSFER Cloning paper for mouse UP; substrate assays on recombinant enzyme. Supporting Evidence: file:human/UPP1/UPP1-uniprot.txt Reaction=2'-deoxyuridine + phosphate = 2-deoxy-alpha-D-ribose 1- PMID:7744869 substrate specificity studies with recombinant protein expressed in COS-7 cells that demonstrated relatively high enzyme activity with uridine as substrate compared low levels when thymidine was used |
| GO:0009032 thymidine phosphorylase activity | IEA GO_REF:0000107 | REMOVE | Summary: Thymidine phosphorylase activity transferred by Ensembl Compara from mouse Upp1, whose positive IMP row (PMID:12077348) coexists with a NOT row (PMID:15772079). Reason: The donor paper itself states that the mouse enzyme, unlike human UP, cleaves thymidine; thymidine phosphorolysis in human is carried out by TYMP (and to some extent UPP2), not UPP1. Human UPP1 acts on ribosides and 2'-deoxyribosides of uracil (RHEA:24388, RHEA:22824); UniProt lists no thymidine reaction. This is a species-specific substrate difference that Compara transfer cannot see, so the IEA is a demonstrably wrong propagation. The mouse GOA row is additionally contested by a NOT annotation from the knockout study. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE LINEAGE OR TAXON MISMATCH Sources checked: UniProtKB:P52624 · Upp1 SUPPORTS SOURCE BUT NOT TARGET Mouse Upp1 does cleave thymidine (PMID:12077348 abstract), but the same abstract says human UP does not; mouse GOA also carries NOT|enables for this term (PMID:15772079). Supporting Evidence: PMID:12077348 Murine uridine phosphorylase (UP), unlike human UP, cleaves thymidine, as well as uridine. PMID:7744869 substrate specificity studies with recombinant protein expressed in COS-7 cells that demonstrated relatively high enzyme activity with uridine as substrate compared low levels when thymidine was used |
| GO:0044206 UMP salvage | IEA GO_REF:0000120 | ACCEPT | Summary: UMP salvage (combined IEA incl. UniPathway UPA00574): UPP1 supplies uracil for the phosphorylase route of pyrimidine salvage. Replaces the former GO_REF:0000041 row, which GOA no longer carries. Reason: Matches the UniProt pathway assignment (UMP biosynthesis via salvage, uracil from uridine, step 1/1) and the knockout evidence that loss of UPase shifts cells toward salvage and away from de novo synthesis and 5-FU activation (PMID:11956089). Retained as core. Supporting Evidence: file:human/UPP1/UPP1-uniprot.txt Pyrimidine metabolism; UMP biosynthesis via salvage pathway; PMID:11956089 we establish the critical role of UPase as an important anabolic enzyme in 5-fluorouracil (5-FU) activation and pyrimidine salvage pathway regulation |
| GO:0046050 UMP catabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: UMP catabolic process transferred from mouse Upp1 (MGI IDA, PMID:7744869, PMID:14715930); UMP -> uridine -> uracil. Reason: UPP1 does not act on the nucleotide itself; it catalyses the downstream nucleoside step (uridine or deoxyuridine + phosphate -> uracil + (deoxy)ribose 1-phosphate) after 5'-nucleotidase and, for cytidine nucleotides, cytidine deaminase. That is genuine participation in the catabolic pathway of the nucleotide, and the mouse donor annotations are experimental (IDA), so the transfer is sound. It is a pathway context of the single core activity rather than an additional function, hence non-core. Upp1 knockout mice accumulate uridine ribonucleotides, confirming the enzyme sits on the UMP degradation route in vivo. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P52624 · Upp1 SUPPORTS TRANSFER Mouse IDA; knockout (PMID:15772079) corroborates in vivo. Supporting Evidence: PMID:15772079 In the liver, gut, kidney, and lung of UPase-/- mice, total uridine ribonucleotide concentrations increased 2-3 times as compared with control mice. file:human/UPP1/UPP1-uniprot.txt Catalyzes the reversible phosphorylytic cleavage of uridine |
| GO:0046074 dTMP catabolic process | IEA GO_REF:0000107 | REMOVE | Summary: dTMP catabolic process transferred from mouse Upp1 (IMP PMID:12077348, with a NOT row from PMID:15772079 on the same donor). Reason: Participation in dTMP breakdown would require thymidine phosphorylase activity, which the donor paper explicitly denies for human UP. In human the thymidine step is TYMP's. Same propagation failure as GO:0009032. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE LINEAGE OR TAXON MISMATCH Sources checked: UniProtKB:P52624 · Upp1 SUPPORTS SOURCE BUT NOT TARGET Valid for mouse (thymidine-cleaving UP), not for human UPP1. Supporting Evidence: PMID:12077348 Murine uridine phosphorylase (UP), unlike human UP, cleaves thymidine, as well as uridine. |
| GO:0046079 dUMP catabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: dUMP catabolic process transferred from mouse Upp1 (MGI IDA, PMID:14154460); dUMP -> deoxyuridine -> uracil via UPP1's deoxyuridine phosphorylase activity. Reason: UPP1 does not act on the nucleotide itself; it catalyses the downstream nucleoside step (uridine or deoxyuridine + phosphate -> uracil + (deoxy)ribose 1-phosphate) after 5'-nucleotidase and, for cytidine nucleotides, cytidine deaminase. That is genuine participation in the catabolic pathway of the nucleotide, and the mouse donor annotations are experimental (IDA), so the transfer is sound. It is a pathway context of the single core activity rather than an additional function, hence non-core. The human enzyme's deoxyuridine reaction is documented by UniProt/Rhea. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P52624 · Upp1 SUPPORTS TRANSFER 1964 substrate-specificity study of mouse UP; abstract not available in cache, title only. Supporting Evidence: file:human/UPP1/UPP1-uniprot.txt Reaction=2'-deoxyuridine + phosphate = 2-deoxy-alpha-D-ribose 1- |
| GO:0047847 deoxyuridine phosphorylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Deoxyuridine phosphorylase activity (combined IEA incl. RHEA:22824). Replaces the former GO_REF:0000116 Rhea-only row, which GOA no longer carries. Reason: UniProt documents the 2'-deoxyuridine reaction (RHEA:22824) as a catalytic activity of UPP1; the mouse orthologue shows the same specificity. Secondary but genuine catalytic activity, kept as core. Supporting Evidence: file:human/UPP1/UPP1-uniprot.txt Reaction=2'-deoxyuridine + phosphate = 2-deoxy-alpha-D-ribose 1- |
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Download this section (compressed HTML)Q: Has thymidine phosphorolysis by purified human UPP1 been measured directly and shown to be negligible (as the mouse/human contrast in PMID:12077348 implies), so that the removed IEA can be replaced by a NOT annotation as MGI did for mouse?
Q: Is the HPA nucleoplasm signal for UPP1 reproducible with a second antibody or a tagged construct, or is it antibody cross-reactivity?
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