UPP1 (Uridine phosphorylase 1, Q16831) — review notes

Identity and family

• Human gene UPP1 (HGNC:12576), synonym UP; UniProt Q16831, 310 aa, EC 2.4.2.3
  [file:human/UPP1/UPP1-uniprot.txt "RecName: Full=Uridine phosphorylase 1"; "EC=2.4.2.3"].
• Belongs to the PNP/UDP phosphorylase family (nucleoside phosphorylase-I superfamily)
  [file:human/UPP1/UPP1-uniprot.txt "Belongs to the PNP/UDP phosphorylase family"].
• InterPro/PANTHER: Nucleoside_phosphorylase_d (IPR000845), Uridine_phosphorylase_euk
  (IPR010059), PANTHER PTHR43691:SF10 URIDINE PHOSPHORYLASE 1.

Catalytic function

• Reversible phosphorolysis of uridine: uridine + phosphate <=> alpha-D-ribose 1-phosphate + uracil
  (RHEA:24388, EC 2.4.2.3), physiological direction left-to-right
  [file:human/UPP1/UPP1-uniprot.txt "Reaction=uridine + phosphate = alpha-D-ribose 1-phosphate + uracil"].
• Also acts on 2'-deoxyuridine: 2'-deoxyuridine + phosphate <=> 2-deoxy-alpha-D-ribose 1-phosphate + uracil
  (RHEA:22824) [file:human/UPP1/UPP1-uniprot.txt "Reaction=2'-deoxyuridine + phosphate = 2-deoxy-alpha-D-ribose 1-"].
• Function summary: "Catalyzes the reversible phosphorylytic cleavage of uridine to uracil and
  ribose-1-phosphate which can then be utilized as carbon and energy sources or in the rescue of
  pyrimidine bases for nucleotide synthesis"
  [file:human/UPP1/UPP1-uniprot.txt "Catalyzes the reversible phosphorylytic cleavage of uridine"].
• Broad substrate specificity, can also accept deoxyuridine and analogues (Probable)
  [file:human/UPP1/UPP1-uniprot.txt "Shows broad substrate specificity and can"].
• Cloned and enzymatically characterized from human colorectal tumor line HCT116; recombinant enzyme
  in COS-7 cells showed "specific enzyme activity with uridine as the substrate; this activity was
  inhibited by the competitive inhibitor 2,2'-anhydro-5-ethyluridine"
  PMID:7488099 (abstract-only cache;
  curated as IDA GO:0004850 / GO:0006218 by UniProt from the full text).

Pathway context

• UniProt PATHWAY: "Pyrimidine metabolism; UMP biosynthesis via salvage pathway; uracil from uridine
  (phosphorylase route): step 1/1" (UniPathway UPA00574/UER00633)
  [file:human/UPP1/UPP1-uniprot.txt "UMP biosynthesis via salvage pathway"].
• Reactome places UPP1 in "Pyrimidine salvage" (R-HSA-73614) and "Pyrimidine catabolism"
  (R-HSA-73621); catalyzes the reversible reactions R-HSA-74372 / R-HSA-74376
  [reactome:R-HSA-74376 "Cytosolic uridine phosphorylase (isoforms UPP1 and UPP2) catalyzes the
  reversible reactions of uridine or deoxyuridine with orthophosphate to yield uracil"].
• Uracil liberated by UPP1 is further degraded by the reductive pyrimidine catabolic pathway
  (DPYD -> DPYS -> UPB1); the ribose-1-phosphate feeds the pentose pool. Uridine phosphorylase is
  "a ubiquitous enzyme involved in pyrimidine salvage and maintenance of uridine homeostasis"
  PMID:19291308.

Quaternary structure (identical protein binding)

• Homodimer [file:human/UPP1/UPP1-uniprot.txt "Homodimer."].
• Crystallography confirms the human enzyme is dimeric (contrasting the hexameric microbial UPPs):
  PMID:19291308;
  PMID:20856879. The two annotations of
  GO:0042802 (identical protein binding, IPI, WITH UniProtKB:Q16831) capture this self-association.
• Structures: 3EUE, 3EUF (ligand-free / BAU-inhibited; 1.9 A) and 3NBQ (5-FU complex; 2.3 A).

Localization

• Cytosolic enzyme (Reactome "Cytosolic uridine phosphorylase"; UniProt has no signal/TM features).
• GOA carries a nucleoplasm IDA (GO:0005654) from HPA (GO_REF:0000052). UPP1 has no known nuclear
  role; the physiologically supported and family-conserved location is the cytosol/cytoplasm. Treated
  as an over-annotation (HPA immunofluorescence localization), not removed (experimental IDA).

Regulation / physiology

• Induced by vitamin D3 and inflammatory cytokines TNF, IL1, IFNG
  [file:human/UPP1/UPP1-uniprot.txt "By vitamin D3 and a mixture of inflammatory cytokines"].
• The GO:0042149 (cellular response to glucose starvation) annotation is IEA transferred from the rat
  ortholog (GO_REF:0000107, WITH ENSRNOP00000006765). Plausible but unverified in human; kept
  non-core.

Pharmacology / disease relevance

• Activates fluoropyrimidine chemotherapeutics: 5-fluorouracil (5-FU) and its prodrug capecitabine;
  elevated tumor UPP levels contribute to drug selectivity. Specific inhibitors (e.g.
  5-benzylacyclouridine, BAU) raise endogenous uridine and protect normal tissue
  PMID:19291308. DrugBank: Fluorouracil, Capecitabine, 5-Benzylacyclouridine.

Isoforms

• Isoform 2 ("Truncated", Q16831-2) diverges at residues 15-36 and is missing 37-310; annotated
  Inactive [file:human/UPP1/UPP1-uniprot.txt "[Isoform 2]: Inactive."].

Curation decisions (summary)

• ACCEPT (core): GO:0004850 (MF, IBA+IEA+IDA), GO:0006218 (BP, IBA+IEA+IDA), GO:0005829 (CC,
  IBA+TASx2), GO:0005737 (CC, IEA), GO:0047847 (deoxyuridine phosphorylase, secondary catalytic
  activity documented by UniProt), GO:0044206 (UMP salvage, matches UniProt UniPathway pathway).
• MARK_AS_OVER_ANNOTATED: GO:0003824 (catalytic activity, root MF), GO:0016763 (pentosyltransferase,
  over-general parent), GO:0009116 (nucleoside metabolic process, over-general parent),
  GO:0006139 (nucleobase-containing compound metabolic process, over-general), GO:0005654
  (nucleoplasm IDA — experimental, not removed).
• REMOVE: GO:0009166 (nucleotide catabolic process, IEA) — UPP1 acts on the nucleoSIDE uridine, not
  on nucleoTIDES; wrong-branch electronic InterPro inference (correct process is pyrimidine nucleoside
  catabolism).
• KEEP_AS_NON_CORE: GO:0042149 (cellular response to glucose starvation, IEA from rat ortholog).
• ACCEPT (informative self-association, homodimer, structurally verified): GO:0042802 x2.

2026-09-28 — re-review against the current GOA snapshot (claude4go, from outside the repo)

• Deep research not run (no provider keys); this section is the manual synthesis for the new rows.
• GOA now has 28 rows vs the 21 reviewed above. seed-goa added 9 rows; two earlier rows
  (deoxyuridine phosphorylase IEA under GO_REF:0000116, UMP salvage IEA under GO_REF:0000041)
  are no longer in GOA and were dropped, their reviews carried onto the replacement rows
  under GO_REF:0000120.
• Species divergence caught in the Ensembl transfers. The new IEAs for GO:0009032 thymidine phosphorylase activity and GO:0046074 dTMP catabolic process come from mouse Upp1, and the
  donor paper says the opposite for human: PMID:12077348. Mouse GOA also carries NOT rows for
  both terms from the Upp1 knockout study (PMID:15772079). Both human IEAs are REMOVED with a
  propagation_review (PROPAGATION_BAD; FUNCTIONAL_DIVERGENCE + LINEAGE_OR_TAXON_MISMATCH).
• The other Ensembl transfers (UMP, CMP, dCMP, dUMP catabolic process) are kept as
  non-core: UPP1 performs the nucleoside-cleaving step of those pathways, the mouse rows are
  IDA, and knockout mice accumulate uridine ribonucleotides PMID:15772079.
• Earlier decision revised. GO:0009166 nucleotide catabolic process (InterPro IEA) was
  REMOVE with a "nucleoside not nucleotide, wrong branch" argument. That argument is contradicted
  by the specific nucleotide catabolic rows above, so it is now MARK_AS_OVER_ANNOTATED
  (granularity only).
• GO:0042149 cellular response to glucose starvation stays non-core; the rat donor row is IEP
  PMID:18457515.
• Cytosol (Ensembl IEA), UMP salvage and deoxyuridine phosphorylase (combined IEA) ACCEPT.
• Status set to COMPLETE. Final tally over 28 rows: 15 ACCEPT, 5 KEEP_AS_NON_CORE,
  6 MARK_AS_OVER_ANNOTATED, 2 REMOVE.