NUDT2 (P50583) review notes

Summary of evidence

• Human asymmetrical Ap4A hydrolase, Nudix (MutT motif) family; cDNA cloned 1995; unrelated
  to prokaryotic/fungal Ap4A-degrading enzymes (the symmetrical ApaH type).
  PMID:7487923
• NMR structures, free and ATP-bound; asymmetric cleavage of Ap4A to ATP + AMP.
  PMID:15596429
• Loss of function raises Ap4A ~175-fold in KBM-7 cells and changes thousands of transcripts
  (interferon/inflammation genes down, MHC II up).
  PMID:27144453
• Mast-cell signalling: NUDT2 degrades LysRS-produced Ap4A after FcepsilonRI activation;
  knockdown alters MITF/USF2 target genes (Ap4A releases MITF/USF2 from HINT1).
  PMID:18644867
• RNA 5'-end activity: recombinant NUDT2 sequentially removes phosphates from 5'-PPP RNA,
  enabling XRN1 decay; E58A inactive; NUDT2 KO cells/MEFs support more growth of PPP-RNA
  viruses (VSV, IAV) but not HSV-1/SFV; Nudt2-/- mice viable, no VSV survival difference.
  PMID:34824277
• Localisation: nucleus and cytoplasm in human cells.
  PMID:34824277
• Non-canonical cap removal in vitro: FAD and dpCoA caps (not NAD); no FAD-cap change in KO cells.
  PMID:32432673
  Ap4A-capped RNA is cleaved by NUDT2 and DXO.
  PMID:37934413
• Disease: biallelic loss-of-function variants cause IDDPN (ID +/- peripheral neuropathy);
  18 patients/10 families; variants lose activity; add-back of a decapping-defective
  enzyme implicates decapping loss in altered mRNA homeostasis.
  PMID:38141063
  PMID:33058507
  PMID:38243213
• Cancer: overexpressed in breast carcinoma, promotes proliferation; reported to bind Rag
  GTPases and promote mTORC1 lysosomal recruitment (single lab, abstract only).
  PMID:20533549
  PMID:28089905
• PRPP pyrophosphatase: weak in vitro (kcat 0.057 s-1); not annotated in human GOA and not proposed.
  PMID:12370170

Curation decisions (consistent with genes/worm/ndx-4)

• GO:0004081 asymmetrical tetraphosphatase (IBA, IEA, 2x ISS, Reactome TAS): ACCEPT.
• GO:0008803 symmetrical tetraphosphatase TAS (PMID:7487923): MODIFY to GO:0004081; the cited
  paper itself says the human enzyme is unrelated to the prokaryotic (symmetrical) enzymes.
• AMP/ATP biosynthetic process IBA (PTN000482012, seeded only by ndx-4): MARK_AS_OVER_ANNOTATED,
  product-based inference (same call as ndx-4).
• Apoptotic process ISS (from ndx-4 TAS, PMID:11937063): REMOVE (worm source TAS removed).
• Mitochondrial matrix TAS (Reactome): REMOVE; Reactome compartment artefact, data show nucleus/cytoplasm.
• Cellular response to oxidative stress TAS (Reactome ROS detox pathway): REMOVE; pathway is SOD/catalase/peroxidase.
• Nucleobase-containing compound metabolic process TAS: MODIFY to GO:0015967.
• Hydrolase activity IEA: MODIFY to GO:0004081. GO:0008796 IEA: ACCEPT.
• Protein binding IPI x3 (HuRI/Y2H: MCM6, DDIT4L, PLEKHF2): REMOVE (uninformative).
• NEW: GO:0015967 (IMP, PMID:27144453), GO:0140818 (IDA, PMID:34824277), GO:0110154 RNA decapping
  (IMP, PMID:38141063), GO:0005634 and GO:0005737 (IDA, PMID:34824277).
• Not proposed: defense response to virus (in vitro/cellular effect only; no in vivo phenotype;
  flagged as a question), mTORC1 regulation (single lab, mechanism unclear), PRPP pyrophosphatase.

PAINT (PTHR21340) observations

• PTN000482012 carries GO:0004081 (seeds: pig NUDT2, P. falciparum C0H4F3, ndx-4) - sound.
• PTN000482012 AMP biosynthetic (GO:0006167) and ATP biosynthetic (GO:0006754) IBDs are seeded only
  by worm ndx-4 IDA rows that are product-based; GO:0015967 diadenosine tetraphosphate catabolic
  process would be the better node assertion and is absent.
• No CC asserted at the node; human and fly data support nucleus/cytoplasm.

Caveats

Abstract-only caches: PMID:7487923, 15596429, 18644867, 38141063, 37934413, 28089905, 27431290,
20533549, 12370170, 11738085, 11937063. PMID:30059600 (founder nonsense variant) could not be cached.

Deep research status

OpenScientist completed on 2026-10-08 (~12 min): NUDT2-deep-research-openscientist.md.
Falcon/perplexity are not available in this environment.

Agreements with the review: core asymmetrical Ap4A hydrolase (ATP + AMP), signal
termination in the LysRS-Ap4A-HINT1-MITF axis PMID:18644867, 175-fold Ap4A rise on
disruption PMID:27144453, decapping activity and IDDPN disease PMID:38141063, PRPP as a
low-relevance secondary substrate PMID:12370170, and that extracellular Ap4A hydrolysis is
done by ecto-PDE/ENPP enzymes, not NUDT2.

Additions used: human crystal structures (monomeric Nudix alpha-beta-alpha fold, E58 active site)
PMID:23384440.

Points treated with caution:
- It calls NUDT2 an "m7G mRNA decapping" enzyme; the Brain abstract only says "mRNA decapping",
and in vitro decapping data cover Ap4A-, FAD- and dpCoA-capped RNA. The cap type is left
unspecified (GO:0110154 RNA decapping).
- It says direct human localisation data are sparse; it missed PMID:34824277, which reports
nucleus + cytoplasm immunolocalisation in human cells and the 5'-PPP RNA dephosphorylation
activity. Neither omission changes the decisions.
- Ap4A as a DNA-damage replication-initiation inhibitor [PMID:26204256, per deep research] concerns
the substrate's role; NUDT2 does not participate in that process, so no annotation is proposed.