NCGR_LOCUS3088

UniProt ID: A0A811MJ28
Organism: Miscanthus lutarioriparius
Review Status: DRAFT
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Gene Description

Inosine triphosphate pyrophosphatase (ITPase) of the HAM1 NTPase family. Hydrolyzes non-canonical purine nucleoside triphosphates (ITP, dITP, XTP) to the corresponding monophosphates, preventing their incorporation into DNA and RNA. Functions as a homodimer requiring Mg2+ or Mn2+ cofactor. Part of a conserved nucleotide pool sanitization system found across all domains of life that protects genome integrity.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0036220 ITP diphosphatase activity
IEA
GO_REF:0000104 		ACCEPT
Summary: Core enzymatic activity of ITPase. Hydrolysis of ITP to IMP and diphosphate is the primary characterized function of the HAM1/ITPA family across all organisms. Well-supported by HAMAP rule MF_03148 and extensive biochemical characterization of orthologs in Arabidopsis [PMID:36464781].
Supporting Evidence:
PMID:36464781
Inosine triphosphate pyrophosphatase dephosphorylates deaminated nucleoside di- and triphosphates to the respective monophosphates
file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
HAM1/ITPase family is well-characterized across bacteria, yeast, plants, and mammals
GO:0035870 dITP diphosphatase activity
IEA
GO_REF:0000104 		ACCEPT
Summary: Core enzymatic activity. HAM1/ITPase family enzymes do not distinguish between deoxy- and ribose forms of non-canonical purines. dITP hydrolysis is essential for preventing deoxyinosine incorporation into DNA [PMID:36464781].
Supporting Evidence:
PMID:36464781
an elevated inosine and deoxyinosine content in RNA and DNA, respectively
file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
HAM1/ITPase family is well-characterized across bacteria, yeast, plants, and mammals
GO:0036222 XTP diphosphatase activity
IEA
GO_REF:0000104 		ACCEPT
Summary: Core enzymatic activity. Hydrolysis of xanthosine 5'-triphosphate is a well-documented activity of the HAM1/ITPase family, supported by HAMAP rule MF_03148 and catalytic activity annotations in UniProt.
Supporting Evidence:
file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
HAM1/ITPase family is well-characterized across bacteria, yeast, plants, and mammals
GO:0047429 nucleoside triphosphate diphosphatase activity
IEA
GO_REF:0000104 		KEEP AS NON CORE
Summary: This is a parent term of the three specific substrate activities (ITP, dITP, XTP diphosphatase). While not incorrect, it is redundant given the more specific annotations are present. Should be kept as non-core since it adds no information beyond what the specific terms provide.
Supporting Evidence:
file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
HAM1/ITPase family is well-characterized across bacteria, yeast, plants, and mammals
GO:0046872 metal ion binding
IEA
GO_REF:0000104 		KEEP AS NON CORE
Summary: ITPase requires Mg2+ or Mn2+ as cofactor (1 per subunit) for catalytic activity. However, metal ion binding is a very generic MF term that provides little functional insight. The metal binding is intrinsic to the catalytic mechanism rather than a distinct function.
Supporting Evidence:
file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
HAM1/ITPase family is well-characterized across bacteria, yeast, plants, and mammals
GO:0000166 nucleotide binding
IEA
GO_REF:0000104 		KEEP AS NON CORE
Summary: Nucleotide binding is intrinsic to the pyrophosphatase activity and is captured by the more specific substrate-level MF annotations. This generic term adds no functional insight and is redundant.
Supporting Evidence:
file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
HAM1/ITPase family is well-characterized across bacteria, yeast, plants, and mammals
GO:0009143 nucleoside triphosphate catabolic process
IEA
GO_REF:0000104 		KEEP AS NON CORE
Summary: Correct biological process for ITPase activity. The enzyme catalyzes catabolic hydrolysis of nucleoside triphosphates. However, it is a parent of the more specific deoxyribonucleoside triphosphate catabolic process and is somewhat redundant. Keep as non-core.
Supporting Evidence:
file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
HAM1/ITPase family is well-characterized across bacteria, yeast, plants, and mammals
GO:0009204 deoxyribonucleoside triphosphate catabolic process
IEA
GO_REF:0000104 		ACCEPT
Summary: Correct biological process capturing the deoxyribonucleotide catabolism aspect of ITPase function. Well-supported by the enzyme's role in hydrolyzing dITP to prevent deoxyinosine incorporation into DNA [PMID:36464781].
Supporting Evidence:
PMID:36464781
ITPA loss-of-function causes inosine di- and triphosphate accumulation in vivo and an elevated inosine and deoxyinosine content in RNA and DNA
file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
HAM1/ITPase family is well-characterized across bacteria, yeast, plants, and mammals
GO:0009117 nucleotide metabolic process
IEA
GO_REF:0000104 		KEEP AS NON CORE
Summary: Very broad biological process term. Redundant with the more specific catabolic process annotations (GO:0009143, GO:0009204). Provides minimal functional insight.
Supporting Evidence:
file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
HAM1/ITPase family is well-characterized across bacteria, yeast, plants, and mammals
GO:0005737 cytoplasm
IEA
GO_REF:0000104 		ACCEPT
Summary: Cytoplasmic localization is well-supported by HAMAP rule MF_03148 and consistent with the nucleotide pool sanitization function. ITPase orthologs across organisms are cytoplasmic enzymes that act on cytosolic nucleotide pools.
Supporting Evidence:
PMID:36464781
Inosine triphosphate pyrophosphatase is part of a molecular protection system in plants
file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
HAM1/ITPase family is well-characterized across bacteria, yeast, plants, and mammals

Core Functions

Hydrolysis of non-canonical purine nucleoside triphosphates (ITP, dITP, XTP) to the corresponding monophosphates, sanitizing the cellular nucleotide pool to prevent incorporation of aberrant bases into DNA and RNA

Molecular Function:
ITP diphosphatase activity
Directly Involved In:
deoxyribonucleoside triphosphate catabolic process
Cellular Locations:
cytoplasm

References

GO_REF:0000104
Electronic Gene Ontology annotations created by transferring manual GO annotations between orthologous microbial proteins.
PMID:36464781
An inosine triphosphate pyrophosphatase safeguards plant nucleic acids from aberrant purine nucleotides
  • Arabidopsis ITPA dephosphorylates deaminated nucleoside di- and triphosphates to the respective monophosphates
  • ITPA loss-of-function causes inosine di- and triphosphate accumulation in vivo and an elevated inosine and deoxyinosine content in RNA and DNA
  • Inosine triphosphate pyrophosphatase is part of a molecular protection system in plants, preventing the accumulation of (d)ITP and its usage for nucleic acid synthesis
file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
Research notes on NCGR_LOCUS3088 ITPase
  • HAM1/ITPase family is well-characterized across bacteria, yeast, plants, and mammals
  • All annotations are IEA via HAMAP rule MF_03148 or UniProtKB keywords

📚 Additional Documentation

Notes

(NCGR_LOCUS3088-notes.md)

NCGR_LOCUS3088 - Inosine Triphosphate Pyrophosphatase (ITPase) Notes

Gene Identity

  • UniProt: A0A811MJ28 (TrEMBL, unreviewed)
  • Organism: Miscanthus lutarioriparius (NCBITaxon:422564), a Poaceae grass
  • ORF name: NCGR_LOCUS3088
  • EC: 3.6.1.66
  • Family: HAM1 NTPase family
  • Domains: Ham1p_like (Pfam PF01725), ITPase (InterPro IPR027502), RdgB/HAM1 (InterPro IPR002637)
  • PANTHER: PTHR11067:SF9 (Inosine triphosphate pyrophosphatase)
  • HAMAP rule: MF_03148 (HAM1_NTPase)
  • 201 amino acids, homodimer, Mg2+/Mn2+ cofactor

Function Summary

ITPase/HAM1 family enzymes are highly conserved "nucleotide pool sanitizers" found across all domains of life. They hydrolyze non-canonical purine nucleoside triphosphates (ITP, dITP, XTP, dHAPTP) to the corresponding monophosphates and diphosphate. This prevents incorporation of aberrant bases into DNA and RNA, which could cause mutagenesis or chromosomal lesions.

Key Literature

Plant-specific ITPase function

  • [PMID:36464781 "An inosine triphosphate pyrophosphatase safeguards plant nucleic acids from aberrant purine nucleotides", Straube et al. 2023, New Phytologist] - Characterized Arabidopsis ITPA. Loss of ITPA causes accumulation of (d)ITP, elevated inosine in RNA and deoxyinosine in DNA, salicylic acid accumulation, premature senescence, and upregulation of immune-related transcripts. Demonstrates ITPA is part of a molecular protection system in plants.

Human ITPA function

  • [PMID:22384212 "Pivotal role of inosine triphosphate pyrophosphatase in maintaining genome stability and the prevention of apoptosis in human cells", Menezes et al. 2012, PLoS One] - ITPA knockdown sensitizes cells to HAP-induced DNA breaks and apoptosis. Demonstrates role in genome stability.

Reviews

  • [PMID:36651037 "Inosine triphosphate pyrophosphatase: A guardian of the cellular nucleotide pool and potential mediator of RNA function", Schroader et al. 2023, WIREs RNA] - Comprehensive review of ITPase biology including nucleotide pool sanitization and emerging RNA-related functions.
  • [PMID:24151201 "ITPA (inosine triphosphate pyrophosphatase): from surveillance of nucleotide pools to human disease and pharmacogenetics", Burgis 2013, PMC] - Review covering ITPase from nucleotide pool surveillance to clinical relevance.

Annotation Assessment

All annotations are IEA (Inferred from Electronic Annotation) via HAMAP rule MF_03148, ARBA rules, or UniProtKB keywords. No experimental evidence exists for this specific Miscanthus protein. However, the HAM1/ITPase family is extremely well-characterized biochemically across multiple organisms (E. coli RdgB, yeast Ham1, human ITPA, Arabidopsis ITPA), and the HAMAP rule MF_03148 is well-supported.

The specific substrate annotations (dITP, ITP, XTP diphosphatase activities) are well-supported by the HAMAP rule and family biochemistry. The more general annotations (nucleotide binding, metal ion binding, nucleotide metabolic process) are redundant with the specific ones but not incorrect.

Notes on Annotation Quality

  • GO:0035870 (dITP diphosphatase activity) - core enzymatic activity, well-supported
  • GO:0036220 (ITP diphosphatase activity) - core enzymatic activity, well-supported
  • GO:0036222 (XTP diphosphatase activity) - core enzymatic activity, well-supported
  • GO:0047429 (nucleoside triphosphate diphosphatase activity) - parent term of the specific activities; redundant
  • GO:0046872 (metal ion binding) - true but very generic; Mg2+/Mn2+ cofactor binding is part of the catalytic mechanism
  • GO:0000166 (nucleotide binding) - true but very generic; substrate binding
  • GO:0009143 (nucleoside triphosphate catabolic process) - correct BP for the activity
  • GO:0009204 (deoxyribonucleoside triphosphate catabolic process) - correct, more specific BP
  • GO:0009117 (nucleotide metabolic process) - very broad, redundant with more specific BP terms
  • GO:0005737 (cytoplasm) - well-supported by HAMAP and literature

📄 View Raw YAML

 
id: A0A811MJ28
gene_symbol: NCGR_LOCUS3088
product_type: PROTEIN
taxon:
  id: NCBITaxon:422564
  label: Miscanthus lutarioriparius
description: Inosine triphosphate pyrophosphatase (ITPase) of the HAM1 NTPase family.
  Hydrolyzes non-canonical purine nucleoside triphosphates (ITP, dITP, XTP) to the
  corresponding monophosphates, preventing their incorporation into DNA and RNA.
  Functions as a homodimer requiring Mg2+ or Mn2+ cofactor. Part of a conserved nucleotide
  pool sanitization system found across all domains of life that protects genome integrity.
references:
- id: GO_REF:0000104
  title: Electronic Gene Ontology annotations created by transferring manual GO annotations
    between orthologous microbial proteins.
  findings: []
- id: PMID:36464781
  title: An inosine triphosphate pyrophosphatase safeguards plant nucleic acids from
    aberrant purine nucleotides
  findings:
  - statement: Arabidopsis ITPA dephosphorylates deaminated nucleoside di- and triphosphates
      to the respective monophosphates
  - statement: ITPA loss-of-function causes inosine di- and triphosphate accumulation
      in vivo and an elevated inosine and deoxyinosine content in RNA and DNA
  - statement: Inosine triphosphate pyrophosphatase is part of a molecular protection
      system in plants, preventing the accumulation of (d)ITP and its usage for nucleic
      acid synthesis
- id: file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
  title: Research notes on NCGR_LOCUS3088 ITPase
  findings:
  - statement: HAM1/ITPase family is well-characterized across bacteria, yeast, plants,
      and mammals
  - statement: All annotations are IEA via HAMAP rule MF_03148 or UniProtKB keywords
existing_annotations:
- term:
    id: GO:0036220
    label: ITP diphosphatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  review:
    summary: Core enzymatic activity of ITPase. Hydrolysis of ITP to IMP and diphosphate
      is the primary characterized function of the HAM1/ITPA family across all organisms.
      Well-supported by HAMAP rule MF_03148 and extensive biochemical characterization
      of orthologs in Arabidopsis [PMID:36464781].
    action: ACCEPT
    supported_by:
    - reference_id: PMID:36464781
      supporting_text: Inosine triphosphate pyrophosphatase dephosphorylates deaminated
        nucleoside di- and triphosphates to the respective monophosphates
    - reference_id: file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
      supporting_text: HAM1/ITPase family is well-characterized across bacteria, yeast,
        plants, and mammals
- term:
    id: GO:0035870
    label: dITP diphosphatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  review:
    summary: Core enzymatic activity. HAM1/ITPase family enzymes do not distinguish
      between deoxy- and ribose forms of non-canonical purines. dITP hydrolysis is
      essential for preventing deoxyinosine incorporation into DNA [PMID:36464781].
    action: ACCEPT
    supported_by:
    - reference_id: PMID:36464781
      supporting_text: an elevated inosine and deoxyinosine content in RNA and DNA,
        respectively
    - reference_id: file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
      supporting_text: HAM1/ITPase family is well-characterized across bacteria, yeast,
        plants, and mammals
- term:
    id: GO:0036222
    label: XTP diphosphatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  review:
    summary: Core enzymatic activity. Hydrolysis of xanthosine 5'-triphosphate is
      a well-documented activity of the HAM1/ITPase family, supported by HAMAP rule
      MF_03148 and catalytic activity annotations in UniProt.
    action: ACCEPT
    supported_by:
    - reference_id: file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
      supporting_text: HAM1/ITPase family is well-characterized across bacteria, yeast,
        plants, and mammals
- term:
    id: GO:0047429
    label: nucleoside triphosphate diphosphatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  review:
    summary: This is a parent term of the three specific substrate activities (ITP,
      dITP, XTP diphosphatase). While not incorrect, it is redundant given the more
      specific annotations are present. Should be kept as non-core since it adds no
      information beyond what the specific terms provide.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
      supporting_text: HAM1/ITPase family is well-characterized across bacteria, yeast,
        plants, and mammals
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  review:
    summary: ITPase requires Mg2+ or Mn2+ as cofactor (1 per subunit) for catalytic
      activity. However, metal ion binding is a very generic MF term that provides
      little functional insight. The metal binding is intrinsic to the catalytic mechanism
      rather than a distinct function.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
      supporting_text: HAM1/ITPase family is well-characterized across bacteria, yeast,
        plants, and mammals
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  review:
    summary: Nucleotide binding is intrinsic to the pyrophosphatase activity and is
      captured by the more specific substrate-level MF annotations. This generic term
      adds no functional insight and is redundant.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
      supporting_text: HAM1/ITPase family is well-characterized across bacteria, yeast,
        plants, and mammals
- term:
    id: GO:0009143
    label: nucleoside triphosphate catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  review:
    summary: Correct biological process for ITPase activity. The enzyme catalyzes
      catabolic hydrolysis of nucleoside triphosphates. However, it is a parent of
      the more specific deoxyribonucleoside triphosphate catabolic process and is
      somewhat redundant. Keep as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
      supporting_text: HAM1/ITPase family is well-characterized across bacteria, yeast,
        plants, and mammals
- term:
    id: GO:0009204
    label: deoxyribonucleoside triphosphate catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  review:
    summary: Correct biological process capturing the deoxyribonucleotide catabolism
      aspect of ITPase function. Well-supported by the enzyme's role in hydrolyzing
      dITP to prevent deoxyinosine incorporation into DNA [PMID:36464781].
    action: ACCEPT
    supported_by:
    - reference_id: PMID:36464781
      supporting_text: ITPA loss-of-function causes inosine di- and triphosphate accumulation
        in vivo and an elevated inosine and deoxyinosine content in RNA and DNA
    - reference_id: file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
      supporting_text: HAM1/ITPase family is well-characterized across bacteria, yeast,
        plants, and mammals
- term:
    id: GO:0009117
    label: nucleotide metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  review:
    summary: Very broad biological process term. Redundant with the more specific
      catabolic process annotations (GO:0009143, GO:0009204). Provides minimal functional
      insight.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
      supporting_text: HAM1/ITPase family is well-characterized across bacteria, yeast,
        plants, and mammals
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  review:
    summary: Cytoplasmic localization is well-supported by HAMAP rule MF_03148 and
      consistent with the nucleotide pool sanitization function. ITPase orthologs
      across organisms are cytoplasmic enzymes that act on cytosolic nucleotide pools.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:36464781
      supporting_text: Inosine triphosphate pyrophosphatase is part of a molecular
        protection system in plants
    - reference_id: file:9POAL/NCGR_LOCUS3088/NCGR_LOCUS3088-notes.md
      supporting_text: HAM1/ITPase family is well-characterized across bacteria, yeast,
        plants, and mammals
core_functions:
- description: Hydrolysis of non-canonical purine nucleoside triphosphates (ITP, dITP,
    XTP) to the corresponding monophosphates, sanitizing the cellular nucleotide pool
    to prevent incorporation of aberrant bases into DNA and RNA
  molecular_function:
    id: GO:0036220
    label: ITP diphosphatase activity
  directly_involved_in:
  - id: GO:0009204
    label: deoxyribonucleoside triphosphate catabolic process
  locations:
  - id: GO:0005737
    label: cytoplasm
status: DRAFT