Affinage

ITPK1

Inositol-tetrakisphosphate 1-kinase · UniProt Q13572

Length
414 aa
Mass
45.6 kDa
Annotated
2026-04-28
19 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ITPK1 is a reversible, stereospecific inositol phosphate kinase that occupies a central branch point in inositol phosphate metabolism, coupling phospholipase C signaling to chloride channel regulation and providing a lipid-independent route to higher inositol phosphates. The enzyme transfers phosphate between inositol phosphates via a tightly bound nucleotide intermediate (intersubstrate phosphotransfer), converting PLC-generated Ins(1,3,4)P3 into Ins(3,4,5,6)P4—a physiological inhibitor of Ca2+-activated chloride channels—and localizes to the apical membrane of epithelial cells to spatially couple this synthesis to channel regulation (PMID:17616525, PMID:18272466, PMID:16537650). ITPK1 also phosphorylates Ins(3)P1 derived from glucose-6-phosphate and Ins(1)P1 from sphingolipid catabolism, enabling a soluble, PLC-independent route to IP5/IP6 synthesis that is controlled by cellular metabolic and energy status (PMID:31754032). Its activity and stability are tuned by reversible lysine acetylation written by CBP/p300 and erased by SIRT2, with acetylation reducing both catalytic activity and protein half-life (PMID:22308441).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2005 High

    Establishing that ITPK1 is highly stereospecific resolved which enantiomeric inositol phosphates are physiological substrates versus non-substrates, ruling out Ins(1,4,5,6)P4 and defining the enzyme's catalytic selectivity.

    Evidence In vitro kinase assays with synthetic stereospecific inositol phosphate enantiomers and quantitative Km measurements

    PMID:16376887

    Open questions at the time
    • Structural basis for stereospecificity was not yet determined
    • In vivo relevance of enantiomeric discrimination not tested
  2. 2006 High

    Demonstrating apical membrane localization of ITPK1 in tracheal epithelial cells established that Ins(3,4,5,6)P4 synthesis is spatially compartmentalized adjacent to its chloride channel targets, and that ITPK1 expression is reduced in cystic fibrosis epithelia.

    Evidence Confocal immunofluorescence in mouse tracheal epithelial cells; HPLC inositol phosphate quantification; comparison of wild-type and CF cells

    PMID:16537650

    Open questions at the time
    • Mechanism of apical targeting not identified
    • Whether reduced ITPK1 in CF is cause or consequence of CFTR loss not resolved
  3. 2007 High

    The crystal structure of ITPK1 revealed that it catalyzes intersubstrate phosphotransfer through a tightly bound nucleotide intermediate without releasing it to bulk medium, a mechanism unique to the human enzyme and absent in plant and protozoan homologues.

    Evidence High-resolution crystal structure determination, in vitro kinase assays, mutagenesis, and comparative enzymology across species

    PMID:17616525

    Open questions at the time
    • Physiological consequences of intersubstrate transfer versus classical kinase mechanism not tested in cells
    • No structural data for enzyme–membrane complex
  4. 2008 High

    Defining the full substrate-product repertoire of ITPK1—including 5- and 6-kinase and 1-phosphatase activities—established how the enzyme links PLC activation to control of Ins(3,4,5,6)P4 abundance and thereby to Ca2+-activated chloride channel inhibition.

    Evidence In vitro enzyme activity assays with defined substrates/products; cell-based inositol phosphate measurements

    PMID:18272466

    Open questions at the time
    • Direct demonstration of chloride current regulation by endogenous ITPK1 manipulation not shown
    • Identity of the specific chloride channel isoform regulated not determined
  5. 2012 High

    Identification of CBP/p300 as the acetyltransferase and SIRT2 as the deacetylase for ITPK1 at three surface lysines established a post-translational regulatory axis that tunes both enzyme stability and catalytic output, linking metabolic signaling to inositol phosphate levels.

    Evidence Mass spectrometry acetylation site mapping; overexpression of writers/erasers; stable cell lines with inositol phosphate profiling

    PMID:22308441

    Open questions at the time
    • Physiological signals that trigger acetylation/deacetylation cycle not identified
    • Impact of acetylation on intersubstrate phosphotransfer mechanism not examined
  6. 2012 Medium

    Reconstitution of ITPK1 in Drosophila S3 cells showed that PLC activation alone is insufficient to drive Ins(3,4,5,6)P4 production, indicating that substrate mass action does not fully account for ITPK1 signaling output and additional regulatory inputs exist.

    Evidence Heterologous expression in Drosophila S3 cells; [3H]-inositol labeling; HPLC profiling; dsRNA knockdown

    PMID:22928859

    Open questions at the time
    • Nature of the missing regulatory input not identified
    • Heterologous system may lack mammalian cofactors or localizing factors
  7. 2019 High

    Discovery that ITPK1 mediates a lipid-independent route to IP6 synthesis by phosphorylating Ins(3)P1 from glucose-6-phosphate and Ins(1)P1 from sphingolipids revealed that the enzyme integrates metabolic status with inositol phosphate signaling, expanding its role beyond PLC-coupled pathways.

    Evidence PAGE mass assay; [3H]-inositol labeling; ITPK1 knockout; phosphate starvation experiments in mammalian cells

    PMID:31754032

    Open questions at the time
    • Relative quantitative contribution of soluble versus PLC-dependent routes under physiological conditions not determined
    • Metabolic sensors upstream of ITPK1 in this pathway not identified
  8. 2024 Medium

    An in vivo CRISPR screen revealed that ITPK1 kinase activity sensitizes tumor cells to IgA-dependent neutrophil-mediated killing, establishing a previously unknown immunological role for inositol phosphate metabolism in tumor immune surveillance.

    Evidence Genome-wide in vivo CRISPR screen; hCD89 transgenic mouse model; ITPK1 KO and kinase-dead rescue

    PMID:39213127

    Open questions at the time
    • Specific inositol phosphate product mediating neutrophil sensitivity not identified
    • Mechanism linking ITPK1 kinase activity to tumor cell vulnerability unknown
    • Not independently replicated in a second in vivo model
  9. 2026 Medium

    Selective IP5 depletion by ITPK1 knockdown in β-cells accelerated termination of mTORC1 signaling without affecting its initiation, implicating ITPK1-derived IP5 in stabilizing active mTORC1 and revealing compensatory IP5 supply by IPMK.

    Evidence (preprint) ITPK1 siRNA knockdown with IPMK co-inhibition; inositol phosphate profiling; mTORC1 activity assays in β-cells

    PMID:41867875

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Direct physical interaction between IP5 and mTORC1 components not demonstrated
    • Generalizability beyond β-cells not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of physiological signals that control ITPK1 acetylation dynamics, the structural basis of its apical membrane targeting, the specific inositol phosphate species mediating its immunological and mTORC1-related functions, and how PLC-dependent and lipid-independent routes are coordinated in vivo.
  • No structural model of ITPK1 at the membrane or in complex with regulatory partners
  • The specific chloride channel isoform regulated by ITPK1-produced Ins(3,4,5,6)P4 remains unidentified
  • Relative flux through PLC-dependent versus soluble IP6 synthesis routes under physiological conditions is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0016787 hydrolase activity 1
Localization
GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 3 GO:0016740 transferase activity 1 R-HSA-1430728 Metabolism 1
Partners
CBPEP300IPMKSIRT2

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Human ITPK1 is a reversible, poly-specific inositol phosphate kinase that transfers phosphate between inositol phosphates via a tightly bound nucleotide intermediate (intersubstrate phosphate transfer), without releasing the nucleotide into bulk medium. This mechanism allows Ins(1,3,4)P3 to stimulate increased cellular concentrations of Ins(3,4,5,6)P4. High-resolution crystal structure identified novel secondary structural features imparting substrate selectivity and enhancing nucleotide binding. This intersubstrate transfer is specific to the human enzyme and absent in plant or protozoan homologues. Crystal structure determination, in vitro kinase assays, mutagenesis, comparative enzymology across species The Journal of biological chemistry High 17616525
2008 Human ITPK1 links receptor-dependent phospholipase C activation to Ca2+-activated chloride channel regulation: it phosphorylates Ins(1,3,4)P3 at the 5 or 6 positions and Ins(3,4,5,6)P4 at the 1 position, and dephosphorylates Ins(1,3,4,5,6)P5 to Ins(3,4,5,6)P4, thereby controlling the abundance of Ins(3,4,5,6)P4, which inhibits plasma membrane Ca2+-activated chloride channels. In vitro enzyme activity assays, cell-based inositol phosphate measurements, mechanistic analysis of intersubstrate phosphate transfer Science signaling High 18272466
2005 Human ITPK1 is highly stereospecific: it phosphorylates only the 1-hydroxyl of Ins(3,5,6)P3 and Ins(4,5,6)P3, and has >13,000-fold preference for Ins(3,4,5,6)P4 over its enantiomer Ins(1,4,5,6)P4, establishing that Ins(1,4,5,6)P4 is not a physiological substrate of hITPK1. In vitro kinase assays with stereospecific inositol phosphate substrates and enantiomers; comparative Km measurements FEBS letters High 16376887
2006 ITPK1 is concentrated at the apical membrane of mouse tracheal epithelial cells (MTEs), as determined by confocal immunofluorescence microscopy. This apical localization compartmentalizes Ins(3,4,5,6)P4 synthesis adjacent to Ca2+-activated Cl- channels, amplifying its regulatory capacity. In CF MTEs, ITPK1 expression and Ins(3,4,5,6)P4 levels are ~50–60% lower than wild-type, relieving Cl- channel inhibition. Confocal immunofluorescence microscopy for localization; HPLC for inositol phosphate quantification; real-time PCR for expression; cell-permeable Ins(3,4,5,6)P4 analogue functional assay Journal of cell science High 16537650
2012 ITPK1 is regulated by reversible lysine acetylation. Acetyltransferases CBP/p300 acetylate ITPK1 at lysines 340, 383, and 410 (surface residues), reducing its stability (shortening half-life) and enzymatic activity. SIRT2 deacetylates ITPK1. HEK293 cells stably expressing acetylated ITPK1 show reduced levels of higher inositol phosphates. Mass spectrometry identification of acetylation sites; overexpression of acetyltransferases (CBP, p300) and deacetylase (SIRT2); stable cell lines; inositol phosphate profiling Proceedings of the National Academy of Sciences of the United States of America High 22308441
2012 In Drosophila S3 cells expressing human ITPK1, GBP cytokine-stimulated PLC activation did not result in Ins(3,4,5,6)P4 synthesis, contradicting the hypothesis that ITPK1's PLC-coupled phosphotransferase activity [Ins(1,3,4,5,6)P5 + Ins(1,3,4)P3 → Ins(3,4,5,6)P4 + Ins(1,3,4,6)P4] is driven solely by mass action, indicating additional regulatory control of ITPK1 signaling beyond substrate availability. Heterologous expression of human ITPK1 in Drosophila S3 cells under inducible metallothionein promoter; [3H]inositol labeling; HPLC inositol phosphate analysis; dsRNA knockdown of IP3 receptor The Biochemical journal Medium 22928859
2019 In mammalian cells, PLC-generated inositol phosphates are rapidly recycled to inositol, and ITPK1 mediates an alternative 'soluble' (lipid-independent) route to inositol phosphate synthesis: ITPK1 phosphorylates I(3)P1 originating from glucose-6-phosphate and I(1)P1 generated from sphingolipids, enabling synthesis of IP6. Metabolic blockage by phosphate starvation increases IP6 levels in an ITPK1-dependent manner, establishing a route to IP6 controlled by cellular metabolic status. PAGE mass assay for inositol phosphates; [3H]-inositol labeling; genetic manipulation (ITPK1 knockdown/knockout); phosphate starvation metabolic experiments; comparative enzymology Proceedings of the National Academy of Sciences of the United States of America High 31754032
2024 ITPK1 kinase activity sensitizes tumor cells to IgA-dependent neutrophil-mediated killing in vivo. Deletion of ITPK1 increases survival of IgA-opsonized target cells in anti-Her2 IgA-treated mice in a neutrophil-dependent manner; a kinase-dead ITPK1 does not rescue this phenotype, establishing that the kinase domain is required. Genome-wide in vivo CRISPR screen; hCD89 transgenic mouse model; ITPK1 deletion and kinase-domain mutant rescue experiments; in vivo survival assays with neutrophil depletion controls Journal of immunology Medium 39213127
2026 ITPK1 knockdown in pancreatic β-cells selectively reduces cellular IP5 levels without altering IP6, and impairs basal and insulin-stimulated mTORC1 signaling. Combined inhibition of IPMK and ITPK1 nearly abolishes IP5 and reduces IP6, demonstrating compensatory supply of IP5 for IP6 synthesis. IP5 depletion accelerates termination of the mTORC1 signal (without affecting initiation), implicating IP5 in stabilizing the active mTORC1 complex. ITPK1 siRNA knockdown; IPMK inhibition; inositol phosphate profiling; mTORC1 activity assays; PI3K/Akt pathway measurements; β-cell model system bioRxivpreprint Medium 41867875

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 ITPK1 is an InsP6/ADP phosphotransferase that controls phosphate signaling in Arabidopsis. Molecular plant 79 34274522
2018 Arabidopsis inositol phosphate kinases IPK1 and ITPK1 constitute a metabolic pathway in maintaining phosphate homeostasis. The Plant journal : for cell and molecular biology 78 29779236
2019 ITPK1 mediates the lipid-independent synthesis of inositol phosphates controlled by metabolism. Proceedings of the National Academy of Sciences of the United States of America 74 31754032
2019 Arabidopsis ITPK1 and ITPK2 Have an Evolutionarily Conserved Phytic Acid Kinase Activity. ACS chemical biology 60 31525024
2020 An ATP-responsive metabolic cassette comprised of inositol tris/tetrakisphosphate kinase 1 (ITPK1) and inositol pentakisphosphate 2-kinase (IPK1) buffers diphosphosphoinositol phosphate levels. The Biochemical journal 42 32706850
2007 Integration of inositol phosphate signaling pathways via human ITPK1. The Journal of biological chemistry 42 17616525
2021 Arabidopsis inositol polyphosphate kinases IPK1 and ITPK1 modulate crosstalk between SA-dependent immunity and phosphate-starvation responses. Plant cell reports 38 34797387
2019 Microstructural changes in the brain mediate the association of AK4, IGFBP5, HSPB2, and ITPK1 with cognitive decline. Neurobiology of aging 19 31479860
2008 Human ITPK1: a reversible inositol phosphate kinase/phosphatase that links receptor-dependent phospholipase C to Ca2+-activated chloride channels. Science signaling 19 18272466
2014 The maternal ITPK1 gene polymorphism is associated with neural tube defects in a high-risk Chinese population. PloS one 16 24465924
2006 Apical localization of ITPK1 enhances its ability to be a modifier gene product in a murine tracheal cell model of cystic fibrosis. Journal of cell science 14 16537650
2023 ITPK1 Regulates Jasmonate-Controlled Root Development in Arabidopsis thaliana. Biomolecules 12 37759768
2025 Orchestration of phosphate homeostasis by the ITPK1-type inositol phosphate kinase in the liverwort Marchantia polymorpha. Plant physiology 11 39190827
2005 On the contribution of stereochemistry to human ITPK1 specificity: Ins(1,4,5,6)P4 is not a physiologic substrate. FEBS letters 10 16376887
2012 Activation of PLC by an endogenous cytokine (GBP) in Drosophila S3 cells and its application as a model for studying inositol phosphate signalling through ITPK1. The Biochemical journal 8 22928859
2012 Regulation of inositol 1,3,4-trisphosphate 5/6-kinase (ITPK1) by reversible lysine acetylation. Proceedings of the National Academy of Sciences of the United States of America 5 22308441
2024 ITPK1 Sensitizes Tumor Cells to IgA-dependent Neutrophil Killing In Vivo. Journal of immunology (Baltimore, Md. : 1950) 1 39213127
2026 Suppression of ITPK1 and IPMK activities impairs mTORC1 signaling in pancreatic β-cells and implicates IP5 in stabilizing activated mTORC1. bioRxiv : the preprint server for biology 0 41867875
2022 Genetic Effects of ITPK1 Polymorphisms on the Risk of Neural Tube Defects: a Population-Based Study. Reproductive sciences (Thousand Oaks, Calif.) 0 36323916