Synthesis of Diphosphoinositol Pentakisphosphate by a Newly Identified Family of Higher Inositol Polyphosphate Kinases
Open accessAbstract
Inositol (1,4,5) trisphosphate (Ins(1,4,5)P(3)) is a well-known messenger molecule that releases calcium from intracellular stores. Homologues with up to six phosphates have been characterized and recently, homologues with seven or eight phosphate groups, including pyrophosphates, have been identified. These homologues are diphosphoinositol pentakisphosphate (PP-InsP(5)/InsP(7)) and bis(diphospho)inositol tetrakisphosphate (bis-PP-InsP(4)/InsP(8)) [1], the rapid turnover of which [2] is regulated by calcium [2] and adrenergic receptor activity [3]. It has been proposed that the high-energy pyrophosphates might participate in protein phosphorylation [4]. We have purified InsP(6) kinase [5] and PP-InsP(5) kinase [6], both of which display ATP synthase activity, transferring phosphate to ADP. Here, we report the cloning of two mammalian InsP(6) kinases and a yeast InsP(6) kinase. Furthermore, we show that the yeast protein, ArgRIII, is an inositol-polyphosphate kinase that can convert InsP(3) to InsP(4), InsP(5) and InsP(6). We have identified a new family of highly conserved inositol-polyphosphate kinases that contain a newly identified, unique consensus sequence.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
IPMK generates InsP4, InsP5, and PIP3.
“With dual inositol and lipid kinase activities, IPMK generates pivotal signaling molecules such as InsP4 (inositol tetraphosphate), InsP5 (inositol pentaphosphate), and PIP3 (phosphoinositide 3,4,5-trisphosphate), positioning it as a critical regulator of cellular mechanisms.”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [12]
The Results and discussion section (page unavailable) identifies IPMK as a kinase that phosphorylates InsP3 and InsP4, supporting its production of InsP4 and InsP5. Our copy does not establish lipid kinase activity or PIP3 production, so those parts of the citing sentence are unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredStudies across various organisms demonstrated a significant decrease in both InsP5 and InsP6 production in IPMK-null or kinase-dead cells.
“Studies across various organisms, from yeast to mammalian cells, have demonstrated a significant decrease in both InsP5 and InsP6 production in IPMK-null or kinase-dead cells [12,14].”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [12]
The Results and discussion (page unavailable) show that yeast ArgRIII/IPMK phosphorylates InsP3 and InsP4 and produces higher inositol polyphosphates, including a product consistent with InsP6. They do not report decreased InsP5 or InsP6 production in IPMK-null or kinase-dead cells, whether in yeast or mammalian cells; the HEK293 experiments used transfected enzyme. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIPMK has dual inositol and lipid kinase activities.
“With dual inositol and lipid kinase activities, IPMK generates pivotal signaling molecules such as InsP4 (inositol tetraphosphate), InsP5 (inositol pentaphosphate), and PIP3 (phosphoinositide 3,4,5-trisphosphate), positioning it as a critical regulator of cellular mechanisms.”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [12]
The Results and discussion section describes IPMK as a multifunctional kinase that phosphorylates InsP3 and InsP4, supporting its inositol kinase activity. Our copy does not report lipid kinase activity or PIP3 production, so it does not establish the claimed dual activity. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIPMK is a dual-specificity 6-/3-kinase that generates InsP4 and InsP5 species.
“A key enzyme in this pathway is inositol polyphosphate multikinase (IPMK), a dual-specificity 6-/3-kinase that generates InsP4 and InsP5 species [11,12].”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [12]
The Results and discussion identify ArgRIII as IPMK and report that it phosphorylates InsP3 and InsP4, producing higher inositol polyphosphates; this supports generation of InsP4 and InsP5. The passages do not establish that IPMK phosphorylates specifically at both the 6 and 3 positions, so the dual-specificity 6-/3-kinase description is not supported by our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe reduction in InsP5 and InsP6 upon IPMK deletion is primarily attributed to the decrease in InsP5 levels, which serves as the major precursor of InsP6.
“This reduction is primarily attributed to the decrease in InsP5 levels, which serves as the major precursor of InsP6 upon IPMK deletion, underscoring the critical role of IPMK in regulating HOIPs levels.”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [12]
The Results and discussion section identifies InsP5 as a substrate for conversion to InsP6 and says IPMK can presumably convert InsP3 to InsP6. It does not report IPMK-deletion experiments, reduced InsP5 or InsP6 levels after deletion, or evidence that a fall in InsP5 is the primary cause of a fall in InsP6. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
IPMK can modulate cellular signaling by generating highly phosphorylated inositol phosphates (HOIPs).
“This enzyme can modulate cellular signaling through multiple mechanisms: by generating highly phosphorylated inositol phosphates (HOIPs) [10,12,14], producing phosphatidylinositol 3,4,5-trisphosphate (PIP3) [10,12,14], or even functioning independently of its kinase activity through protein–protein interaction [10,11,12,14].”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [12]
The Results and discussion (page not provided) show that the yeast enzyme ArgRIII, identified as IPMK, generates higher inositol polyphosphates from InsP3. The paper does not show that this production modulates cellular signaling, so it supports the proposed mechanism only in part. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIPMK can modulate cellular signaling independently of its kinase activity through protein-protein interaction.
“This enzyme can modulate cellular signaling through multiple mechanisms: by generating highly phosphorylated inositol phosphates (HOIPs) [10,12,14], producing phosphatidylinositol 3,4,5-trisphosphate (PIP3) [10,12,14], or even functioning independently of its kinase activity through protein–protein interaction [10,11,12,14].”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [12]
The Results and discussion section identifies ArgRIII as IPMK and demonstrates its inositol-phosphate kinase activity. Searches for kinase-independent signaling and protein–protein interactions found no passage in our copy addressing that mechanism. The cited paper therefore does not verify this part of the sentence. (LLM, conf=0.76)
Experimental — accuracy not yet measuredIPMK can modulate cellular signaling by producing phosphatidylinositol 3,4,5-trisphosphate (PIP3).
“This enzyme can modulate cellular signaling through multiple mechanisms: by generating highly phosphorylated inositol phosphates (HOIPs) [10,12,14], producing phosphatidylinositol 3,4,5-trisphosphate (PIP3) [10,12,14], or even functioning independently of its kinase activity through protein–protein interaction [10,11,12,14].”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [12]
The Results and discussion section says IPMK phosphorylates InsP3 and InsP4, but does not say it produces the lipid PIP3 or modulates signaling through PIP3 production. Searches for phosphatidylinositol 3,4,5-trisphosphate and PIP3 found no passage addressing that mechanism; page numbers were not available in our copy. (LLM, conf=0.74)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
No references could be resolved yet.
Research works printed but not linked: 1
- [1]1. Stephens, L ∙ Radenberg, T ∙ Thiel, U ... The detection, purification, structural characterization, and metabolism of diphosphoinositol pentakisphosphate(s) and bisdiphosphoinositol tetrakisphosphate(s) J Biol Chem. 1993; 268:4009-4015
Cited by
Sorted by citations
Signal Transduction Cascades Regulating Fungal Development and Virulence
Lengeler, K. B., Davidson, R. C., D'souza, C., Harashima, T., Shen, W.-C., Wang, P., Pan, X., Waugh, M., & Heitman, J. (2000) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.64.4.746-785.2000 · Cited by 915 · see citing works
A Role for Nuclear Inositol 1,4,5-Trisphosphate Kinase in Transcriptional Control
Odom, A. R., Stahlberg, A., Wente, S. R., & York, J. D. (2000) · Science · doi:10.1126/science.287.5460.2026 · Cited by 394 · see citing works
Inositol pyrophosphates: between signalling and metabolism
Wilson, M. S. C., Livermore, T. M., & Saiardi, A. (2013) · Biochemical Journal · doi:10.1042/bj20130118 · Cited by 256 · see citing works
Self-citationSaiardi, A., Nagata, E., Luo, H. R., Sawa, A., Luo, X., Snowman, A. M., & Snyder, S. H. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.041614598 · Cited by 110 · see citing works
Self-citationNALASKOWSKI, M. M., DESCHERMEIER, C., FANICK, W., & MAYR, G. W. (2002) · Biochemical Journal · doi:10.1042/bj20020327 · Cited by 89 · see citing works
El Alami, M., Messenguy, F., Scherens, B., & Dubois, E. (2003) · Molecular Microbiology · doi:10.1046/j.1365-2958.2003.03562.x · Cited by 83 · see citing works
Nagpal, L., Kornberg, M. D., & Snyder, S. H. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2121946119 · Cited by 22 · see citing works
Self-citationFrom Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease
Mishra, S. H., Chatterjee, S., Viera-Preval, L., & Guha, P. (2025) · Biomolecules · doi:10.3390/biom15091266 · Cited by 1 · see citing works
“A key enzyme in this pathway is inositol polyphosphate multikinase (IPMK), a dual-specificity 6-/3-kinase that generates InsP4 and InsP5 species [11,12].”
Influential
- Authors
- Saiardi, A., Erdjument-Bromage, H., Snowman, A. M., Tempst, P., & Snyder, S. H.
- Affiliations
- Johns Hopkins University (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Snyder, Solomon H.
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 1999-11
- Volume
- 9
- Issue
- 22
- Pages
- 1323-1326
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W2046122733
- Cited by
- 414
- References
- 0
- Citations by year
- 2026: 10 · 2025: 22 · 2024: 21 · 2023: 25 · 2022: 11 · 2021: 20 · 2020: 14 · 2019: 17 · 2018: 13 · 2017: 18 · 2016: 22 · 2015: 15 · 2014: 14 · 2013: 12 · 2012: 12
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institute of Mental Health (MH-18501)
- National Institute on Drug Abuse (DA 00074)
- National Cancer Institute (P30-CA-08748, P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- inositol polyphosphate kinase, inositol hexakisphosphate kinase, inositol trisphosphate, inositol pyrophosphates, ATP synthase activity, protein phosphorylation, calcium signaling
- MeSH terms
- Adenosine Triphosphate, Amino Acid Sequence, Animals, Brain, Female, Fungal Proteins, Multigene Family, Inositol Phosphates, Male, Molecular Sequence Data, Nerve Tissue Proteins, Organ Specificity, Recombinant Fusion Proteins, Consensus Sequence, Sequence Alignment, Sequence Homology, Amino Acid, Phosphotransferases (Alcohol Group Acceptor), Phosphotransferases (Phosphate Group Acceptor), Saccharomyces cerevisiae Proteins, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
