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ITPK1 Mediates the Lipid-Independent Synthesis of Inositol Phosphates Controlled by Metabolism

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Desfougères, Yann, Wilson, Miranda S. C., Laha, Debabrata, Miller, Gregory J., Saiardi, Adolfo·2019·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1911431116PMC PMC6900528
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Abstract

Inositol phosphates (IPs) comprise a network of phosphorylated molecules that play multiple signaling roles in eukaryotes. IPs synthesis is believed to originate with IP 3 generated from PIP 2 by phospholipase C (PLC). Here, we report that in mammalian cells PLC-generated IPs are rapidly recycled to inositol, and uncover the enzymology behind an alternative “soluble” route to synthesis of IPs. Inositol tetrakisphosphate 1-kinase 1 (ITPK1)—found in Asgard archaea, social amoeba, plants, and animals—phosphorylates I(3)P 1 originating from glucose-6-phosphate, and I(1)P 1 generated from sphingolipids, to enable synthesis of IP 6 . We also found using PAGE mass assay that metabolic blockage by phosphate starvation surprisingly increased IP 6 levels in a ITPK1-dependent manner, establishing a route to IP 6 controlled by cellular metabolic status, that is not detectable by traditional [ 3 H]-inositol labeling. The presence of ITPK1 in archaeal clades thought to define eukaryogenesis indicates that IPs had functional roles before the appearance of the eukaryote.

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  • ITPK1 can utilize Glucose-6-phosphate-derived InsP3 to generate InsP4 (InsP 1,3,4,5).

    “However, recent findings [38] suggest that ITPK1 can utilize Glucose-6-phosphate-derived InsP3 to generate InsP4 (InsP 1,3,4,5), and both isoforms of InsP4 are converted to InsP5 (InsP 1,3,4,5,6) exclusively by IPMK.”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [38]

    The Results section, “ITPK1 Can Use I(3)P1 to Generate Higher IPs” (page unavailable), reports that ITPK1 can use a glucose-6-phosphate-derived substrate to make higher inositol phosphates. But it identifies that substrate as I(3)P1, not InsP3, and does not establish that the product is specifically InsP(1,3,4,5)P4. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • IPMK can use either InsP3 or InsP4 to generate InsP5.

    “Hence, IPMK can use either InsP3 or InsP4 to generate InsP5 (Ins 1,3,4,5,6).”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [38]

    The Discussion section (“ITPK1 Is Essential for IPs Synthesis in Mammals”; page unavailable) proposes that IPMK phosphorylates a substrate to produce I(1,3,4,5,6)P5. It does not identify both InsP3 and InsP4 as substrates IPMK can use, so the claim’s either-or specificity is unsupported. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Both isoforms of InsP4 are converted to InsP5 exclusively by IPMK.

    “However, recent findings [38] suggest that ITPK1 can utilize Glucose-6-phosphate-derived InsP3 to generate InsP4 (InsP 1,3,4,5), and both isoforms of InsP4 are converted to InsP5 (InsP 1,3,4,5,6) exclusively by IPMK.”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [38]

    The Discussion (page unavailable) proposes that IPMK phosphorylates a downstream substrate to produce I(1,3,4,5,6)P5. It does not identify both InsP4 isoforms as substrates or establish that IPMK does so exclusively; the Results also show that ITPK1 can produce an IP5, although its isomer was not identified. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Authors
Desfougères, Y., Wilson, M. S. C., Laha, D., Miller, G. J., & Saiardi, A.
Affiliations
  • MRC Laboratory for Molecular Cell Biology (GB)
  • Catholic University of America (US)
Corresponding author
Saiardi, Adolfo
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2019-11-21
Volume
116
Issue
49
Pages
24551-24561
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1911431116
PMC
PMC6900528
OpenAlex
W2989629836
Cited by
93
References
3
Citations by year
2026: 11 · 2025: 18 · 2024: 9 · 2023: 15 · 2022: 13 · 2021: 9 · 2020: 18
FWCI
3.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
Funders
  • European Commission (HORIZON2020, 752903)
  • National Institutes of Health
  • Medical Research Council (MC_UU_12018/4, MC_UU_00012/4)
  • National Institute of General Medical Sciences (R15GM106322)
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 › PI3K/AKT/mTOR signaling in cancer
Keywords
inositol phosphates, phytic acid, inositol tetrakisphosphate, inositol trisphosphate, phospholipase C, glucose-6-phosphate, sphingolipids, phosphate limitation, metabolic regulation, eukaryotic origin, Asgard archaea
MeSH terms
Amino Acid Sequence, Humans, Hydrolysis, Inositol, Inositol Phosphates, Type C Phospholipases, Phosphorylation, Saccharomyces cerevisiae, Sphingolipids, Conserved Sequence, Phosphotransferases (Alcohol Group Acceptor), Archaeal Proteins, HCT116 Cells

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