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This study investigates the metabolic pathways of inositol pyrophosphates (IPPs) in the yeast cell line Pho\n                    <jats:sup>\u0394SPX<\/jats:sup>\n                    and the human tumor cell line HCT116. Utilizing pulse-labelling experiments with\n                    <jats:sup>18<\/jats:sup>\n                    O water and ordinary differential equation (ODE) models, we explore the synthesis and turnover of the highly phosphorylated IPP, 1,5-InsP\n                    <jats:sub>8<\/jats:sub>\n                    . Our findings challenge the notion that 1,5-InsP\n                    <jats:sub>8<\/jats:sub>\n                    can be synthesized through distinct routes, revealing a linear reaction sequence in both systems. Employing model reduction via the profile likelihood method, we achieved statistically concise identifiability analysis that led to significant biological insights. In yeast, we determined that 1,5-InsP\n                    <jats:sub>8<\/jats:sub>\n                    production primarily occurs through the phosphorylation of 5-InsP\n                    <jats:sub>7<\/jats:sub>\n                    , with the pathway involving 1-InsP\n                    <jats:sub>7<\/jats:sub>\n                    deemed unnecessary as its removal did not compromise model accuracy. Crucially, this prediction of altered IPP concentrations was validated experimentally in\n                    <jats:italic>vip1<\/jats:italic>\n                    \u0394 and\n                    <jats:italic>kcs1<\/jats:italic>\n                    \u0394 knockout strains, providing orthogonal biological support for the reduced model. In HCT116 cells, 1,5-InsP\n                    <jats:sub>8<\/jats:sub>\n                    synthesis is mainly driven by 1-InsP\n                    <jats:sub>7<\/jats:sub>\n                    , with variations observed across different experimental conditions. These results underscore the utility of model reduction in enhancing our understanding of metabolic pathways, coupling predictive modeling with experimental validation, and providing a framework for future investigations into the regulation and implications of linear IPP pathways in eukaryotic cells.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1013680","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T18:41:15Z","timestamp":1762800075000},"page":"e1013680","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["A linear pathway for inositol pyrophosphate metabolism revealed by 18O labeling and model reduction"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3608-5969","authenticated-orcid":true,"given":"Jacques","family":"Hermes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3580-2471","authenticated-orcid":true,"given":"Geun-Don","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guizhen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Giovanna","family":"De Leo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Mayer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henning","family":"Jessen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Timmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"key":"pcbi.1013680.ref001","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1146\/annurev.nu.06.070186.003023","article-title":"Metabolism and function of myo-inositol and inositol phospholipids","volume":"6","author":"BJ Holub","year":"1986","journal-title":"Annu Rev Nutr."},{"issue":"6288","key":"pcbi.1013680.ref002","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1126\/science.aad9858","article-title":"Control of eukaryotic phosphate homeostasis by inositol polyphosphate sensor domains","volume":"352","author":"R Wild","year":"2016","journal-title":"Science."},{"issue":"1","key":"pcbi.1013680.ref003","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/s41467-020-20681-4","article-title":"Inositol pyrophosphates promote the interaction of SPX domains with the coiled-coil motif of PHR transcription factors to regulate plant phosphate homeostasis","volume":"12","author":"MK Ried","year":"2021","journal-title":"Nat Commun."},{"issue":"1","key":"pcbi.1013680.ref004","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1038\/s41467-023-38315-w","article-title":"Inositol pyrophosphates activate the vacuolar transport chaperone complex in yeast by disrupting a homotypic SPX domain interaction","volume":"14","author":"J Pipercevic","year":"2023","journal-title":"Nat Commun."},{"issue":"10","key":"pcbi.1013680.ref005","article-title":"Cryo-EM structure of the polyphosphate polymerase VTC reveals coupling of polymer synthesis to membrane transit","volume":"42","author":"W Liu","year":"2023","journal-title":"EMBO J."},{"issue":"6723","key":"pcbi.1013680.ref006","article-title":"Structural basis for inositol pyrophosphate gating of the phosphate channel XPR1","volume":"386","author":"Y Lu","year":"2024","journal-title":"Science."},{"issue":"8031","key":"pcbi.1013680.ref007","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1038\/s41586-024-07852-9","article-title":"Human XPR1 structures reveal phosphate export mechanism","volume":"633","author":"R Yan","year":"2024","journal-title":"Nature."},{"issue":"2","key":"pcbi.1013680.ref008","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1111\/brv.12392","article-title":"The inositol pyrophosphate pathway in health and diseases","volume":"93","author":"A Chakraborty","year":"2018","journal-title":"Biol Rev Camb Philos Soc."},{"issue":"3","key":"pcbi.1013680.ref009","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1007\/s12038-015-9549-x","article-title":"The emerging roles of inositol pyrophosphates in eukaryotic cell physiology","volume":"40","author":"SG Thota","year":"2015","journal-title":"J Biosci."},{"key":"pcbi.1013680.ref010","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.3389\/fmicb.2020.01367","article-title":"Phosphate homeostasis - 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