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dc.contributor.authorGeorge, KW
dc.contributor.authorThompson, M
dc.contributor.authorKim, J
dc.contributor.authorBaidoo, EEK
dc.contributor.authorWang, G
dc.contributor.authorBenites, VT
dc.contributor.authorPetzold, CJ
dc.contributor.authorChan, LJG
dc.contributor.authorYilmaz, S
dc.contributor.authorTurhanen, P
dc.contributor.authorAdams, PD
dc.contributor.authorKeasling, JD
dc.contributor.authorLee, TS
dc.date.accessioned2018-05-16T12:45:55Z
dc.date.available2018-05-16T12:45:55Z
dc.date.issued2018
dc.identifier.urihttps://erepo.uef.fi/handle/123456789/6613
dc.description.abstractIsopentenyl pyrophosphate (IPP) toxicity presents a challenge in engineered microbial systems since its formation is unavoidable in terpene biosynthesis. In this work, we develop an experimental platform to study IPP toxicity in isoprenol-producing Escherichia coli. We first characterize the physiological response to IPP accumulation, demonstrating that elevated IPP levels are linked to growth inhibition, reduced cell viability, and plasmid instability. We show that IPP toxicity selects for pathway “breakage”, using proteomics to identify a reduction in phosphomevalonate kinase (PMK) as a probable recovery mechanism. Next, using multi-omics data, we demonstrate that endogenous E. coli metabolism is globally impacted by IPP accumulation, which slows nutrient uptake, decreases ATP levels, and perturbs nucleotide metabolism. We also observe the extracellular accumulation of IPP and present preliminary evidence that IPP can be transported by E. coli, findings that might be broadly relevant for the study of isoprenoid biosynthesis. Finally, we discover that IPP accumulation leads to the formation of ApppI, a nucleotide analog of IPP that may contribute to observed toxicity phenotypes. This comprehensive assessment of IPP stress suggests potential strategies for the alleviation of prenyl diphosphate toxicity and highlights possible engineering targets for improved IPP flux and high titer isoprenoid production.
dc.language.isoenglanti
dc.publisherElsevier BV
dc.relation.ispartofseriesMetabolic Engineering
dc.relation.urihttp://dx.doi.org/10.1016/j.ymben.2018.03.004
dc.rightsCC BY-NC-ND https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectIsopentenyl pyrophosphate (IPP)
dc.subjectIPP toxicity
dc.subjectIsoprenol
dc.subjectApppI
dc.subjectmevalonate pathway
dc.subjectmulti-omics
dc.titleIntegrated analysis of isopentenyl pyrophosphate (IPP) toxicity in isoprenoid-producing Escherichia coli
dc.description.versionfinal draft
dc.contributor.departmentSchool of Pharmacy, Activities
uef.solecris.id53241463en
dc.type.publicationTieteelliset aikakauslehtiartikkelit
dc.rights.accessrights© International Metabolic Engineering Society.
dc.relation.doi10.1016/j.ymben.2018.03.004
dc.description.reviewstatuspeerReviewed
dc.format.pagerange60-72
dc.relation.issn1096-7176
dc.relation.volume47
dc.rights.accesslevelopenAccess
dc.type.okmA1
uef.solecris.openaccessEi


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