@article{dea02058a9fd4a45bda3d12b41cc8bb0,
title = "Critical Roles of the Pentose Phosphate Pathway and GLN3 in Isobutanol-Specific Tolerance in Yeast",
abstract = "This study provides insights into the yeast response to isobutanol and mechanisms underlying specific toxicity and tolerance to isobutanol. Deletion of GLN3 markedly increases yeast tolerance specifically to branched-chain alcohols and isobutanol production. Deletion of GLN3 evades the native nitrogen starvation response induced by isobutanol, enhancing isobutanol tolerance. These findings illustrate how adaptive mechanisms to tolerate stress can lead to toxicity in chemical production and provide a promising strategy to boost production by genetically disrupting such mechanisms.",
keywords = "GCN4, GLN3, Saccharomyces cerevisiae, TOR, alcohol tolerance, amino acid biosynthesis, genome-wide screen, isobutanol, nitrogen catabolite repression, pentose phosphate pathway",
author = "Kouichi Kuroda and Hammer, {Sarah K.} and Yukio Watanabe and {Monta{\~n}o L{\'o}pez}, Jos{\'e} and Fink, {Gerald R.} and Gregory Stephanopoulos and Mitsuyoshi Ueda and Avalos, {Jos{\'e} L.}",
note = "Funding Information: This work was supported by the US Department of Energy, Office of Science, Office of Biological and Environmental Research, Genomic Science Program under award number DESC0019363 (to J.L.A.), as well as the NSF CAREER award 1751840, the Pew Charitable Trusts, the Alfred P. Sloan Foundation, and the Yang Family Foundation for Engineering from Princeton University SEAS (to J.L.A.); the John Mung Program Kyoto University (to K.K.); the SPIRITS 2017 of Kyoto University (to K.K. and M.U.); the NSF Graduate Research Fellowship Program grant DGE-1656466 (to S.K.H.); NIH grant GM035010 (to G.R.F.); and DOE grant 6935036 (to G.S.). K.K. G.R.F. and J.L.A. conceived the project and designed the experiments. S.K.H. conducted isobutanol production experiments and NADPH/NADP+ ratio measurements. Y.W. carried out RNA-seq analysis and quantification of intracellular amino acids. J.M.L. analyzed RNA-seq data and prepared the volcano plots. K.K. performed isobutanol production in the in-house-prepared medium and all other experiments. K.K. S.K.H. G.R.F. and J.L.A. analyzed the results. K.K. G.R.F. G.S. M.U. and J.L.A. allocated materials and resources. K.K. and J.L.A. supervised the project. K.K. S.K.H. and J.L.A. wrote the manuscript in consultation with G.R.F. G.S. and M.U. The authors declare no competing interests. A patent application describing the isobutanol hypertolerant mutants is currently pending. Funding Information: This work was supported by the US Department of Energy, Office of Science, Office of Biological and Environmental Research , Genomic Science Program under award number DESC0019363 (to J.L.A.), as well as the NSF CAREER award 1751840 , the Pew Charitable Trusts , the Alfred P. Sloan Foundation , and the Yang Family Foundation for Engineering from Princeton University SEAS (to J.L.A.); the John Mung Program Kyoto University (to K.K.); the SPIRITS 2017 of Kyoto University (to K.K. and M.U.); the NSF Graduate Research Fellowship Program grant DGE-1656466 (to S.K.H.); NIH grant GM035010 (to G.R.F.); and DOE grant 6935036 (to G.S.). Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = dec,
day = "18",
doi = "10.1016/j.cels.2019.10.006",
language = "English (US)",
volume = "9",
pages = "534--547.e5",
journal = "Cell Systems",
issn = "2405-4712",
publisher = "Cell Press",
number = "6",
}