{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T07:55:31Z","timestamp":1789718131717,"version":"4.0.1"},"reference-count":57,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T00:00:00Z","timestamp":1782000000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":82,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002835","name":"Chalmers University of Technology","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002835","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Although abolishing the Crabtree effect in\n                    <jats:italic>Saccharomyces cerevisiae<\/jats:italic>\n                    through a pyruvate dehydrogenase bypass eliminates carbon loss through ethanol overflow metabolism, it compromises growth rates. While the Crabtree effect has been a valuable natural adaptation, it is energetically inferior to respiration and is generally undesirable in cell factories engineered to produce assimilatory compounds. Restoring growth efficiency in Crabtree-negative strains remains a central challenge. Through adaptive laboratory evolution of the engineered strain (sZJD23) and subsequent reverse engineering, a variant (sZJD28) with markedly improved growth was identified. This improvement is driven primarily by a mutation in MED2 (encoding a Mediator complex subunit) and, to a lesser extent, a mutation in GPD1 (encoding glycerol-3-phosphate dehydrogenase). By integrating quantitative proteomics with enzyme-constrained genome-scale modelling, we demonstrate that these mutations jointly enable a more efficient mode of oxidative stress adaptation and energy utilization. The GPD1 mutation suppresses a protein-costly, suboptimal NAD\u207a-recycling strategy reliant on glycerol synthesis, while the MED2 mutation reshapes the oxidative stress response towards peroxisomal detoxification. Collectively, these adjustments optimize metabolic flux distribution and reduce protein costs in energy metabolism, thereby increasing ATP availability. Our findings reveal how coordinated mutations in regulatory and metabolic genes restore growth fitness in engineered Crabtree-negative yeast.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-58495-x","type":"journal-article","created":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T12:45:39Z","timestamp":1782045939000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Model-driven analysis reveals oxidative stress adaptation enabling efficient energy utilization in a Crabtree-negative Saccharomyces cerevisiae"],"prefix":"10.1038","volume":"16","author":[{"given":"Albert","family":"Tafur Rangel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9s","family":"Castillo Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl","family":"Malina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Siewers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduard J.","family":"Kerkhoven","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,21]]},"reference":[{"key":"58495_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep22264","volume":"6","author":"A Nilsson","year":"2016","unstructured":"Nilsson, A. & Nielsen, J. Metabolic trade-offs in yeast are caused by F1F0-ATP synthase. Sci. Rep. 6, 1\u201311 (2016).","journal-title":"Sci. Rep."},{"key":"58495_CR2","doi-asserted-by":"crossref","unstructured":"Malina, C., Yu, R., Bjorkeroth, J., Kerkhoven, E. J. & Nielsen, J. Adaptations in metabolism and protein translation give rise to the Crabtree effect in yeast. Proc. Natl. Acad. Sci. U. S. A. 118 (2021).","DOI":"10.1073\/pnas.2112836118"},{"key":"58495_CR3","doi-asserted-by":"publisher","DOI":"10.1016\/j.copbio.2025.103391","volume":"97","author":"B Teusink","year":"2026","unstructured":"Teusink, B., Grigaitis, P., Remeijer, M., Bruggeman, F. & Steuer, R. Resource allocation models: theory and applications in microbial biotechnology. Curr. Opin. Biotechnol. 97, 103391 (2026).","journal-title":"Curr. Opin. Biotechnol."},{"key":"58495_CR4","doi-asserted-by":"publisher","first-page":"17","DOI":"10.3389\/fmolb.2014.00017","volume":"1","author":"T Pfeiffer","year":"2014","unstructured":"Pfeiffer, T. & Morley, A. An evolutionary perspective on the Crabtree effect. Front. Mol. Biosci. 1, 17 (2014).","journal-title":"Front. Mol. Biosci."},{"key":"58495_CR5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-018-05409-9","volume":"9","author":"Z Dai","year":"2018","unstructured":"Dai, Z., Huang, M., Chen, Y., Siewers, V. & Nielsen, J. Global rewiring of cellular metabolism renders Saccharomyces cerevisiae Crabtree negative. Nat. Commun. 9, 1\u20138 (2018).","journal-title":"Nat. Commun."},{"key":"58495_CR6","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1002\/(SICI)1097-0061(19960315)12:3<247::AID-YEA911>3.0.CO;2-I","volume":"12","author":"MT Flikweert","year":"1996","unstructured":"Flikweert, M. T. et al. Pyruvate decarboxylase: an indispensable enzyme for growth of Saccharomyces cerevisiae on glucose. Yeast 12, 247\u2013257 (1996).","journal-title":"Yeast"},{"key":"58495_CR7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1475-2859-11-131","volume":"11","author":"B Oud","year":"2012","unstructured":"Oud, B. et al. An internal deletion in MTH1 enables growth on glucose of pyruvate-decarboxylase negative, non-fermentative Saccharomyces cerevisiae. Microb. Cell Fact. 11, 1\u201310 (2012).","journal-title":"Microb. Cell Fact."},{"key":"58495_CR8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0068734","volume":"8","author":"A Hagman","year":"2013","unstructured":"Hagman, A., S\u00e4ll, T., Compagno, C. & Piskur, J. Yeast \u201cmake-accumulate-consume\u201d life strategy evolved as a multi-step process that predates the whole genome duplication. PLoS ONE 8, e68734 (2013).","journal-title":"PLoS ONE"},{"key":"58495_CR9","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.micres.2015.01.003","volume":"171","author":"M Fondi","year":"2015","unstructured":"Fondi, M. & Li\u00f2, P. Multi -omics and metabolic modelling pipelines: challenges and tools for systems microbiology. Microbiol. Res. 171, 52\u201364 (2015).","journal-title":"Microbiol. Res."},{"key":"58495_CR10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/femsyr\/fow038","volume":"16","author":"AA Sibirny","year":"2016","unstructured":"Sibirny, A. A. Yeast peroxisomes: structure, functions and biotechnological opportunities. FEMS Yeast Res. 16, 1\u201314 (2016).","journal-title":"FEMS Yeast Res."},{"key":"58495_CR11","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.molcel.2018.10.032","volume":"73","author":"Z Cheng","year":"2019","unstructured":"Cheng, Z. et al. Small and large ribosomal subunit deficiencies lead to distinct gene expression signatures that reflect cellular growth rate. Mol. Cell 73, 36-47.e10 (2019).","journal-title":"Mol. Cell"},{"key":"58495_CR12","doi-asserted-by":"crossref","unstructured":"Albert, B. et al. A ribosome assembly stress response regulates transcription to maintain proteome homeostasis. Elife 8 (2019).","DOI":"10.7554\/eLife.45002"},{"key":"58495_CR13","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/1471-2180-1-11","volume":"1","author":"MD Pereira","year":"2001","unstructured":"Pereira, M. D., Eleutherio, E. C. A. & Panek, A. D. Acquisition of tolerance against oxidative damage in Saccharomyces cerevisiae. BMC Microbiol. 1, 11 (2001).","journal-title":"BMC Microbiol."},{"key":"58495_CR14","doi-asserted-by":"publisher","first-page":"477","DOI":"10.3389\/fmicb.2022.822864","volume":"13","author":"N Kocaefe-\u00d6z\u015fen","year":"2022","unstructured":"Kocaefe-\u00d6z\u015fen, N. et al. Physiological and molecular characterization of an oxidative stress-resistant Saccharomyces cerevisiae strain obtained by evolutionary engineering. Front. Microbiol. 13, 477 (2022).","journal-title":"Front. Microbiol."},{"key":"58495_CR15","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1016\/j.bbagen.2007.12.004","volume":"1780","author":"E Herrero","year":"2008","unstructured":"Herrero, E., Ros, J., Bell\u00ed, G. & Cabiscol, E. Redox control and oxidative stress in yeast cells. Biochimica et Biophysica Acta (BBA) - General Subj. 1780, 1217\u20131235 (2008).","journal-title":"Biochimica et Biophysica Acta (BBA) - General Subj."},{"key":"58495_CR16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13059-019-1730-3","volume":"20","author":"C Gu","year":"2019","unstructured":"Gu, C., Kim, G. B., Kim, W. J., Kim, H. U. & Lee, S. Y. Current status and applications of genome-scale metabolic models. Genome Biol. 20, 1\u201318 (2019).","journal-title":"Genome Biol."},{"key":"58495_CR17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12859-019-3329-9","volume":"21","author":"PS Bekiaris","year":"2020","unstructured":"Bekiaris, P. S. & Klamt, S. Automatic construction of metabolic models with enzyme constraints. BMC Bioinf. 21, 1\u201313 (2020).","journal-title":"BMC Bioinf."},{"key":"58495_CR18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-021-25158-6","volume":"12","author":"O Oftadeh","year":"2021","unstructured":"Oftadeh, O. et al. A genome-scale metabolic model of Saccharomyces cerevisiae that integrates expression constraints and reaction thermodynamics. Nat. Commun. 12, 1\u201310 (2021).","journal-title":"Nat. Commun."},{"key":"58495_CR19","doi-asserted-by":"publisher","first-page":"935","DOI":"10.15252\/msb.20167411","volume":"13","author":"BJ S\u00e1nchez","year":"2017","unstructured":"S\u00e1nchez, B. J. et al. Improving the phenotype predictions of a yeast genome-scale metabolic model by incorporating enzymatic constraints. Mol. Syst. Biol. 13, 935 (2017).","journal-title":"Mol. Syst. Biol."},{"key":"58495_CR20","doi-asserted-by":"publisher","first-page":"16017","DOI":"10.1038\/npjsba.2016.17","volume":"2","author":"R Gro\u00dfeholz","year":"2016","unstructured":"Gro\u00dfeholz, R. et al. Integrating highly quantitative proteomics and genome-scale metabolic modeling to study pH adaptation in the human pathogen Enterococcus faecalis. NPJ Syst. Biol. Appl. 2, 16017 (2016).","journal-title":"NPJ Syst. Biol. Appl."},{"key":"58495_CR21","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.coisb.2021.03.003","volume":"25","author":"Y Chen","year":"2021","unstructured":"Chen, Y. & Nielsen, J. Mathematical modeling of proteome constraints within metabolism. Curr. Opin. Syst. Biol. 25, 50\u201356 (2021).","journal-title":"Curr. Opin. Syst. Biol."},{"key":"58495_CR22","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1038\/s41596-023-00931-7","volume":"19","author":"Y Chen","year":"2024","unstructured":"Chen, Y. et al. Reconstruction, simulation and analysis of enzyme-constrained metabolic models using GECKO Toolbox 3.0. Nat. Protoc. 19, 629\u2013667 (2024).","journal-title":"Nat. Protoc."},{"key":"58495_CR23","doi-asserted-by":"publisher","first-page":"17592","DOI":"10.1073\/pnas.1906569116","volume":"116","author":"Y Chen","year":"2019","unstructured":"Chen, Y. & Nielsen, J. Energy metabolism controls phenotypes by protein efficiency and allocation. Proc. Natl. Acad. Sci. U. S. A. 116, 17592\u201317597 (2019).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"58495_CR24","doi-asserted-by":"publisher","DOI":"10.3390\/biom11050725","author":"LK Bertels","year":"2021","unstructured":"Bertels, L. K., Murillo, L. F. & Heinisch, J. J. The pentose phosphate pathway in yeasts\u2013more than a poor cousin of glycolysis. Biomolecules https:\/\/doi.org\/10.3390\/biom11050725 (2021).","journal-title":"Biomolecules"},{"key":"58495_CR25","doi-asserted-by":"crossref","unstructured":"Altinta\u015f, A., Martini, J., Mortensen, U. H. & Workman, C. T. Quantification of oxidative stress phenotypes based on high-throughput growth profiling of protein kinase and phosphatase knockouts. FEMS Yeast Res. 16 (2016).","DOI":"10.1093\/femsyr\/fov101"},{"key":"58495_CR26","doi-asserted-by":"publisher","first-page":"22480","DOI":"10.1074\/jbc.273.35.22480","volume":"273","author":"C Godon","year":"1998","unstructured":"Godon, C. et al. The H2O2 stimulon in Saccharomyces cerevisiae. J. Biol. Chem. 273, 22480\u201322489 (1998).","journal-title":"J. Biol. Chem."},{"key":"58495_CR27","doi-asserted-by":"publisher","first-page":"3555","DOI":"10.1074\/jbc.M007164200","volume":"276","author":"AK P\u00e5hlman","year":"2001","unstructured":"P\u00e5hlman, A. K., Granath, K., Ansell, R., Hohmann, S. & Adler, L. The yeast glycerol 3-phosphatases Gpp1p and Gpp2p are required for glycerol biosynthesis and differentially involved in the cellular responses to osmotic, anaerobic, and oxidative stress. J. Biol. Chem. 276, 3555\u20133563 (2001).","journal-title":"J. Biol. Chem."},{"key":"58495_CR28","doi-asserted-by":"publisher","first-page":"2179","DOI":"10.1093\/emboj\/16.9.2179","volume":"16","author":"R Ansell","year":"1997","unstructured":"Ansell, R., Granath, K., Hohmann, S., Thevelein, J. M. & Adler, L. The two isoenzymes for yeast NAD+-dependent glycerol 3-phosphate dehydrogenase encoded by GPD1 and GPD2 have distinct roles in osmoadaptation and redox regulation. EMBO J. 16, 2179\u20132187 (1997).","journal-title":"EMBO J."},{"key":"58495_CR29","doi-asserted-by":"crossref","unstructured":"Blomberg, A. Yeast osmoregulation \u2013 glycerol still in pole position. FEMS Yeast Res. 22 (2022)","DOI":"10.1093\/femsyr\/foac035"},{"key":"58495_CR30","doi-asserted-by":"crossref","unstructured":"Rezk Khattab, S. M. & Watanabe, T. Efficient conversion of glycerol to ethanol by an engineered Saccharomyces cerevisiae strain. Appl. Environ. Microbiol. 87, (2021).","DOI":"10.1128\/AEM.00268-21"},{"key":"58495_CR31","doi-asserted-by":"publisher","first-page":"362","DOI":"10.3389\/fphys.2016.00362","volume":"7","author":"HR Molavian","year":"2016","unstructured":"Molavian, H. R., Kohandel, M. & Sivaloganathan, S. High concentrations of H2O2 make aerobic glycolysis energetically more favorable for cellular respiration. Front. Physiol. 7, 362 (2016).","journal-title":"Front. Physiol."},{"key":"58495_CR32","doi-asserted-by":"publisher","first-page":"9629","DOI":"10.1073\/pnas.1307485110","volume":"110","author":"AI Stettner","year":"2013","unstructured":"Stettner, A. I. & Segr\u00e8, D. The cost of efficiency in energy metabolism. Proc. Natl. Acad. Sci. U. S. A. 110, 9629\u20139630 (2013).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"58495_CR33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/jbiol61","volume":"6","author":"M Ralser","year":"2007","unstructured":"Ralser, M. et al. Dynamic rerouting of the carbohydrate flux is key to counteracting oxidative stress. J. Biol. 6, 1\u201318 (2007).","journal-title":"J. Biol."},{"key":"58495_CR34","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1016\/j.bbagen.2011.04.005","volume":"1810","author":"DB Murray","year":"2011","unstructured":"Murray, D. B., Haynes, K. & Tomita, M. Redox regulation in respiring Saccharomyces cerevisiae. Biochimica et Biophysica Acta (BBA) - General Subjects 1810, 945\u2013958 (2011).","journal-title":"Biochimica et Biophysica Acta (BBA) - General Subjects"},{"key":"58495_CR35","doi-asserted-by":"publisher","first-page":"3273","DOI":"10.1128\/AEM.03319-12","volume":"79","author":"WT Ding","year":"2013","unstructured":"Ding, W. T., Zhang, G. C. & Liu, J. J. 3\u2032 truncation of the GPD1 promoter in Saccharomyces cerevisiae for improved ethanol yield and productivity. Appl. Environ. Microbiol. 79, 3273\u20133281 (2013).","journal-title":"Appl. Environ. Microbiol."},{"key":"58495_CR36","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1002\/(SICI)1097-0061(19980315)14:4<347::AID-YEA226>3.0.CO;2-9","volume":"14","author":"C Larsson","year":"1998","unstructured":"Larsson, C. et al. The importance of the glycerol 3-phosphate shuttle during aerobic growth of Saccharomyces cerevisiae. Yeast 14, 347\u2013357 (1998).","journal-title":"Yeast"},{"key":"58495_CR37","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2022.119238","volume":"1869","author":"AR Pallapati","year":"2022","unstructured":"Pallapati, A. R., Prasad, S. & Roy, I. Glycerol 3-phosphate dehydrogenase regulates heat shock response in Saccharomyces cerevisiae. Biochimica et Biophysica Acta (BBA) - Molecular Cell Res. 1869, 119238 (2022).","journal-title":"Biochimica et Biophysica Acta (BBA) - Molecular Cell Res."},{"key":"58495_CR38","unstructured":"R Core Team. R: A Language and Environment for Statistical Computing. Preprint at http:\/\/www.r-project.org\/ (2022)."},{"key":"58495_CR39","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","volume":"43","author":"ME Ritchie","year":"2015","unstructured":"Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47\u2013e47 (2015).","journal-title":"Nucleic Acids Res."},{"key":"58495_CR40","doi-asserted-by":"publisher","first-page":"4378","DOI":"10.1093\/nar\/gkt111","volume":"41","author":"L V\u00e4remo","year":"2013","unstructured":"V\u00e4remo, L., Nielsen, J. & Nookaew, I. Enriching the gene set analysis of genome-wide data by incorporating directionality of gene expression and combining statistical hypotheses and methods. Nucleic Acids Res. 41, 4378\u20134391 (2013).","journal-title":"Nucleic Acids Res."},{"key":"58495_CR41","doi-asserted-by":"publisher","first-page":"3439","DOI":"10.1093\/bioinformatics\/bti525","volume":"21","author":"S Durinck","year":"2005","unstructured":"Durinck, S. et al. BioMart and bioconductor: a powerful link between biological databases and microarray data analysis. Bioinformatics 21, 3439\u20133440 (2005).","journal-title":"Bioinformatics"},{"key":"58495_CR42","doi-asserted-by":"publisher","first-page":"1184","DOI":"10.1038\/nprot.2009.97","volume":"4","author":"S Durinck","year":"2009","unstructured":"Durinck, S., Spellman, P. T., Birney, E. & Huber, W. Mapping identifiers for the integration of genomic datasets with the R\/Bioconductor package biomaRt. Nat. Protoc. 4, 1184\u20131191 (2009).","journal-title":"Nat. Protoc."},{"key":"58495_CR43","unstructured":"Wickham, H. stringr: Simple, consistent wrappers for common string operations. Preprint at (2021)."},{"key":"58495_CR44","unstructured":"M\u00fcller, K. & Wickham, H. tibble: Simple data frames. Preprint at (2022)."},{"key":"58495_CR45","doi-asserted-by":"crossref","unstructured":"Wickham, H., Hester, J. & Bryan, J. readr: Read rectangular text data. Preprint at (2022).","DOI":"10.32614\/CRAN.package.meltr"},{"key":"58495_CR46","unstructured":"Wickham, H., Fran\u00e7ois, R., Henry, L. & M\u00fcller, K. dplyr: A grammar of data manipulation. Preprint at (2022)."},{"key":"58495_CR47","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-24277-4","volume-title":"Ggplot2: Elegant Graphics for Data Analysis","author":"H Wickham","year":"2016","unstructured":"Wickham, H. Ggplot2: Elegant Graphics for Data Analysis (Springer-Verlag, 2016)."},{"key":"58495_CR48","doi-asserted-by":"publisher","unstructured":"S\u00e1nchez, B. et al. SysBioChalmers\/yeast-GEM: yeast 8.5.0. https:\/\/doi.org\/10.5281\/ZENODO.5062615 (2021).","DOI":"10.5281\/ZENODO.5062615"},{"key":"58495_CR49","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-019-11581-3","volume":"10","author":"H Lu","year":"2019","unstructured":"Lu, H. et al. A consensus S. cerevisiae metabolic model Yeast8 and its ecosystem for comprehensively probing cellular metabolism. Nat. Commun. 10, 1\u201313 (2019).","journal-title":"Nat. Commun."},{"key":"58495_CR50","doi-asserted-by":"publisher","first-page":"D523","DOI":"10.1093\/nar\/gkac1052","volume":"51","author":"A Bateman","year":"2023","unstructured":"Bateman, A. et al. UniProt: the universal protein knowledgebase in 2023. Nucleic Acids Res. 51, D523\u2013D531 (2023).","journal-title":"Nucleic Acids Res."},{"key":"58495_CR51","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1038\/s41929-022-00798-z","volume":"5","author":"F Li","year":"2022","unstructured":"Li, F. et al. Deep learning-based kcat prediction enables improved enzyme-constrained model reconstruction. Nat. Catal. 5, 662\u2013672 (2022).","journal-title":"Nat. Catal."},{"key":"58495_CR52","doi-asserted-by":"publisher","first-page":"D498","DOI":"10.1093\/nar\/gkaa1025","volume":"49","author":"A Chang","year":"2021","unstructured":"Chang, A. et al. BRENDA, the ELIXIR core data resource in 2021: new developments and updates. Nucleic Acids Res. 49, D498\u2013D508 (2021).","journal-title":"Nucleic Acids Res."},{"key":"58495_CR53","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1006541","volume":"14","author":"H Wang","year":"2018","unstructured":"Wang, H. et al. RAVEN 2.0: a versatile toolbox for metabolic network reconstruction and a case study on Streptomyces coelicolor. PLoS Comput. Biol. 14, e1006541 (2018).","journal-title":"PLoS Comput. Biol."},{"key":"58495_CR54","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1021\/sb500366v","volume":"4","author":"ME Lee","year":"2015","unstructured":"Lee, M. E., DeLoache, W. C., Cervantes, B. & Dueber, J. E. A highly characterized yeast toolkit for modular, multipart assembly. ACS Synth. Biol. 4, 975\u2013986 (2015).","journal-title":"ACS Synth. Biol."},{"key":"58495_CR55","doi-asserted-by":"publisher","first-page":"3461","DOI":"10.1021\/acssynbio.1c00408","volume":"10","author":"M Otto","year":"2021","unstructured":"Otto, M. et al. Expansion of the yeast modular cloning toolkit for CRISPR-based applications, genomic integrations and combinatorial libraries. ACS Synth. Biol. 10, 3461\u20133474 (2021).","journal-title":"ACS Synth. Biol."},{"key":"58495_CR56","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.ymben.2012.01.006","volume":"14","author":"MD Mikkelsen","year":"2012","unstructured":"Mikkelsen, M. D. et al. Microbial production of indolylglucosinolate through engineering of a multi-gene pathway in a versatile yeast expression platform. Metab. Eng. 14, 104\u2013111 (2012).","journal-title":"Metab. Eng."},{"key":"58495_CR57","doi-asserted-by":"publisher","DOI":"10.1093\/femsyr\/fov004","volume":"15","author":"R Mans","year":"2015","unstructured":"Mans, R. et al. CRISPR\/Cas9: a molecular Swiss army knife for simultaneous introduction of multiple genetic modifications in Saccharomyces cerevisiae. FEMS Yeast Res. 15, fov004 (2015).","journal-title":"FEMS Yeast Res."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-58495-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-58495-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-58495-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T23:09:25Z","timestamp":1789081765000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-58495-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,21]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["58495"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-58495-x","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,21]]},"assertion":[{"value":"13 January 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"28412"}}