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Here, we introduce AdaptUC, a computational framework that demonstrates how the fraction of biomass precursors synthesized from unadapted carbon sources governs both the evolutionary driving force and the minimal substrate requirement. AdaptUC predicts gene knockout strategies for constructing the starting strain for adaptive laboratory evolution by selectively blocking metabolic pathways, thereby rendering specific precursor pools dependent on the unadapted substrate. We show that smaller dependency fractions correspond to higher driving forces for evolution of the starting strain. Case studies in\n            <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic>\n            and\n            <jats:italic toggle=\"yes\">Corynebacterium glutamicum<\/jats:italic>\n            , validated against experimental records and literature, confirm AdaptUC\u2019s ability to identify knockout combinations that fine-tune precursor dependency and accelerate adaptation. By leveraging genome-scale metabolic models, AdaptUC navigates vast candidate pools without combinatorial explosion, reducing experimental screening and prioritizing strains with stronger evolutionary drives.\n          <\/jats:p>","DOI":"10.34133\/research.0881","type":"journal-article","created":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T08:00:16Z","timestamp":1755244816000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":1,"title":["Exploring Biomass Precursor Synthesis as a Determinant in Microbial Adaptation to Unadapted Carbon Sources with AdaptUC"],"prefix":"10.34133","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2018-1174","authenticated-orcid":true,"given":"Jingyi","family":"Cai","sequence":"first","affiliation":[{"name":"Key Laboratory of Engineering Biology for Low-Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, \rChinese Academy of Sciences, Tianjin 300308, China."},{"name":"National Center of Technology Innovation for Synthetic Biology","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayu","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Engineering Biology for Low-Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, \rChinese Academy of Sciences, Tianjin 300308, China."},{"name":"University of Chinese Academy of Sciences","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Wei","sequence":"additional","affiliation":[{"name":"Key Laboratory of Engineering Biology for Low-Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, \rChinese Academy of Sciences, Tianjin 300308, China."},{"name":"University of Chinese Academy of Sciences","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjun","family":"Wu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Engineering Biology for Low-Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, \rChinese Academy of Sciences, Tianjin 300308, China."},{"name":"Tianjin University of Science & Technology","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqi","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Engineering Biology for Low-Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, \rChinese Academy of Sciences, Tianjin 300308, China."},{"name":"Tianjin University of Science & Technology","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Engineering Biology for Low-Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, \rChinese Academy of Sciences, Tianjin 300308, China."},{"name":"National Center of Technology Innovation for Synthetic Biology","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0749-0749","authenticated-orcid":false,"given":"Qianqian","family":"Yuan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Engineering Biology for Low-Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, \rChinese Academy of Sciences, Tianjin 300308, China."},{"name":"National Center of Technology Innovation for Synthetic Biology","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwu","family":"Ma","sequence":"additional","affiliation":[{"name":"Key Laboratory of Engineering Biology for Low-Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, \rChinese Academy of Sciences, Tianjin 300308, China."},{"name":"National Center of Technology Innovation for Synthetic Biology","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1038\/s41467-022-29698-3","article-title":"In situ dual doping for constructing efficient CO2-to-methanol electrocatalysts","volume":"13","author":"Li P","year":"2022","unstructured":"Li P, Bi J, Liu J, Zhu Q, Chen C, Sun X, Zhang J, Han B. 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