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<p>Methanol is a promising one-carbon (C1) feedstock for microbial bioconversion; however, engineered <i>Saccharomyces cerevisiae</i> often faces energetic constrains during its assimilation. Here, we develop SC-AOX<sub>25</sub>, an energy-efficient methylotrophic <i>S. cerevisiae</i>, through engineering of heterologous methanol-formaldehyde-formate (MFF) oxidation pathways coupled with adaptive laboratory evolution. SC-AOX<sub>25</sub> efficiently generates adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NADH) during methanol metabolism while co-assimilating methanol-derived intermediates (formaldehyde, formate, and CO₂) via native glyoxylate-serine cycle, pentose phosphate pathway, and reductive glycine pathway. Key energy modules - Fdh1<sub>sc</sub>, Adh2<sub>m</sub>, Aox<sub>m</sub>, and Rgi2<sub>m</sub> - are characterized for their roles in ATP/NADH synthesis and methylotrophic growth. Formaldehyde-induced DNA-protein crosslinks (DPCs) and large repeated DNA fragments suggest strategies for methanol detoxification and phenotype enhancement. Utilizing SC-AOX<sub>25</sub>, we enable CO₂ assimilation through non-native Calvin cycle during methanol fermentation, establishing the engineered strain as a robust and energy-efficient methylotrophic platform for further C1 engineering.</p>

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Engineering energy-efficient Saccharomyces cerevisiae for methanol and CO2 assimilation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月17日

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  • Wei Zhong,
  • Nana Liu,
  • Binbin Chen,
  • Huiqi Sun,
  • Xiao Fei,
  • Jiazhang Lian,
  • Junling Guo,
  • Bo Wang,
  • Yajie Wang

摘要

Methanol is a promising one-carbon (C1) feedstock for microbial bioconversion; however, engineered Saccharomyces cerevisiae often faces energetic constrains during its assimilation. Here, we develop SC-AOX25, an energy-efficient methylotrophic S. cerevisiae, through engineering of heterologous methanol-formaldehyde-formate (MFF) oxidation pathways coupled with adaptive laboratory evolution. SC-AOX25 efficiently generates adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NADH) during methanol metabolism while co-assimilating methanol-derived intermediates (formaldehyde, formate, and CO₂) via native glyoxylate-serine cycle, pentose phosphate pathway, and reductive glycine pathway. Key energy modules - Fdh1sc, Adh2m, Aoxm, and Rgi2m - are characterized for their roles in ATP/NADH synthesis and methylotrophic growth. Formaldehyde-induced DNA-protein crosslinks (DPCs) and large repeated DNA fragments suggest strategies for methanol detoxification and phenotype enhancement. Utilizing SC-AOX25, we enable CO₂ assimilation through non-native Calvin cycle during methanol fermentation, establishing the engineered strain as a robust and energy-efficient methylotrophic platform for further C1 engineering.