Engineering Yeast Yarrowia lipolytica for Methanol Assimilation

Guokun Wang*, Mattis Olofsson-Dolk, Frederik Gleerup Hansson, Stefano Donati, Xiaolin Li, Hong Chang, Jian Cheng, Jonathan Dahlin, Irina Borodina

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review


Conferring methylotrophy on industrial microorganisms would enable the production of diverse products from one-carbon feedstocks and contribute to establishing a low-carbon society. Rebuilding methylotrophs, however, requires a thorough metabolic refactoring and is highly challenging. Only recently was synthetic methylotrophy achieved in model microorganisms─Escherichia coli and baker's yeast Saccharomyces cerevisiae. Here, we have engineered industrially important yeast Yarrowia lipolytica to assimilate methanol. Through rationally constructing a chimeric assimilation pathway, rewiring the native metabolism for improved precursor supply, and laboratory evolution, we improved the methanol assimilation from undetectable to a level of 1.1 g/L per 72 h and enabled methanol-supported cellular maintenance. By transcriptomic analysis, we further found that fine-tuning of methanol assimilation and ribulose monophosphate/xylulose monophosphate (RuMP/XuMP) regeneration and strengthening formate dehydrogenation and the serine pathway were beneficial for methanol assimilation. This work paves the way for creating synthetic methylotrophic yeast cell factories for low-carbon economy.

Original languageEnglish
JournalACS Synthetic Biology
Issue number12
Pages (from-to)3537–3550
Number of pages14
Publication statusPublished - 2021

Bibliographical note

Funding Information:
G.W. acknowledges the financial support from Tianjin Synthetic Biotechnology Innovation Capacity Improvement Project (TSBICIP-CXRC-041, TSBICIP-CXRC-031, and TSBICIP-CXRC-038) and Science and Technology Partnership Program, Ministry of Science and Technology of China (KY202001017). I.B. acknowledges the financial support from the Novo Nordisk Foundation (grant agreement no. NNF20CC0035580 and NNF20OC0060809) and the European Research Council under the European Union’s Horizon 2020 research and innovation programme (YEAST-TRANS project, grant agreement no. 757384). We thank Dr. Chunjun Zhan and Dr. Simone Schmitz for the insightful discussion. We thank Dr. Xiaoping Liao for the technical assistance of the omics data analysis.

Publisher Copyright:
© 2021 American Chemical Society.


  • C1 technology
  • laboratory evolution
  • synthetic biology
  • systems metabolic engineering
  • Yarrowia lipolytica


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