Realization of methyl-trophic Saccharomyces cerevisiae by synthetic biology strategies

Recently, Dr. Chunjun Zhan of Professor Bai Zhonghu’s team from the National Fermentation Engineering Center of Jiangnan University has made important progress in constructing a carbon (Methanol) trophic microorganism, and the research results “Reprogramming methanol utilization pathways to convert Saccharomyces cerevisiae to a synthetic methylotroph” Published online May 16 in the journal Nature Catalysis.

Prof. Zhonghu Bai (National Center for Fermentation Engineering, Jiangnan University), Prof. Jens Nielsen and Dr. Yun Chen (Chalmers University of Tech., Denmark) and Prof. Jay D. Keasling (University of California Berkeley, USA) are co-corresponding authors of the paper. Dr. Chunjun Zhan is the first author of the paper. Jiangnan University is the first research institution.

Methanol is considered to be an important one-carbon resource due to its abundant source, liquid form at room temperature, high energy density and many other excellent characteristics. However, at present, methanol can only be used by a small number of non-model microorganisms such as methyl-trophic microorganisms, so how to transform model microorganisms into methyl-trophic microorganisms will not only help transform methanol into high-value by-products, but also provide important reference for the construction of other one-carbon microorganisms to promote the realization of carbon neutrality.

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In the study, the researchers first presented a report on S. The current main methanol metabolic pathway and related heterozygous metabolic pathway were evaluated in cerevisiae, and it was found that the methanol metabolic pathway (XuMP) derived from Pichia pasteur showed high activity. However, due to the high energy requirements of this pathway, a variety of harmful metabolites (formaldehyde) are produced during metabolism, so it cannot support cell growth alone. Based on the analysis of other methanol metabolic pathways, the researchers co-expressed methanol dehydrogenase (Mdh) derived from the RuMP pathway with the XuMP pathway to achieve energy balance. At the same time, the researchers located the above methanol metabolic pathway in the modified peroxisome through compartmentalization strategy to reduce the damage of harmful metabolites to organelles and cell membranes. It turned out that the remodeled S. Cerreiae can be grown in basal medium with methanol as the only carbon source.

In order to further improve the metabolic capacity of engineered bacteria on methanol, the researchers adjusted and balanced different metabolic pathways and related anti-stress capabilities in the modified bacteria through laboratory adaptive evolution strategies, and found that the evolved strains showed stronger methanol metabolism capacity. The discovery of ergosterol pathway associated with membrane resistance and gSerine pathway associated with formaldehyde/formic acid utilization by transcriptome and genome resequencing play an important role in enhancing the methanol metabolism of evolved strains.

The research has been supported by the National Youth Fund of China (21908077) and the National Key Research and Development Program of China (2021YFC2100203). (Source: Science Network)

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