| Summary: | Summary Since methylotrophic yeasts such as Ogataea methanolica can use methanol as a sole carbon feedstock, they could be applied to produce valuable products from methanol, a next‐generation energy source synthesized from natural gases, using genetic engineering tools. In this study, metabolite profiling of O. methanolica was conducted under glucose (Glc) and low and high methanol (L‐ and H‐MeOH) conditions to show the adaptation mechanism to a H‐MeOH environment. The yeast strain responded not only to the presence of methanol but also to its concentration based on the growth condition. Under H‐MeOH conditions, O. methanolica downregulated the methanol utilization, glycolytic pathway and alcohol oxidase (AOD) isozymes and dihydroxyacetone synthase (DAS) expression compared with L‐MeOH‐grown cells. However, levels of energy carriers, such as ATP, were maintained to support cell survival. In H‐MeOH‐grown cells, reactive oxygen species (ROS) levels were significantly elevated. Along with increasing ROS levels, ROS scavenging system expression was significantly increased in H‐MeOH‐grown cells. Thus, we concluded that formaldehyde and H2O2, which are products of methanol oxidation by AOD isozymes in the peroxisome, are overproduced in H‐MeOH‐grown cells, and excessive ROS derived from these cells is generated in the cytosol, resulting in upregulation of the antioxidant system and downregulation of the methanol‐utilizing pathway to suppress overproduction of toxic intermediates.
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