Dalian Institute of Chemistry, Chinese Academy of Sciences, realizes methanol biotransformation and efficient synthesis of fatty acid derivatives

Recently, the team of researcher Zhou Yongjin of the Synthetic Microbiology Research Group of the Dalian Institute of Chemical Physics of the Chinese Academy of Sciences has made new progress in the research direction of methanol biotransformation. Using methanol yeast as a cell catalyst, the research team realized methanol biotransformation and efficient synthesis of fatty acid derivatives through a combination of adaptive evolution and rational metabolic engineering.

The research results are “Rescuing yeast from cell death enables overproduction of fatty acids from sole methanol” and “Methanol biotransformation toward high-level production of fatty acid derivatives by engineering the industrial yeast Pichia pastoris” was published in Nature Metabolism and PNAS on July 11, 2022.

The first authors of the work are Gao Jiaoqi, assistant researcher of dalian institute of chemicals of the Chinese Academy of Sciences, and Cai Peng, doctoral candidate.

With the increasing depletion of resources such as oil, there is a growing need for new raw materials to meet people’s growing demand for biorefining. Methanol is an ideal renewable raw material with high energy density and wide range of sources. Fatty acid derivatives are a class of natural renewable resources with low oxygen content, high energy density and rich hydrocarbons, which are the basic raw materials for the production of liquid biofuels, oleochemicals, foods and materials, and are widely used in daily production, life and other aspects. The limited production of traditional animal and vegetable oils and fats is difficult to meet the growing demand, and it is urgent to develop new technologies for oil and fat production. Methanol biotransformation can establish a fatty acid supply route that does not depend on arable land, however, methanol metabolism in microbial cells is complex, and it is difficult to achieve efficient directional transformation.

The cover image was produced by the Science Visualization Center of China Science Newspaper

In this work, the research team found that engineered strains could not grow in methanol during the modification of endogenous metabolic synthetic fatty acids hosted by henson yeast multiforme. The research team also found that domesticated strains obtained through adaptive evolution in the laboratory were able to grow normally in methanol and efficiently produce fatty acids; Identification by multi-omics techniques found that double knocking out of two key mutant genes LPL1 (presumed lipase) and IZH3 (membrane protein associated with Zn metabolism) can significantly alleviate methanol metabolic stress; Through lipidomic analysis, it was found that the synthesis of fatty acid-producing strains of phospholipids was hindered, affecting the integrity of the peroxisome membrane, resulting in the leakage of formaldehyde from key toxic intermediates, causing cell necrosis. Based on the above findings, the research team, under the guidance of transcriptomics, rearranged the global metabolism within the cell, strengthened the supply of precursor acetyl-CoA and cofactor NADPH, and enabled Hanson Yeast to synthesize fatty acids with methanol as the only carbon source, with a yield of 15.9 g/L.

In addition, the research team also found in Pichia yeast that the accumulation of formaldehyde in the process of methanol metabolism also affects the biotransformation efficiency of methanol; By optimizing the cytocentric metabolism and cofactor regeneration process and strengthening the methanol metabolic pathway, the research team significantly reduced formaldehyde accumulation and increased fatty acid production (23.4 g/L). The research team also adopted the strategy of metabolic switching to quickly transform fatty acid production strains into fatty alcohol cell factories, simplifying the strain construction process and achieving fat alcohol yields of 2.0 g/L.

The above work reveals the regulation of methanol metabolism and the molecular mechanism of metabolic pressure in yeast, which provides new ideas for methanol biotransformation and CO2 high-value conversion applications.

Professor Eun-Yeol Lee, a biochemical scholar at Kyung Hee University in South Korea, published a bright review article “Methanol-tolerant yeast for biofuel production” in Nature-Metabolism, emphasizing that this study strengthens methanol tolerance and achieves the efficient conversion of methanol into synthetic fatty acids, which will provide a potential supply route for future oleochemical and biofuel supply.

The above work has been funded by the National Key Research and Development Program, the National Natural Science Foundation of China Outstanding Youth Fund, the Noodle Project, and the Dalian Institute of Chemicals Scientific Research and Innovation Fund. (Source: Science Network)

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