Methanol biotransformation for the production of the biodegradable plastic monomer L-lactate in yeast

Methanol is an ideal feedstock for biomanufacturing that can be produced from CO2 in massive quantities. Methanol biotransformation to promote the production of the biodegradable plastic monomer lactate is a promising approach for mitigating white pollution in a carbon-neutral manner. However, it is still challenging to engineer microbes for lactate production from methanol because of the strong competition between product synthesis and cell growth. Here, we extensively modified the methylotrophic yeast Ogataea polymorpha to synthesize L-lactate from methanol alone and found that the cofactor ratio of NADPH/NADP+ was higher than that of NADH/NAD+ during methanol metabolism. By engineering the gene expression and cofactor preference levels of lactate dehydrogenase, enhancing cell viability, modifying cofactor homeostasis, and performing mitochondrial compartmentalization, 2.5 g/L L-lactate was produced from 10 g/L methanol in a shake flask. Fed-batch fermentation in a 1 L bioreactor resulted in the highest yield of 25.0 g/L L-lactate from methanol, which was chemically synthesized from CO2 with a yield of 0.22 g/g. A technoeconomic analysis and life cycle assessment were performed to evaluate the commercial potential of CO2-derived L-lactate, its environmental impacts, and its greenhouse gas mitigation performance. This study could lay the foundation for the carbon-neutral production of biodegradable plastic polylactic acid from CO2, thus establishing a circular economy.