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

Methanol is an ideal feedstock for biomanufacturing, and production of the biodegradable plastic monomer lactate from methanol is a promising approach for mitigating white pollution. However, it is challenging to engineer microbes for lactate production from methanol because of strong competition between product synthesis and cell growth. Here, Ogataea polymorpha is rewired to synthesize L-lactate from methanol, where the cofactor ratio of NADPH/NADP⁺ is higher than that of NADH/NAD⁺. By engineering gene expression, enhancing cell viability, modifying cofactor homeostasis, and performing mitochondrial compartmentalization, 2.5 g/L L-lactate is produced in a shake flask. Fed-batch fermentation in a bioreactor results in the highest titer of 25.0 g/L L-lactate from methanol, which is chemically synthesized from CO₂. A techno-economic analysis and life cycle assessment are performed to evaluate the commercial potential, environmental impacts, and greenhouse gas mitigation performance of CO₂-derived L-lactate. This study could lay the foundation for the carbon-neutral production of biodegradable plastic polylactic acid from CO₂.