Yeast as C1 cell factory: Transforming methanol and Formate into high-value compounds

Microbial transformation of greenhouse gases, such as carbon dioxide and methane, into valuable biochemicals appears as a key strategy to sustainably decarbonize manufacturing industries. Numerous unresolved technological constraints still hamper the industrial adoption of these single‑carbon (C1) gas-based bioprocesses. Conversion of these gases into liquid C1 compounds like methanol and formate helps to reduce emissions and close the carbon loop. Certain industrial yeasts possess intrinsic capabilities to tolerate and assimilate methanol and formate, which opens an attractive route to eco-efficiently valorise these compounds. To increase the C1-based biomanufacturing potential of yeasts, synthetic methylotrophy has been developed in versatile non-methylotrophic chassis. Strategic non-rational genome engineering and strain evolutions combined with rational designs brings to light hidden C1-pathways and mechanisms of substrate tolerance. Developments in methanol-based bioproduction include simple organic acids with clear promise for industrial scale-up as well as proof-of-concept investigations of complex polyketides with intricate pathways. Recent advances in bioproduction have demonstrated encouraging results from techniques such as modular co-culture engineering and peroxisomal coupling of biosynthetic pathways with C1 metabolism. Formate-based growth and biosynthesis in yeasts is in its early stages but holds the potential to be transformative in the coming decade. This review discusses the advances, challenges, and future perspectives in methanol-based biomanufacturing and innovative initiatives in formatotrophy in yeasts. Although it is a long way off, developments in synthetic biology assisted evolutionary engineering and artificial pathways will fill up the gaps in the scalability of C1-based bioprocesses, transforming yeasts into a reliable, climate-neutral, and resource-efficient platform for the green bioeconomy of the future.