Advancements and challenges in the bioproduction of raspberry ketone by precision fermentation

Abstract

Raspberry ketone (RK, 4-(4-hydroxyphenyl)-2-butanone), a naturally occurring phenolic compound responsible for the characteristic aroma of raspberries, has attracted significant interest due to its wide applications in the food, fragrance, and health industries. While traditional extraction from fruits is limited by low natural abundance and chemical synthesis raises sustainability concerns, microbial production through precision fermentation offers a promising alternative to address these challenges. This review summarises various approaches for RK synthesis, including plant, chemical and microbial synthesis, with an emphasis on the recent advances in microbial production achieved through different engineering strategies. We point out three bottlenecks in the microbial RK productions, including enzyme activity limitation, insufficient precursor supply and intermediate toxicity. We explore potential synthetic biology and precision fermentation strategies that can potentially address these challenges and present directions for future research, including pathway balancing, protein engineering, multi-omics approaches, adaptive laboratory evolution (ALE), downstream process optimisation, and alternative application exploration. This comprehensive analysis provides insights for developing more efficient and sustainable RK microbial cell factories and may also inform the development of precision fermentation strategies for other valuable compounds, contributing to the broader advancement of industrial biotechnology.