Static metabolic regulation during microbial synthesis of polyphenolic compounds leads to tyrosol accumulation, inducing cellular toxicity and growth inhibition. Dynamic regulation effectively alleviates the imbalance between cell growth and production; yet, a tyrosol-responsive dynamic system for yeast adaptive regulation remains unreported. In this study, endogenous tyrosol-responsive promoters were mined via transcriptomics, and the optimal promoter PYOR153W was identified. Subsequently, a novel tyrosol-responsive biosensor composed of the responsive promoter and CRISPR/dSpCas9-VPR was designed to dynamically regulate green fluorescent protein (GFP) expression and hydroxytyrosol biosynthesis, respectively. This strategy successfully enhanced hydroxytyrosol production by 1.53-fold with negligible tyrosol accumulation. Furthermore, this dynamic system improved strain robustness during longer yeast fermentation periods, and the hydroxytyrosol titer increased to 4.26 g/L in a 5 L bioreactor. Our findings establish the first tyrosol-responsive biosensor in yeast and provide a framework for the efficient biosynthesis of high-value tyrosol derivatives.
Hu et al. (2026) studied this question.