Stress-driven dynamic regulation of multiple genes to reduce accumulation of toxic aldehydes

Abstract

Aldehydes are ubiquitous metabolites in living cells. As reactive electrophiles, they have the capacity to form adducts with cellular protein thiols and amines, leading to potential toxicity. Dynamic regulation has proven to be an effective strategy for addressing the accumulation of toxic metabolites. However, there are limited reports on applying dynamic control specifically to mitigate aldehyde accumulation. In this study, the cinnamaldehyde accumulation in the biosynthesis of cinnamylamine was used as a model to evaluate a two-way dynamic regulation strategy. First, we utilized whole-genome transcript arrays to identify the cinnamaldehyde-responsive promoters: the upregulated promoter P₄ and the downregulated promoter P_d. They were then employed as biosensors to dynamically regulate the synthesis and consumption of cinnamaldehyde, mitigating its toxic effects on the host. This strategy successfully reduced cinnamaldehyde accumulation by 50 % and increased the production of cinnamylamine by 2.9 times. This study demonstrated a cinnamaldehyde-induced autoregulatory system that facilitated the conversion of cinnamic acid into cinnamylamine without the need for costly external inducers, presenting a promising and economically viable approach. The strategy also serves as a reference for alleviating the inhibitory effects of other toxic aldehydes on microorganisms. Additionally, the biosensors (P_d and P₄) can respond to a range of aldehyde compounds, offering a rapid and sensitive method for detecting toxic aldehydes in both environmental samples and microorganisms, thus provide a valuable tool for screening strains enhanced aldehyde yield.