In-depth understanding of molecular mechanisms of aldehyde toxicity to engineer robust Saccharomyces cerevisiae.

Aldehydes are ubiquitous electrophilic compounds that ferment microorganisms including Saccharomyces cerevisiae encounter during the fermentation processes to produce food, fuels, chemicals, and pharmaceuticals. Aldehydes pose severe toxicity to the growth and metabolism of the S. cerevisiae through a variety of toxic molecular mechanisms, predominantly via damaging macromolecules and hampering the production of targeted compounds. Compounds with aldehyde functional groups are far more toxic to S. cerevisiae than all other functional classes, and toxic potency depends on physicochemical characteristics of aldehydes. The yeast synthetic biology community established a design-build-test-learn framework to develop S. cerevisiae cell factories to valorize the sustainable and renewable biomass, including the lignin-derived substrates. However, thermochemically pretreated biomass-derived substrate streams contain diverse aldehydes (e.g., glycolaldehyde and furfural), and biological conversions routes of lignocellulosic compounds consist of toxic aldehyde intermediates (e.g., formaldehyde and methylglyoxal), and some of the high-value targeted products have aldehyde functional group (e.g., vanillin and benzaldehyde). Numerous studies comprehensively characterized both single and additive effects of aldehyde toxicity via systems biology investigations, and novel molecular approaches have been discovered to overcome the aldehyde toxicity. Based on those novel approaches, researchers successfully developed synthetic yeast cell factories to convert lignocellulosic substrates to valuable products, including aldehyde compounds. In this mini-review, we highlight the salient relationship of physicochemical characteristics and molecular toxicity of aldehydes, the molecular detoxification and macromolecules protection mechanisms of aldehydes, and the advances of engineering robust S. cerevisiae against complex mixtures of aldehyde inhibitors. KEY POINTS: • We reviewed structure-activity relationships of aldehyde toxicity on S. cerevisiae. • Two-tier protection mechanisms to alleviate aldehyde toxicity are presented. • We highlighted the strategies to overcome the synergistic toxicity of aldehydes.