Engineering tolerance to industrially relevant stress factors in yeast cell factories

Abstract

The main focus in development of yeast cell factories has generally been on establishing optimal activity of heterologous pathways and further metabolic engineering of the host strain to maximize product yield and titer. Adequate stress tolerance of the host strain has turned out to be another major challenge for obtaining economically viable performance in industrial production. Although general robustness is a universal requirement for industrial microorganisms, production of novel compounds using artificial metabolic pathways presents additional challenges. Many of the bio-based compounds desirable for production by cell factories are highly toxic to the host cells in the titers required for economic viability. Artificial metabolic pathways also turn out to be much more sensitive to stress factors than endogenous pathways, likely because regulation of the latter has been optimized in evolution in myriads of environmental conditions. We discuss different environmental and metabolic stress factors with high relevance for industrial utilization of yeast cell factories and the experimental approaches used to engineer higher stress tolerance. Improving stress tolerance in a predictable manner in yeast cell factories should facilitate their widespread utilization in the bio-based economy and extend the range of products successfully produced in large scale in a sustainable and economically profitable way.

The wide‐ranging phenotypes of ergosterol biosynthesis mutants, and implications for microbial cell factories

“…For example, Cdr1 (the C. albicans homologue of Pdr5) has been found to export β‐estradiol (Krishnamurthy, Gupta, Snehlata, & Prasad, ), therefore ergΔ strains with reduced Pdr5 activity may accumulate β‐estradiol (which currently costs approximately £1,700 per 100 g) at a faster rate than wild type. On the other hand, some feedstocks contain inhibitors to yeast growth, such as furfural and coniferyl alcohol (Deparis, Claes, Foulquié‐Moreno, & Thevelein, ), which may have an increased impact on strains with altered sterol content.…”

Control of metabolite efflux in microbial cell factories: current advances and future prospects

“…[128][129][130]). In microbes, where they have also presumably evolved to remove environmental toxins that had been taken up [131], they can play a leading role in microbial resistance to anti-infectives [132][133][134][135][136][137][138][139]. In each of these cases, it is easy to understand why natural evolution would select for such activities.…”

Stress-Induced Expression is Enriched for Evolutionarily Young Genes in Diverse Budding Yeasts

“…For the species above, adaptation to natural environments enables robustness in industrial biotechnology processes. Understanding an exceptional stress tolerances from specific budding yeast species, might therefore enable the engineering of panrobust industrial strains, thereby reducing process costs and increasing yields 10,11 . Although studies that sought to characterize stress tolerances in S. cerevisiae have elucidated mechanisms that influence robustness 10,12,13 , engineering more robust S. cerevisiae strains without physiological trade-offs remains challenging 9 .…”

“…Although studies that sought to characterize stress tolerances in S. cerevisiae have elucidated mechanisms that influence robustness 10,12,13 , engineering more robust S. cerevisiae strains without physiological trade-offs remains challenging 9 . One complication is that stress exposure often results in hundreds of significant transcriptional changes 13,14 , most of which do not correlate with single gene deletion changes in robustness 11 . These results suggest that several genes from different gene families may contribute additively to robustness and/or that stress genes may exist as duplicates, as is the case for antifreeze protein genes in artic yeasts 15 .…”