AUTHOR=Dahlin Jonathan , Holkenbrink Carina , Marella Eko Roy , Wang Guokun , Liebal Ulf , Lieven Christian , Weber Dieter , McCloskey Douglas , Wang Hong-Lei , Ebert Birgitta E. , Herrgård Markus J. , Blank Lars Mathias , Borodina Irina 

TITLE=Multi-Omics Analysis of Fatty Alcohol Production in Engineered Yeasts Saccharomyces cerevisiae and Yarrowia lipolytica

JOURNAL=Frontiers in Genetics

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2019.00747

DOI=10.3389/fgene.2019.00747

ISSN=1664-8021

ABSTRACT=<p>Fatty alcohols are widely used in various applications within a diverse set of industries, such as the soap and detergent industry, the personal care, and cosmetics industry, as well as the food industry. The total world production of fatty alcohols is over 2 million tons with approximately equal parts derived from fossil oil and from plant oils or animal fats. Due to the environmental impact of these production methods, there is an interest in alternative methods for fatty alcohol production <italic>via</italic> microbial fermentation using cheap renewable feedstocks. In this study, we aimed to obtain a better understanding of how fatty alcohol biosynthesis impacts the host organism, baker’s yeast <italic>Saccharomyces cerevisiae</italic> or oleaginous yeast <italic>Yarrowia lipolytica</italic>. Producing and non-producing strains were compared in growth and nitrogen-depletion cultivation phases. The multi-omics analysis included physiological characterization, transcriptome analysis by RNAseq, <sup>13</sup>Cmetabolic flux analysis, and intracellular metabolomics. Both species accumulated fatty alcohols under nitrogen-depletion conditions but not during growth. The fatty alcohol–producing <italic>Y. lipolytica</italic> strain had a higher fatty alcohol production rate than an analogous <italic>S. cerevisiae</italic> strain. Nitrogen-depletion phase was associated with lower glucose uptake rates and a decrease in the intracellular concentration of acetyl–CoA in both yeast species, as well as increased organic acid secretion rates in <italic>Y. lipolytica</italic>. Expression of the fatty alcohol–producing enzyme fatty acyl–CoA reductase alleviated the growth defect caused by deletion of hexadecenal dehydrogenase encoding genes (<italic>HFD1</italic> and <italic>HFD4</italic>) in <italic>Y. lipolytica</italic>. RNAseq analysis showed that fatty alcohol production triggered a cell wall stress response in <italic>S. cerevisiae</italic>. RNAseq analysis also showed that both nitrogen-depletion and fatty alcohol production have substantial effects on the expression of transporter encoding genes in <italic>Y. lipolytica</italic>. In conclusion, through this multi-omics study, we uncovered some effects of fatty alcohol production on the host metabolism. This knowledge can be used as guidance for further strain improvement towards the production of fatty alcohols.</p>