Systematically Engineered Fatty Acid Catabolite Pathway for the Production of (2<i>S</i>)-Naringenin in <i>Saccharomyces cerevisiae</i>

Abstract

The (2<i>S</i>)-naringenin is an important natural flavonoid with several bioactive effects on human health. It is also a key precursor in the biosynthesis of other high value compounds. The production of (2S)-naringenin is significantly influenced by the acetyl-CoA available in the cytosol. In this study, we increased the acetyl-CoA supply via the β-oxidation of fatty acids in the peroxisomes of <i>Saccharomyces cerevisiae</i>. Several lipases from different sources and <i>PEX11</i>, <i>FOX1</i>, <i>FOX2</i>, and <i>FOX3</i>, the key genes of the fatty acid β-oxidation pathway, were overexpressed during the production of (2<i>S</i>)-naringenin in yeast. The level of acetyl-CoA was 0.205 nmol higher than that in the original strain and the production of (2<i>S</i>)-naringenin increased to 286.62 mg/g dry cell weight when <i>PEX11</i> was overexpressed in <i>S. cerevisiae</i> strain L07. Remarkable (2<i>S</i>)-naringenin production (1129.44 mg/L) was achieved with fed-batch fermentation, with the highest titer reported in any microorganism. Our results demonstrated the use of fatty acid β-oxidation to increase the level of cytoplasmic acetyl-CoA and the production of its derivatives.