Retinal Production by Precision Fermentation of Saccharomyces cerevisiae

Retinoids, including retinol, retinal, and retinoic acid, are a group of vitamin A derivatives with skin-improving effects. Retinoic acid is highly effective for skin anti-aging but can cause irritation, requiring a prescription. Retinol, a less irritating alternative, needs conversion to retinal and then retinoic acid in the skin, whereas direct absorption of retinal enhances efficacy by bypassing this conversion process. This study aimed to produce retinal through precision fermentation using metabolically engineered Saccharomyces cerevisiae. The introduction of heterologous retinal biosynthetic genes and overexpression of the truncated HMG-CoA reductase (tHMG1) and acetyl-CoA acetyltransferase (ERG10) genes in the mevalonate (MVA) pathway increased retinal production up to 10.2 mg/L. At the same time, ethanol was produced as a major byproduct in S. cerevisiae. To address this, a pyruvate decarboxylase (Pdc)-deficient S. cerevisiae strain, incapable of producing ethanol, was employed. Overexpression of ERG10 and tHMG1 in the Pdc-deficient S. cerevisiae harboring the retinal biosynthetic plasmids achieved a retinal production up to 117.4 mg/L in the dodecane layer without ethanol through a two-phase in situ fermentation and extraction. This study demonstrates that eliminating pyruvate decarboxylase activity effectively redirects carbon flux toward retinal biosynthesis in the recombinant S. cerevisiae, offering a promising approach for sustainable retinal production through precision fermentation.