| Summary: | Z,Z-farnesol (Z,Z-FOH), the all-<i>cis</i> isomer of farnesol, holds enormous potential for application in cosmetics, daily chemicals, and pharmaceuticals. In this study, we aimed to metabolically engineer <i>Escherichia coli</i> to produce Z,Z-FOH. First, we tested five Z,Z-farnesyl diphosphate (Z,Z-FPP) synthases that catalyze neryl diphosphate to form Z,Z-FPP in <i>E. coli</i>. Furthermore, we screened thirteen phosphatases that could facilitate the dephosphorylation of Z,Z-FPP to produce Z,Z-FOH. Finally, through site-directed mutagenesis of <i>cis</i>-prenyltransferase, the optimal mutant strain was able to produce 572.13 mg/L Z,Z-FOH by batch fermentation in a shake flask. This achievement represents the highest reported titer of Z,Z-FOH in microbes to date. Notably, this is the first report on the de novo biosynthesis of Z,Z-FOH in <i>E. coli</i>. This work represents a promising step toward developing synthetic <i>E. coli</i> cell factories for the de novo biosynthesis of Z,Z-FOH and other <i>cis</i>-configuration terpenoids.
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