## 4 Common Strategies for Optimizing Sesquietpenol Biosynthesis  
To date, six sesquiterpenols have been employed in biosynthetic processes. These include acyclic sesquiterpenols, such as farnesol and nerolidol, monocyclic sesquiterpenols, like bisabolol, bicyclic sesquiterpenols, such as cedrol, and polycyclic sesquiterpenols, including patchoulol and santalol. Given the significant potential of biosynthetic pathways for sesquiterpenols production, numerous effective strategies have been developed to optimize biosynthetic production (Table 2). This review focuses on recent advances and examines the optimization approaches for sesquiterpenol biosynthesis from four key perspectives: enzyme engineering, metabolic regulation, subcellular organelle engineering, and tolerance to terpenoid-related toxicity. \begin{table}
\begin{tabular}{c c c c c c c} \hline \hline
**Classification** & **Sesquietpenol** & **Host** & **STRATEGIES** & **Scales** & **Titers (mg/L)** & **Reference** \\ \hline \multirow{8}{*}{Acyclic} & \multirow{8}{*}{Z,Z- famesol} & \multirow{8}{*}{_Escherichia coli_} & tested five Z, Z-farnesyl & \multirow{8}{*}{flask} & \multirow{8}{*}{572.13} & \multirow{8}{*}{[6]} \\  & & & diphosphate (Z, Z-FPP) & & & \\  & & & synthases; screened thirteen & & & \\  & & & phosphatases; site-directed & & & \\  & & & mutagenesis of & & & \\  & & & cis-prepyltransferase & & & \\ \hline \multirow{8}{*}{Acyclic} & \multirow{8}{*}{farnesol} & \multirow{8}{*}{_Saccharomyces cerevisiae_} & overexpressed HMGR1 and & \multirow{8}{*}{flask} & \multirow{8}{*}{393.13} & \multirow{8}{*}{[55]} \\  & & & ERG20; replacement of the & & & \\  & & natural ERG9 promoter with & & & & \\  & & & neutral ERG9 promoter with & & & \\  & & & the hxt1 promoter; & & & \\  & & & overexpressed of endogenous & & & \\  & & & phosphatase PAH1 & & & \\ \hline \multirow{8}{*}{Acyclic} & \multirow{8}{*}{farnesol} & \multirow{8}{*}{_Saccharomyces cerevisiae_} & replaced the natural ERG9 promoter with the tunable & \multirow{8}{*}{flask} & \multirow{8}{*}{20.2} & \multirow{8}{*}{[60]} \\  & & & MET3 promoter & & & \\ \hline \multirow{8}{*}{farnesol} & \multirow{8}{*}{_Saccharomyces cerevisiae_} & \multirow{8}{*}{overexpressed tHMGR1} & bioreactor & \multirow{8}{*}{145.7} & \multirow{8}{*}{[61]} \\  & & & & & \\  & & & & & \\ \hline \multirow{2}{*}{farnesol} & \multirow{2}{*}{_Escherichia coli_} & overexpressed ispA; & \multirow{2}{*}{flask} & \multirow{2}{*}{135.5} & \multirow{2}{*}{[62]} \\  & & introduced the MVA pathway & & & & \\ \hline \multirow{2}{*}{nerolidol} & \multirow{2}{*}{_Saccharomyces cerevisiae_} & fused of nerolidol synthase to & \multirow{2}{*}{flask} & \multirow{2}{*}{4200} & \multirow{2}{*}{[56]} \\  & & & farnesyl diphosphate synthase & & & \\ \hline \multirow{2}{*}{nerolidol} & \multirow{2}{*}{_Saccharomyces cerevisiae_} & depleted hexokinase-2 to lifts & \multirow{2}{*}{flask} & \multirow{2}{*}{3500} & \multirow{2}{*}{[63]} \\  & & glucose expression, depleted & & & \\  & & acetyl1-CoA carboxylase & & & \\  & & & (Acc1p) & & & \\ \hline \multirow{8}{*}{nerolidol} & \multirow{8}{*}{_Saccharomyces cerevisiae_} & engineered a eukaryote-like & \multirow{8}{*}{flask} & \multirow{8}{*}{2540} & \multirow{8}{*}{[64]} \\  & & & tetracycline-mediated circuit & & & \\ \cline{1-1}  & & to minimize metabolic burden & & & \\ \cline{1-1}  & & during strain development & & & \\ \cline{1-1}  & & and maintenance & & & \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Summary of strategies for the sesquiterpenols heterologous production.