Shaking up ancient scents: Insights into santalol synthesis in engineered Escherichia coli

• Sandalwood oil is an important essential oil in industries of cosmetics, medicine, food, and confectionary.
• Engineering of Escherichia coli for santalol production is a promising alternative to extraction from mature Santalum plants.
• Advances in metabolic engineering and synthetic biology will benefit the manipulation of santalol biosynthetic pathway in Escherichia coli.

Sandalwood oil is an essential oil that is derived from sandalwood and has important uses in cosmetics and medicine. Sandalwood oil is mainly composed of α-, β- and epi-β-santalols, which are responsible for the pleasant woody aroma. The syntheses of santalols begin with the condensation of the universal C5 precursors dimethylallyl diphosphate and isopentenyl diphosphate via farnesyl diphosphate (FPP) synthase. The resulting FPP undergoes multiple rearrangements and cyclization via santalene synthase to generate α-, β- and/or epi-β-santalenes, which are finally hydroxylated at the C12 position by cytochrome P450 monooxygenase in cooperation with an NADPH-dependent cytochrome P450 reductase (CPR) to form santalols. Advances in metabolic engineering and protein engineering can increase the use of enzymes to synthesize valuable chemicals. In this review, we summarize the metabolic pathway for santalol synthesis and associated enzymes. We also review the advances in metabolic engineering and biotechnology that can be utilized to manipulate Escherichia coli for santalol synthesis. We expect that the insights brought out by this review will shed light on metabolic engineering processes for santalol production in E. coli.