Sclareol synthase from Salvia sclarea (SsSS) naturally acts on 8α-hydroxy-copalyl diphosphate (1), stereoselectively adding water to produce (13R)-sclareol (2a), and similarly yields hydroxylated products with many-fold other such bicyclic diterpene precursors. Here, a key residue for this addition of water was identified. Strikingly, substitution with glutamine switches stereochemical outcome with 1, leading to the selective production of (13S)-sclareol (2b). Moreover, changes to the stereospecificity of water addition with the structurally closely related substrate copalyl diphosphate (4) could be accomplished with alternative substitutions. Thus, this approach is expected to provide biosynthetic access to both epimers of 13-hydroxylated derivatives of many-fold labdane-related diterpenes.
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