Changing Face: A Key Residue for the Addition of Water by Sclareol Synthase

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 manifold 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 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 manifold labdane-related diterpenes.