Enantioselective Phenol Coupling by Laccases in the Biosynthesis of Fungal Dimeric Naphthopyrones

Biaryl compounds are ubiquitous metabolites that are often formed by dimerization through oxidative phenol coupling. Hindered rotation around the biaryl bond can cause axial chirality. In nature, dimerizations are catalyzed by oxidative enzymes such as laccases. This class of enzymes is known for non-specific oxidase reactions while inherent enantioselectivity is hitherto unknown. Here, we describe four related fungal laccases that catalyze γ-naphthopyrone dimerization in a regio- and atropselective manner. In vitro assays revealed that three enzymes were highly P-selective (ee >95 %), while one enzyme showed remarkable flexibility. Its selectivity for M- or P-configured dimers varied depending on the reaction conditions. For example, a lower enzyme concentration yielded primarily (P)-ustilaginoidin A, whereas the M atropisomer was favored at higher concentration. These results demonstrate inherent enantioselectivity in an enzyme class that was previously thought to comprise only non-selective oxidases.