LimF is a versatile prenyltransferase catalyzing histidine-C-geranylation on diverse nonnatural substrates
Prenylation plays an important role in diversifying structure and function of secondary metabolites. Although several cyanobactin prenyltransferases have been characterized, their modes of action are mainly limited to the modification of electron-rich hetero atoms. Here we report a unique prenyltransferase originating from Limnothrix sp. CACIAM 69d, referred to as LimF, which catalyzes an unprecedented His-C-geranylation. Interestingly, LimF executes the geranylation on not only its native peptide substrate but also a wide range of exotic peptides, including thioether-closed macrocycles. We have also serendipitously uncovered an ability of Tyr-O-geranylation as the secondary function of LimF, indicating it is an unusual bifunctional prenyltransferase. Crystallographic analysis of LimF complexed with a pentapeptide substrate and a prenyl donor analog provides structural basis for its unique His recognition and its bifunctionality. Lastly, we show the LimF’s prenylation ability on various bioactive molecules containing an imidazole group, highlighting its potential as a versatile biocatalyst for site-specific geranylation.