UNDERSTANDING THE ALKYL DONOR SPECIFICITY OF AROMATIC PRENYLTRANSFERASES

Abstract

Chemoenzymatic synthesis is a leading technique in the diversification and late stage modification of complex molecules, due to the high regio and stereo specificities of the enzymes. Over the last decade, the broad aromatic substrate scope for a class of prenyltransferases known as aromatic prenyltransferases has been extensively studied. Aromatic prenyltransferase catalyzed prenylation reactions are highly prevalent in nature and contribute to the amazing structural and functional diversity of natural products. Given their natural function and broad aromatic substrate promiscuity, aromatic prenyltransferases have been investigated as biocatalytic tool essential to facilitate chemoenzymatic natural product diversification. Although many studies have accomplished highlighting the acceptor substrate scope of this class of enzyme none have explored the enzyme’s potential to transfer unnatural alkyl groups. Herein, we investigate the alkyl donor specificity of four aromatic prenyltransferases, SirD, FgaPT2, NphB and CdpNPT, in combination with our extensive library of synthetic alkyl pyrophosphates. To further highlight the feasibility of aromatic prenyltransferases as a powerful biocatalyst, we successfully diversified FDA approved drug compounds, subsequently resulting in the improved in vitro activity of the modified compounds.