As humankind sets out to move towards a sustainable future, the production of organic commodity and speciality chemicals, drugs and other small molecules of interest will gradually incorporate more biochemical processes. Some of these products may be obtained directly from engineered organisms, while others may be generated ex vivo – either through purely enzymatic processes or by interfacing biological chemistry with organic synthesis.

Harnessing the efficiency, selectivity and diversity of enzymatic reactions found in nature is key to reaching the goal of a fully-fledged biobased economy. Some enzymes can carry out demanding reactions that have little or no equivalent in synthetic chemistry. In particular, the ability of certain enzymes to selectively act on unactivated carbon centers has attracted much attention as they can be used to functionalize typically intractable positions with high precision. A particular group of bacteria – Cyanobacteria – tend to incorporate saturated fatty acid-derived moieties into their natural products. In many such structures, we find modifications and decorations that can only be explained by the action of regio- and stereoselective enzymes, many acting on unactivated carbon centers. It is this richness of alkyl-chain modifying biocatalysts that we aim to reveal with this proposal. We will use several unusual structural motifs from acyl moieties in cyanobacterial natural products as starting points for enzyme discovery. These will include C-H bond activating enzymes as well as those acting on C-C bonds. We will bring to light an arsenal of biocatalysts that can be used to selectively functionalize or modify a variety of alkyl chain positions that would otherwise be inaccessible to conventional chemical synthesis. GreasedLightning blends discovery and hypothesis-driven research at the chemistry/biosynthesis interface, drawing on the PI’s experience on the (bio)chemistry of lipidic cyanobacterial metabolites.