Harnessing and engineering amide bond forming ligases for the synthesis of amides

The amide functional group is ubiquitous in nature and one of the most important motifs in pharmaceuticals, agrochemicals and other valuable products. Whilst coupling amides and carboxylic acids is a trivial synthetic transformation, it often requires protective group manipulation, along with stoichiometric quantities of expensive and deleterious coupling reagents. Nature has evolved a range of enzymes to construct amide bonds the vast majority of which utilize adenosine triphosphate (ATP) to activate the carboxylic acid substrate for amine coupling. Despite the fact that these enzymes operate under mild conditions, as well as possessing chemoselectivity and regioselectivity that obviates the need for protecting groups, their synthetic potential has been largely unexplored. In this review we discuss recent research into the discovery, characterisation and development of amide bond forming enzymes, with an emphasis on stand-alone ligase enzymes that can generate amides directly from simple carboxylic acid and amine substrates.