Fatty acyl-AMP ligases in bacterial natural product biosynthesis

Fatty Acyl-AMP Ligases (FAALs) belong to the family of adenylate-forming enzymes and activate fatty acyl substrates through adenylation. FAALs were discovered as key players in various natural product biosynthetic pathways, particularly in the assembly of polyketides and non-ribosomal peptides. These enzymes exhibit a conserved structural architecture that distinguishes them from their close relatives, the Fatty Acyl-CoA Ligases. FAALs display the starter unit in the biosynthesis of diverse natural products where they shuttle fatty acyl substrates into secondary metabolism for further chain elongation and/or modification. In this review, we cover the discovery, distribution and structure of FAALs as well as their role in natural product biosynthesis. In addition, we provide an overview about their genomic and biosynthetic contexts and summarize approaches used to analyze FAAL activity, predict their substrate specificity and to discover new compounds whose biosyntheses involve these enzymes.