Mechanistic understanding of bacterial FAALs and the role of their homologs in eukaryotes

Abstract Fatty acids are used in fundamental cellular processes, such as membrane biogenesis, energy generation, post‐translational modification of proteins, and so forth. These processes require the activation of fatty acids by adenosine triphosphate (ATP), followed by condensation with coenzyme‐A (CoA), catalyzed by the omnipresent enzyme called Fatty acyl‐CoA ligases (FACLs). However, Fatty acyl‐AMP ligases (FAALs), the structural homologs of FACLs, operate in an unprecedented CoA‐independent manner. FAALs transfer fatty acids to the acyl carrier protein (ACP) domain of polyketide synthases (PKS) and non‐ribosomal peptide synthetases (NRPS) for the biosynthesis of various antibiotics, lipopeptides, virulent complex lipids, and so forth in bacteria. Recent structural and biochemical insights from our group provide a detailed understanding of the mode of CoA rejection and ACP acceptance by FAALs. In this review, we have discussed advances in the mechanistic, evolutionary, and functional understanding of FAALs and FAAL‐like domains across life forms. Here, we are proposing a “Five‐tier” mechanistic model to explain the specificity of FAALs. We further demonstrate how FAAL‐like domains have been repurposed into a new family of proteins in eukaryotes with a novel function in lipid metabolism.