Investigating the Role of Class I Adenylate-Forming Enzymes in Natural Product Biosynthesis.

Abstract

Adenylate-forming enzymes represent one of the most important enzyme classes in biology, responsible for the activation of carboxylate substrates for biosynthetic modifications. The by-product of the adenylate-forming enzyme acetyl-CoA synthetase, acetyl-CoA, is incorporated into virtually every primary and secondary metabolic pathway. Modification of acetyl-CoA by an array of other adenylate-forming enzymes produces complex classes of natural products including non-ribosomal peptides, polyketides, phenylpropanoids, lipopeptides, and terpenes. Adenylation domains possess a variety of unique structural and functional features that provide for such diversification in their resulting metabolites. As the number of organisms with sequenced genomes increases, more adenylate-forming enzymes are being identified, each with roles in metabolite production that have yet to be characterized. In this review, we explore the broad role of class I adenylate-forming enzymes in the context of natural product biosynthesis, and how they contribute to primary and secondary metabolism by focusing on important work conducted in the field. We highlight features of subclasses from this family that facilitate the production of structurally diverse metabolites, including those from non-canonical adenylation domains, and additionally discuss when biological roles for these compounds are known.