Abstract
Microorganisms produce a large number of peptide-based natural products that display a broad range of biologically interesting properties, including antimicrobial, immunosuppressant, and anticancer activities, as well as behaving as virulence factors and signaling molecules. These peptide natural products are composed of proteinogenic amino acids, as well as a number of other compound classes, including non-proteinogenic amino acids, aryl acids, fatty acids, hydroxyl acids, heterocyclic rings, and sugars, which provide a complex level of chemical diversity. Many of these natural products are biosynthesized by large, highly versatile multifunctional megasynthetases, which are known as nonribosomal peptide synthetases (NRPSs). The adenylation (A) domains found in all NRPS modules are essential catalytic components and function as gatekeepers to select the appropriate amino acid building blocks during nonribosomal peptide (NRP) biosynthesis. The results of extensive periods of genetic, biochemical, and bioinformatic investigations have provided a detailed understanding of the functional characteristics and molecular basis underpinning the A domain enzymology in NRP biosynthesis. This review will therefore focus on the recent discoveries and breakthroughs in the structural elucidation, molecular mechanism, and chemical biology underlying the A domains within NRPS enzymes.
Keywords: Adenylation domain, chemical proteomics, nonribosomal peptide synthetase, peptide-based natural product, protein engineering, reprogramming, protein–protein interaction, synthetic probe.
Graphical Abstract
Call for Papers in Thematic Issues
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