Recent advances in the structural analysis of adenylation domains in natural product biosynthesis

Adenylation (A) domains catalyze the biosynthetic incorpora-tion of acyl building blocks into nonribosomal peptides and related natural products by selectively transferring acyl sub-strates onto cognate carrier proteins (CP). The use of nonca-nonical acyl units, such as nonproteinogenic amino acids and keto acids, by A domains expands the structural diversity of natural products. Furthermore, interrupted A domains, which have embedded auxiliary domains, are able to modify the incorporated acyl units. Structural information on A domains is important for rational protein engineering to generate unnatural compounds. In this review, we summarize recent advances in the structural analysis of A domains. First, we discuss the mechanisms by which A domains recognize noncanonical acyl units. We then focus on the interactions of A domains with CP domains and embedded auxiliary domains.