Engineered Biosynthesis through the Adenylation Domains from Nonribosomal Peptide Synthetases

Abstract

Nonribosomal peptide synthetases, consisting of multiple catalytic domains, are involved in the biosynthesis of an important family of bioactive natural products in a coordinated manner. Among the functional domains, adenylation domains are specifically responsible for recognizing carboxylic acid building blocks and synthesizing aminoacyl adenylates. Given their critical roles in the biosynthesis of the growing peptide, A-domains are also referred to as the “gatekeeper”. In this review, very recent developments in the A-domains from NRPSs are reviewed to expand the fundamental knowledge of the A domain, including knowledge on the structures, functions, and molecular interactions. Several recent examples were also discussed to highlight the great .potential of A-domain engineering. This study should provide a framework for the combinatorial biosynthesis or synthetic biology-driven microbial production of novel nonribosomal peptides.

Cell-free protein synthesis for nonribosomal peptide synthetic biology

“…Briefly, NRPSs are comprised of modules, wherein each module consists of a set of discrete enzymatic domains that are responsible for the one cycle of the chain extension in a colinear fashion (Bozhüyük et al, 2019;Beck et al, 2020;Lu et al, 2023;Xu et al, 2023). A typical NRPS module contains a minimum of three core domains: the adenylation (A) domain, the condensation (C) domain, and the peptidyl carrier protein (PCP) otherwise known as a thiolation (T) domain.…”