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Directed Evolution Reveals the Functional Sequence Space of an Adenylation Domain Specificity Code.

Abstract：

:Nonribosomal peptides are important natural products biosynthesized by nonribosomal peptide synthetases (NRPSs). Adenylation (A) domains of NRPSs are highly specific for the substrate they recognize. This recognition is determined by 10 residues in the substrate-binding pocket, termed the specificity code. This finding led to the proposal that nonribosomal peptides could be altered by specificity code swapping. Unfortunately, this approach has proven, with few exceptions, to be unproductive; changing the specificity code typically results in broadened specificity or poor function. To enhance our understanding of A domain substrate selectivity, we carried out a detailed analysis of the specificity code from the A domain of EntF, an NRPS involved in enterobactin biosynthesis in Escherichia coli. Using directed evolution and a genetic selection, we determined which sites in the code have strict residue requirements and which are tolerant of variation. We showed that the EntF A domain, and other l-Ser-specific A domains, have a functional sequence space for l-Ser recognition, rather than a single code. This functional space is more expansive than the aggregate of all characterized l-Ser-specific A domains: we identified 152 new l-Ser specificity codes. Together, our data provide essential insights into how to overcome the barriers that prevent rational changes to A domain specificity.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Throckmorton K,Vinnik V,Chowdhury R,Cook T,Chevrette MG,Maranas C,Pfleger B,Thomas MG

doi

10.1021/acschembio.9b00532

subject

Has Abstract

pub_date

2019-09-20 00:00:00

pages

2044-2054

issue

9

eissn

1554-8929

issn

1554-8937

journal_volume

14

pub_type

杂志文章

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