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Issue 4, 2020

A thorough analysis and categorization of bacterial interrupted adenylation domains, including previously unidentified families

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Abstract

Interrupted adenylation (A) domains are key to the immense structural diversity seen in the nonribosomal peptide (NRP) class of natural products (NPs). Interrupted A domains are A domains that contain within them the catalytic portion of another domain, most commonly a methylation (M) domain. It has been well documented that methylation events occur with extreme specificity on either the backbone (N-) or side chain (O- or S-) of the amino acid (or amino acid-like) building blocks of NRPs. Here, through taxonomic and phylogenetic analyses as well as multiple sequence alignments, we evaluated the similarities and differences between interrupted A domains. We probed their taxonomic distribution amongst bacterial organisms, their evolutionary relatedness, and described conserved motifs of each type of M domain found to be embedded in interrupted A domains. Additionally, we categorized interrupted A domains and the M domains within them into a total of seven distinct families and six different types, respectively. The families of interrupted A domains include two new families, 6 and 7, that possess new architectures. Rather than being interrupted between the previously described a2–a3 or a8–a9 of the ten conserved A domain sequence motifs (a1–a10), family 6 contains an M domain between a6–a7, a previously unknown interruption site. Family 7 demonstrates that di-interrupted A domains exist in Nature, containing an M domain between a2–a3 as well as one between a6–a7, displaying a novel arrangement. These in-depth investigations of amino acid sequences deposited in the NCBI database highlighted the prevalence of interrupted A domains in bacterial organisms, with each family of interrupted A domains having a different taxonomic distribution. They also emphasized the importance of utilizing a broad range of bacteria for NP discovery. Categorization of the families of interrupted A domains and types of M domains allowed for a better understanding of the trends of naturally occurring interrupted A domains, which illuminated patterns and insights on how to harness them for future engineering studies.

Graphical abstract: A thorough analysis and categorization of bacterial interrupted adenylation domains, including previously unidentified families

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Article information


Submitted
10 Jun 2020
Accepted
04 Aug 2020
First published
18 Aug 2020

This article is Open Access

RSC Chem. Biol., 2020,1, 233-250
Article type
Paper

A thorough analysis and categorization of bacterial interrupted adenylation domains, including previously unidentified families

T. A. Lundy, S. Mori and S. Garneau-Tsodikova, RSC Chem. Biol., 2020, 1, 233 DOI: 10.1039/D0CB00092B

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