From the journal RSC Chemical Biology Peer review history

20-Jul-2020

Dear Dr Garneau-Tsodikova:

Manuscript ID: CB-ART-06-2020-000092
TITLE: A comprehensive analysis and categorization of interrupted adenylation domains, including previously unidentified families

Thank you for your submission to RSC Chemical Biology, published by the Royal Society of Chemistry. I sent your manuscript to reviewers and I have now received their reports which are copied below.

After careful evaluation of your manuscript and the reviewers’ reports, I will be pleased to accept your manuscript for publication after revisions.

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Professor Zaneta Nikolovska-Coleska
Associate Editor, RSC Chemical Biology

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Reviewer 1

This manuscript provides a detailed bioinformatic analysis of adenylation domains disrupted with methyltransferase found in nonribosomal peptide synthetases (NRPSs). The corresponding author has been at the forefront of this area of NRPS enzymology and the current work extends our understanding of disrupted A domain. The authors begin by using publicly available sequences to identify the currently available disrupted A domains. Comparison of these domains provided the authors with information to divide these A domains into seven classes. Interestingly, two of these classes have disruptions in regions of that A domain that were not previously noted. A taxonomic analysis of these disrupted A domains some types predominate in certain types of organisms (e.g. family I is found predominantly in actinomycetes). Not too surprisingly, the authors also note that phylogenetic analysis of these A domains finds that those found in the same bacterial phylum are relatively homologous to each other. The authors also performed a phylogenetic analysis of the methyltransferase domains and found they group into six types, but they are broadly fit into the broad class I SAM-dependent methyltransferases. Some of these types of MT domains are found in more than one disrupted A domain family. A systematic analysis of the disrupted A domains and associated MT domains provides the authors a means for assessing boundaries for the insertion sites and also predict catalysis and likely substrates and methylation activity.

This manuscript is well-written and is an important contribution to the field of NRPS enzymology since it provides a framework for predicting the function of MT domain within a disrupted A domain. Furthermore, the identification of new sites for A domain disruptions expands the potential for A domain engineering. I have no suggestions for improved the work.

Reviewer 2

The paper by Lundy et al. presents a comprehensive investigation on the NRPS adenylation domains embedding methylation domain(s). It is an important and valuable contribution to the knowledge on these particular domains operating in some NRPS assembly lines, provided by the research group which has previously produced important results on functional and structural characterization of such domains. A large amount of sequence data and bioinformatics tools allowed to gain an insight into the complexity and diversity within the group of known bacterial adenylation-methylation domains, the classification, taxonomic and phylogenetic analysis of both the adenylation and the methylation domains. Moreover, new families of interrupted A domains were identified. The information on the architecture of the various interrupted adenylation domains, the signature motifs of the methylation domains which provide indications on their substrate specificity and activity, as well as the identification of the boundaries between the domains, will help future combinatorial biosynthesis work.
I have few minor comments.
The title would suggest that all the existing interrupted adenylation domains are taken into consideration. Since “only” bacterial A domains are discussed (however involving a large amount of work that the paper contains) a more precise title could be formulated.
On page 7: the … “ In order to perform these functions….” a reference should be inserted, (for example ref 14 Drake et al. which appears only in Fig.1 legend).
Also, on page 27. Line 4. after “….indicating that they are still functional” a reference should be inserted.
This research opens up new horizons for further work on these particular aspects on the nonribosomal peptide biosynthesis, providing a contribution to the growth of knowledge in this field which will facilitate the production of new compounds, possibly having new activities, by combinatorial biosynthesis.

July 20, 2020
Dr. Zaneta Nikolovska-Coleska
Associate Editor of RSC Chemical Biology

RE: Revisions for manuscript CB-ART-06-2020-000092

Dear Dr. Nikolovska-Coleska,

We are submitting revisions requested for our manuscript CB-ART-06-2020-000092 “A thorough analysis and categorization of bacterial interrupted adenylation domains, including previously unidentified families” by Taylor A. Lundy, Shogo Mori, and Sylvie Garneau-Tsodikova for publication in RSC Chemical Biology. We would like to thank the reviewers and the RSC Chemical Biology editorial team. We have revised the manuscript (submitted with and without tracked changes) and provided a point-to-point response to the reviewers’ comments below. We hope that we have addressed the editorial and reviewers’ comments to your/their satisfaction.

We would like to thank you for reconsidering our manuscript for publication in RSC Chemical Biology and are looking forward to answering any further questions (if any remain) you may have regarding our manuscript.

Sincerely Yours,
Sylvie Garneau-Tsodikova, Ph.D.

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REVIEWER #1:
Comment 1: I have no suggestions to improve the work.
Our response: We thank the reviewer for his/her time in reviewing our manuscript and truly appreciate the very positive feedback.

______________
REVIEWER #2:
Comment 1: The title would suggest that all the existing interrupted adenylation domains are taken into consideration. Since “only” bacterial A domains are discussed (however involving a large amount of work that the paper contains) a more precise title could be formulated.
Our response: We have adjusted the title of our manuscript to “A thorough analysis and categorization of bacterial interrupted adenylation domains, including previously unidentified families”. In this new title, to address the comment, we have replaced the word “comprehensive” by “thorough” and we have added the word bacterial as requested.

Comment 2: On page 7: the … “in order to perform these functions…” a reference should be inserted (for example ref 14 Drake et al. which appears only in Fig. 1 legend).
Our response: We thank the reviewer for pointing out the missing citation. We added the reference suggested along with two more references to support that statement.

Comment 3: On page 27, line 4 after “… indicating that they are still functional” a reference should be inserted.
Our response: We thank the reviewer for the suggestion and have added the missing citation for that claim.

04-Aug-2020

Dear Dr Garneau-Tsodikova:

Manuscript ID: CB-ART-06-2020-000092.R1
TITLE: A thorough analysis and categorization of bacterial interrupted adenylation domains, including previously unidentified families

Thank you for submitting your revised manuscript to RSC Chemical Biology. After considering the changes you have made, I am pleased to accept your manuscript for publication in its current form. I have copied any final comments from the reviewer(s) below.

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With best wishes,

Professor Zaneta Nikolovska-Coleska
Associate Editor, RSC Chemical Biology

Reviewer 1

the authors have adequately addressed the minor changes that were suggested after the initial review.