Research Progress in the Biosynthetic Mechanisms of Marine Polyether Toxins

Round 1

Reviewer 1 Report

The authors propose herein an interesting review on the metabolic pathways of polyether toxins produced by marine dinoflagellates. This is a hot topic that will be of interest for a broad range of scientists ranging from natural product chemists, molecular biologists, pharmacologists but also toxicologists so it clearly deserves publication in Marine Drugs. Overall the text is well written and easy to read. 

As major change I would just say that the authors could structure a bit more their review by including some subparts in each part.

I would suggest some minor changes:

as soon as there is a transformation the authors should use the terms scheme. In Scheme 3 4 and 5 they should pay more attention in the mechanisms and arrows representing movement of electrons. Some of the transformations do not seem perfectly correct like in scheme 5 part B. For figure 6 some protons are missing as it is strange to see a nucleophilic oxygen attacking a nucleophilic double bond Some arrows are missing in figure 9

Author Response

Dear Reviewer:
Thank you for your letter and for the comments concerning our manuscript entitled “Research Progress in the Biosynthetic Mechanisms of Marine Polyether Toxins” (ID: marinedrugs-614808). Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our research. We have studied the comments carefully and have made corrections which we hope meet with approval. Revised portion were highlighted in the paper using the "Track Changes" function. The main corrections in the paper and the responds to the reviewer’s comments are as flowing:

Responses to the reviewer’s comments:
1. Comment: “As major change I would just say that the authors could structure a bit more their review by including some subparts in each part”.
Response: We do think this is a good suggestion, which will make our paper more clear and well-organized. We have divided the 2th part - Carbon Skeleton Deletion into three subparts, divided the 3th part - Pendant Alkylation into three subparts, divided the 4th part - Polyether Ring Formation into four subparts, and divided the 5th part - Gene Mining into two subparts, which we would hope will meet with approval.

2. Comments: “as soon as there is a transformation the authors should use the terms scheme. In Scheme 3, 4, and 5 they should pay more attention in the mechanisms and arrows representing movement of electrons. Some of the transformations do not seem perfectly correct like in scheme 5 part B. For figure 6 some protons are missing as it is strange to see a nucleophilic oxygen attacking a nucleophilic double bond. Some arrows are missing in figure 9.”
Response: we have rechecked the schemes carefully and consulted other literatures and professional books relevant to our paper, so as to ensure our schemes representing normatively and correctly, especially the electrons movement, protons transformation, and arrows orientation. Therefore, we redraw the Scheme 1, 3, 4, 5, 6, and 9, including the necessary arrows and protons, which we hope will meet with approval.

Once again, Special thanks to you for your good comments and suggestions.

Reviewer 2 Report

see attached file

Comments for author File: Comments.pdf

Author Response

Dear Reviewer:
Thank you for your letter and for the comments concerning our manuscript entitled “Research Progress in the Biosynthetic Mechanisms of Marine Polyether Toxins” (ID: marinedrugs-614808). Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our research. We have studied the comments carefully and have made corrections which we hope meet with approval. Revised portion were highlighted in the paper using the "Track Changes" function. The main corrections in the paper and the responses to the reviewer’s comments are as flowing:

Responses to the reviewer’s comments:

1. Comment: “L. 4: affiliation “2” is missing”

Response: We are very sorry for our incorrect writing and have made correction. The author “Ge Yao” also belongs to the affiliation “1”.

2. Comment: “L.30-33 and l. 248: I strongly disagree with the authors’ statement that pectenotoxins and goniodomins are macrolide polyethers. Even though they may appear as macrolides at the first glance, both compound classes are intramolecular esters (lactones) and their macrocycles are not formed by carbon chains. In fact they are better grouped into the linear polyketides such as okadaic acid, palytoxins, etc. “True” macrolides are almost all representatives of the group of cyclic imine toxins, such as spirolides, gymnodimines, pinnatoxins, etc., in which the macrocycles are formed by carbon atoms only. Given the fact that the manuscript has a strong chemical focus, this should be recognized by the authors."

Response: Thank you for your rigorous and kindly suggestion and we agree with that the macrolides are almost all representatives of the group of cyclic imine toxins. We have corrected the introduction about macrolide polyethers and represent the “spirolides, gymnodimines, and pinnatoxins” as the typical examples of macrolide polyethers.

3. Comment: “L. 67-68: it is not true that dinoflagellates are difficult to grow. In fact, the opposite is true that most dinoflagellates can be cultured easily and there are only a few species or strains that are difficult to grow.”

Response: We are very sorry for our incorrect writing and we have re-written this part according to your kindly suggestion.

4. Comments: “L. 101-103: All mentioned toxins are not single compounds but compound classes and accordingly should be named in plural; not all named compound classes are shown in Figure 1: in order to avoid any confusion the reference to Fig.1 should be made more specifically.”

Response:  According to your suggestion, we have named the toxins in plural except for the “okadaic acid (OA)”, as this style of writing for OA is common in other papers as far as we know.

We redraw the Figure 1 so as to contain all mentioned toxins in this part. As an explanation, due to lack of clear isotope labeling experiment data of karlotoxin, we removed this toxin.

5. Comment: “L. 105: put “acetate unit” into plural”

Response: We are very sorry for our incorrect writing and have made correction.

6. Comment: L. 400: reformat “Vilotijevic”

Response: We are very sorry for our incorrect writing and have reformatted“Vilotijevic” with the uniformity.

7. Comment: “L. 406-408: Biosynthetic processes are entirely intracellular processes and it is completely irrelevant for biosynthetic mechanisms, if the producing organism is an aquatic or terrestrial one. I suggest deleting this sentence. Otherwise, authors should give compelling evidence or references for their hypothesis.”

Response: Thank you for your rigorous suggestion and we agree with that. Considering your suggestion, we changed this sentence to “This discovery suggests that the water molecule plays a role in promoting the activity of epoxide hydrolase for the formation of polycyclic fused ethers, resulting in the disfavored 6-endo-tet cyclization reactions.”

8. Comment: “L. 453: delete space between Gambierdiscus and australe and the species name is: Gambierdicus australes”

Response: We are very sorry for our incorrect writing and have made correction.

9. Comment: “L. 588: the author name is Hégaret”

Response: We rechecked this paper and we are afraid that the author name is “Hégarat”.

10. Comment: “L. 612 f: correct indention”

Response: We are very sorry for our incorrect writing and have made correction.

11. Comment: “L. 616: delete space between abbreviated names of Rhodes”

Response: We are very sorry for our incorrect writing and have deleted space between abbreviated names of Rhodes.

12. Comment: “L. 644: the species name is: Prorocentrum maculosum; needs to be set in italics.”

Response: We are very sorry for our incorrect writing and have corrected “Prorocentrum maculosum” in italics.

13. Comment: “L. 681: -3-methylglutaryl-“

Response: We are very sorry for our incorrect writing and have made correction.

14. Comment: ”L. 695: “beetles” not in italics”

Response: We are very sorry for our incorrect writing and have made correction.

15. Comment: “L. 762: ladders-: put space between word and hyphen”

Response: We are very sorry for our incorrect writing and have made correction.

16. Comment: “L. 774: put Gambierdiscus in italics”

Response: We are very sorry for our incorrect writing and have corrected “Gambierdiscus” in italics.

Once again, Special thanks to you for your good comments and suggestions.