Reflections on the Origin of Coded Protein Biosynthesis

Round 1

Reviewer 1 Report

It is obvious that the review  "Reflections on the origin of biocatalysis" as it is presented is a text reflecting a personal perspective of this topic, and therefore it should be considered as such. It is a readable text, well organized and quite interesting.

Nevertheless, I have some comments that I would like to be considered:

- first, the title does not reflect the contents of the text. It should be modified making it more specific. 

- second, the prefix "bio" is a very powerful one since it evokes a biological system. I think the readers would acknowledge that the author made an effort trying to put the piecemeal information of the review in an overall scenario for life´s origin.

- third, the weight of the "origins" is relatively low in the text as compared with the current, biological information about the mechanisms of peptide bond formation in which everything is on stage. I suggest a more extensive discussion about the origins.   

Author Response

"It is obvious that the review  "Reflections on the origin of biocatalysis" as it is presented is a text reflecting a personal perspective of this topic, and therefore it should be considered as such. It is a readable text, well organized and quite interesting."

Answer: Thanks. As the reviewer rightly concludes my article is a personal interpretation of the available data concerning these putative very old reactions.

Nevertheless, I have some comments that I would like to be considered:

- first, the title does not reflect the contents of the text. It should be modified making it more specific. 

Answer: Although I am convinced that the original title reflected the contents of my Review I have changed it to “Reflections on the origin of coded protein biosynthesis”.

- second, the prefix "bio" is a very powerful one since it evokes a biological system. I think the readers would acknowledge that the author made an effort trying to put the piecemeal information of the review in an overall scenario for life´s origin.

Answer: Since I am commenting on ancestral biocatalysis I believe the term “bio-“ applies.

- third, the weight of the "origins" is relatively low in the text as compared with the current, biological information about the mechanisms of peptide bond formation in which everything is on stage. I suggest a more extensive discussion about the origins.   

Answer: The point I am trying to make is that although initial catalytic biopolymers, i.e., proto-ribosomes and proto-enzymes, lacked the sophistication of later enzymes, they did the job. And, because these reactions are so essential to life, they have been preserved through evolution.  The possible nature of abiotic catalytic precursors of these biopolymers has been extensively discussed by many authors. I have included several references to their work.

Reviewer 2 Report

The manuscript under evaluation entitled “Reflections on the origin of biocatalysis” focus on the revision about biocatalysis origin and evolutions. 

To my opinion, this is a manuscript about a very interesting topic that only requires a few minor corrections before publication.

Comments:

Page 109 -  To our opinion the concept of (“negative catalysis”), must be better explored, as well “entropic trap” in page 144.

Please add the reference number to Steitz et al. (page 132), Sievers et al. (page 140), Weinger et al. (163), Changalov et al. (page 171), Trobro & Aqvist (page 175), Jeltsch et al. (Page 335) and to Akouche et al. (Page 380)

Page 404 – To our opinion “On page 4….” It must replaced by the title of the point or by the interval number of the lines.

Page 422 – To our opinion  “If life exists elsewhere in the universe, it will most likely have a genetic system which components will share the properties of ribose and phosphate…”  this conclusion related to the properties of ribose and phosphate must be improved.

Author Response

With respect to the quality of the English used this reviewer first states that he/she is not proficient enough to judge and then he/she assigns only 3 yellow stars to it (?).

“The manuscript under evaluation entitled “Reflections on the origin of biocatalysis” focus on the revision about biocatalysis origin and evolutions. 
To my opinion, this is a manuscript about a very interesting topic that only requires a few minor corrections before publication.”

Answer: Thanks.

Comments:

(Me: the numbers given by the reviewer apply to lines not to pages):

Page 109 - To our opinion the concept of (“negative catalysis”), must be better explored, as well “entropic trap” in page 144.

Answer: Old line 109: I have added a sentence to explain the “negative catalysis” effect.

Old line 144: I have added an explanatory sentence about the nature of the “entropic trap”

“Please add the reference number to Steitz et al. (page 132), Sievers et al. (page 140), Weinger et al. (163), Changalov et al. (page 171), Trobro & Aqvist (page 175), Jeltsch et al. (Page 335) and to Akouche et al. (Page 380)”

 Answer: I have already provided all these references at the end of the respective sentences. The Editor may decide to move them closer to the beginning of the sentences, next to the authors names.

Page 404 – To our opinion “On page 4….” It must replaced by the title of the point or by the interval number of the lines.

Answer: “page 4” is an internal referential information. The Editor will change it to the appropriate number.

Page 422 – To our opinion  “If life exists elsewhere in the universe, it will most likely have a genetic system which components will share the properties of ribose and phosphate…”  this conclusion related to the properties of ribose and phosphate must be improved.

Answer: I have added a few words to explain that this is due to the possibility of “substrate-assisted catalysis”, as previously stated a number of times in the Review.

Reviewer 3 Report

This perspective/review is a masterpiece that considers what current biological processes related to the central dogma could be in their most primitive forms. The fundamental driving forces that promote biocatalysis of nucleic acid polymerization, peptide formation, and codon assignment are thoroughly discussed. Even though it is impossible for us to travel back to rigorously figure out what ancient biocatalysts that support life can be, the review presents logical hypotheses and results that we do know, allowing us to favor or disfavor certain proposals. One particular point I especially enjoy is emphasis on the roles of biocatalysts being auxiliary; the substrates are already self-promoting. In some way, I wonder why the author, while has worked in the field of metalloenzymes for decades, believes that the primordial form of biocatalysts had hard time accessing radical chemistry (as in ribonucleotide reductases) before the Great Oxygen Event. Given that numerous iron-sulfur/radical SAM based enzymes are capable of executing radical chemistry, would not their ancestors good candidates in the central dogma?

The only very minor thing I ask for is to modify the keyword of "tRNA-aminoacyl synthetase" to "aminoacyl-tRNA synthetase", as I believe the latter is used throughout the main text and is vastly adopted in the community.

Author Response

“This perspective/review is a masterpiece that considers what current biological processes related to the central dogma could be in their most primitive forms. The fundamental driving forces that promote biocatalysis of nucleic acid polymerization, peptide formation, and codon assignment are thoroughly discussed. Even though it is impossible for us to travel back to rigorously figure out what ancient biocatalysts that support life can be, the review presents logical hypotheses and results that we do know, allowing us to favor or disfavor certain proposals. One particular point I especially enjoy is emphasis on the roles of biocatalysts being auxiliary; the substrates are already self-promoting. In some way, I wonder why the author, while has worked in the field of metalloenzymes for decades, believes that the primordial form of biocatalysts had hard time accessing radical chemistry (as in ribonucleotide reductases) before the Great Oxygen Event. Given that numerous iron-sulfur/radical SAM based enzymes are capable of executing radical chemistry, would not their ancestors good candidates in the central dogma?”

Answer: Thank you very much for your nice words. I have added a paragraph to explain how I see the problem of primordial radical biochemistry. Organic radicals are especially reactive and, in the case of ribonucleotide reductases, the radical is transferred as the reaction progresses. It is also necessary to end the radical reaction by dehydration specifically at the ribosyl 2’ position. This requires a very complex stereochemistry that I think was not available at the early stages of biocatalysis evolution.

The only very minor thing I ask for is to modify the keyword of "tRNA-aminoacyl synthetase" to "aminoacyl-tRNA synthetase", as I believe the latter is used throughout the main text and is vastly adopted in the community.

Answer: Done. Thanks.