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Questions and Answers Related to the Prebiotic Production of Oligonucleotide Sequences from 3’,5’ Cyclic Nucleotide Precur- Life Sors

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Review Questions and Answers Related to the Prebiotic Production of Oligonucleotide Sequences from 3’,5’ Cyclic Nucleotide Precur- life sors Review Judit E. Šponer 1,*, Jiří Šponer 1, Aleš Kovařík 1, Ondrej Šedo 2, Zbyněk Zdráhal 2, Giovanna Costanzo 3 and Ernesto Di MauroQuestions 3 and Answers Related to the Prebiotic Production of Oligonucleotide Sequences from 30,50 Cyclic Nucleotide Precursors1 Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 61265 Brno, Czech Republic; [email protected] (J.E.S.); [email protected] (J.S.); [email protected] (A.K.) Judit E. Šponer 1,* , Jiˇrí Šponer2 Central1, Aleš European Kovaˇrík 1 Institute, Ondrej of Technology, Šedo 2 , ZbynˇekZdr Masaryk University,áhal 2, Giovanna Kamenice Costanzo 5, 62500 3Brno, Czech Republic; and Ernesto Di Mauro 3 [email protected] (O.S.); [email protected] (Z.Z.) 3 Institute of Molecular Biology and Pathology, CNR, Piazzale A. Moro 5, 00185 Rome, Italy; giovan- [email protected] (G.C.); [email protected] (E.D.M.) 1 Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 61265 Brno, Czech Republic; * [email protected]: [email protected] (J.Š.); [email protected] (A.K.) 2 Central European Institute of Technology, Masaryk University, Kamenice 5, 62500 Brno, Czech Republic; Abstract:[email protected] Template-free (O.Š.); nonenzymatic [email protected] polymerization (Z.Z.) of 3’,5’ cyclic nucleotides is an emerging 3 Institute of Molecular Biology and Pathology, CNR, Piazzale A. Moro 5, 00185 Rome, Italy; [email protected] of the origin of life (G.C.);research. [email protected] In the last ten years, (E.D.M.) a number of papers have been published *addressingCorrespondence: various [email protected] aspects of this process. These works evoked a vivid discussion among scientists working in the field of prebiotic chemistry. The aim of the current review is to answer the most Abstract: Template-free nonenzymatic polymerization of 30,50 cyclic nucleotides is an emerging topic offrequently the origin of raised life research. questions In the lastrelated ten years, to the a number detectio of papersn and have characterization been published addressingof oligomeric products as variouswell as aspects to the of geological this process. co Thesentext worksof this evoked chemistry. a vivid discussion among scientists working in the field of prebiotic chemistry. The aim of the current review is to answer the most frequently raisedKeywords: questions polymerization; related to the detection cyclic and nucleotides; characterization prebiotic of oligomeric chemistry products as well as to the geological context of this chemistry. Citation: Šponer, J.E.; Šponer, J.; Kovaˇrík,A.; Šedo, O.; Zdráhal, Z.; Citation:Costanzo, Šponer, G.; DiJ. E.; Mauro, Šponer, E. Questions J.; Ko- Keywords: polymerization; cyclic nucleotides; prebiotic chemistry vařík, andA. Life Answers 2021 Related, 11, x. to the Prebiotic https://doi.org/10.3390/xxxxxProduction of Oligonucleotide 1. Introduction Sequences from 30,50 Cyclic Nucleotide Precursors. Life 2021, 11, 1. IntroductionProduction of oligonucleotide sequences from nucleotide precursors in the absence Academic Editor: Michele Fiore And 800. https://doi.org/10.3390/ of enzymesProduction and of oligonucleotide template molecules sequences is from one nucleotide of the most precursors challenging in the absence problems of of modern Emiliano Altamura life11080800 enzymesorigin of and life template research. molecules 2’,3’ iscyclic one of nucleotides the most challenging (see Figure problems 1) have of modern long origin been considered as ofpotent life research. precursors 20,30 cyclic of the nucleotides most ancient (see Figure oligonucleotide1) have long been sequences considered formed as potent on our planet [1– Received:Academic 19 July Editors: 2021 Michele Fiore and precursors4]. This motivated of the most ancient numerous oligonucleotide attempts sequences dealing formedwith the on ourreconstruction planet [1–4]. This of their synthesis Accepted:Emiliano 03 Aug Altamuraust 2021 motivated numerous attempts dealing with the reconstruction of their synthesis under under plausible prebiotic conditions [5–8]. Nonetheless, nucleotides containing a phos- Published: date plausible prebiotic conditions [5–8]. Nonetheless, nucleotides containing a phosphodiester Received: 19 July 2021 linkagephodiester confined linkage in a strained confined 5-membered in a strained ring are 5-me unstablembered in an acidicring environmentare unstable and in an acidic envi- Accepted: 3 August 2021 undergo a quick ring-opening reaction on the timescale of minutes [9]. Publisher’sPublished: Note: 8 August MDPI 2021 stays neu- ronment and undergo a quick ring-opening reaction on the timescale of minutes [9]. tral with regard to jurisdictional claimsPublisher’s in published Note: mapsMDPI and stays institu- neutral with regard to jurisdictional claims in tional affiliations. published maps and institutional affil- iations. Copyright: © 2021 by the authors. SubmittedCopyright: for poss© 2021ible byopen the access authors. publicationLicensee under MDPI, the Basel, terms Switzerland. and con- This article is an open access article ditions of the Creative Commons At- distributed under the terms and tribution (CC BY) license (https://cre- conditions of the Creative Commons ativecommons.org/licenses/by/4.0/).Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ FigureFigure 1. 1.Structural Structural formulas formulas of 30,5 0ofand 3’,5’ 20,3 0andcyclic 2’,3’ nucleotides. cyclic nucleotides. 4.0/). Life 2021, 11, 800. https://doi.org/10.3390/life11080800 https://www.mdpi.com/journal/life Life 2021, 11, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/life Life 2021, 11, 800 2 of 13 In contrast, the 30,50 cyclic form possesses sufficient stability to withstand extreme conditions as conferred by low-pH environments, most likely ubiquitous on the early Earth [10,11]. Partly because of its significance played in modern biology (cGMP and cAMP are cofactors of key biochemical reactions [12]) and partly because of its unique aggregation properties, 30,50 cyclic guanosine monophosphate (hereafter 30,50 cGMP, the rest of the abbreviations used are explained at the end of the paper) was the target of a series of studies aimed at unraveling the process that could lead to the formation of the first oligonucleotide sequences on the early Earth [13–18]. The concept of polymerization studies using 30,50 cyclic nucleotides is strikingly different from that of preceding works published on prebiotic polymerization processes, which set a goal to find high-yielding chemical routes to oligonucleotides. These latter studies (for an overview see e.g., [19]) use highly activated monomers, because they enable achieving higher polymerization yields. Nevertheless, the lower stability of highly activated precursors (e.g., phosphorimidazolides, nucleotide triphosphates or 20,30 cyclic nucleotides) raises questions regarding their accumulation and long-term survival in the prebiotic pool. Polymerization studies targeting 30,50 cyclic nucleotides place a special emphasis on identifying the conditions that are compatible with a sustainable oligonucleotide produc- tion on longer time scales in a geochemical context relevant to the early Earth. This requires not only sufficiently stable monomers, but also a robust chemistry. As Albert Eschenmoser suggested [20], the robustness of a prebiotic synthetic network lies in the multimodality of catalytically accessible chemical pathways between reactants and final products, because it enables adaptation of the chemical system to the quickly changing chemical environment. In the current paper we provide a brief account of the available knowledge on the polymerization of 30,50 cyclic nucleotides. Since this research has been the focus of general attention for a long time, a number of questions and objections have been raised by the prebiotic chemistry community related to this topic. Our main goal with this paper is to provide an in-depth answer to the most frequent ones and to clarify those disputed points, which emerged after publishing the original studies. 2. How Could 30,50 Cyclic Nucleotides Accumulate in the Prebiotic Pool? Synthesis of 20,30 cyclic nucleotides [5–8] was demonstrated by a number of studies both in aqueous and non-aqueous media. In contrast, no attention has so far been devoted to the prebiotic synthesis of 30,50 cyclic nucleotides. Nevertheless, based on historical studies by Khorana et al., a simple potential prebiotic route can be outlined to these compounds: Reference [21] illustrates that in the presence of carbodiimides nucleoside 50-phosphates can be converted into the 30,50 cyclic form. Since carbodiimides form in large amounts upon thermal treatment of formamide in the presence of meteorites [22] and nucleoside-50-phosphates belong to the main products of phosphorylation reactions conducted in formamide [7], accumulation of 30,50 cyclic nucleotides seems to be plausible in a formamide-rich medium under prebiotic conditions. Work on this topic is in progress. 3. Mechanism of Ring-Opening Polymerization Reactions Involving 30,50 Cyclic Nucleotides Ring-opening polymerization reactions of cyclic phosphate and phosphonate esters in non-aqueous medium are well-known in the literature [23,24]. These reactions are commonly catalyzed by DBU suggesting that a base-catalyzed ring-opening polymerization
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