scholarly journals Freeze-thaw Cycles Enable a Prebiotically Plausible and Continuous Pathway from Nucleotide Activation to Nonenzymatic RNA Copying

2021 ◽  
Author(s):  
Stephanie J. Zhang ◽  
Daniel Duzdevich ◽  
Christopher E. Carr ◽  
Jack W. Szostak
Keyword(s):  
Rna Replication ◽  
Primer Extension ◽  
Environmental Fluctuation ◽  
One Pot ◽  
Nucleotide Synthesis ◽  
Freeze Thaw ◽  
Methyl Isocyanide ◽  
Subsequent Conversion ◽  
The Origin Of Life ◽  
Key Steps

AbstractNonenzymatic template-directed RNA copying using chemically activated nucleotides is thought to have played a key role in the emergence of genetic information on the early Earth. A longstanding question concerns the number and nature of different environments that might have been necessary to enable all of the steps from nucleotide synthesis to RNA replication. Here we explore three sequential steps from this overall pathway: nucleotide activation, synthesis of imidazolium-bridged dinucleotides, and template-directed primer extension. We find that all three steps can take place in one reaction mixture, under conditions of multiple freeze-thaw cycles. Recent experiments have demonstrated a potentially prebiotic methyl isocyanide-based nucleotide activation chemistry. Unfortunately, the original version of this approach is incompatible with nonenzymatic RNA copying because the high required concentration of the imidazole activating group prevents the accumulation of the essential imidazolium-bridged dinucleotide needed for primer extension. Here we report that ice eutectic phase conditions facilitate not only the methyl isocyanide-based activation of ribonucleotide 5′-monophosphates with stoichiometric 2-aminoimidazole, but also the subsequent conversion of these activated mononucleotides into imidazolium-bridged dinucleotides. Furthermore, this one pot approach is compatible with template-directed primer extension in the same reaction mixture. Our results suggest that the simple and common environmental fluctuation of freeze-thaw cycles could have played an important role in prebiotic nucleotide activation and nonenzymatic RNA copying.Significance StatementThe replication of RNA without the aid of evolved enzymes may have enabled the inheritance of useful molecular functions during the origin of life. Several key steps on the path to RNA replication have been studied in isolation, including chemical nucleotide activation, synthesis of a key reactive intermediate, and nonenzymatic RNA copying. Here we report a prebiotically plausible scenario under which these reactions can happen together under mutually compatible conditions. Thus, this pathway could potentially have operated in nature without the complicating requirement for exchange of materials between distinct environments.

scholarly journals Nonenzymatic copying of RNA templates containing all four letters is catalyzed by activated oligonucleotides

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Noam Prywes ◽  
J Craig Blain ◽  
Francesca Del Frate ◽  
Jack W Szostak
Keyword(s):  
Prebiotic Chemistry ◽  
Rna World ◽  
Hammerhead Ribozyme ◽  
Primer Extension ◽  
Chemical System ◽  
One Pot ◽  
Nucleotide Synthesis ◽  
A Genome ◽  
Sequential Addition ◽  
The One

The nonenzymatic replication of RNA is a potential transitional stage between the prebiotic chemistry of nucleotide synthesis and the canonical RNA world in which RNA enzymes (ribozymes) catalyze replication of the RNA genomes of primordial cells. However, the plausibility of nonenzymatic RNA replication is undercut by the lack of a protocell-compatible chemical system capable of copying RNA templates containing all four nucleotides. We show that short 5′-activated oligonucleotides act as catalysts that accelerate primer extension, and allow for the one-pot copying of mixed sequence RNA templates. The fidelity of the primer extension products resulting from the sequential addition of activated monomers, when catalyzed by activated oligomers, is sufficient to sustain a genome long enough to encode active ribozymes. Finally, by immobilizing the primer and template on a bead and adding individual monomers in sequence, we synthesize a significant part of an active hammerhead ribozyme, forging a link between nonenzymatic polymerization and the RNA world.

One-Pot Preparation of Physical Hydrogel-Based Photonic Crystal

2018 ◽  
Vol 939 ◽  
pp. 127-132 ◽  
Author(s):  
Cheng Chen ◽  
Zhi Qiang Dong ◽  
Guang Cai Mei ◽  
Zhan Hong Li ◽  
Zhi Gang Zhu
Keyword(s):  
Photonic Crystal ◽  
Drug Release ◽  
Visible Light ◽  
Polymer Solution ◽  
One Pot ◽  
Freeze Thaw ◽  
Self Assembled

We developed a one-pot method for the fabrication of hydrogel-based photonic crystal (PC) materials. An array of monodisperse colloids was self-assembled within a polymer solution, which generates a visible light diffractable photonic mixture. This mixture was molded and gelated into a hydrogel PC material by freeze-thaw treatment. Drug release as well as the structure colour changing properties of the PC hydrogels were discussed, and the experiment results revealed that our one-pot design and the associated modification approach has potential in efficient fabrication of PC materials.

scholarly journals Enzymatic RNA Production from NTPs Synthesized from Nucleosides and Trimetaphosphate

2021 ◽  
Author(s):  
Fabio Chizzolini ◽  
Alexandra Kent ◽  
Luiz F. M. Passalacqua ◽  
Andrej Lupták
Keyword(s):  
Rna Synthesis ◽  
Rna World ◽  
Rna Replication ◽  
High Energy ◽  
Rna Degradation ◽  
T7 Rna Polymerase ◽  
Nucleotide Synthesis ◽  
Enthalpy Of Activation ◽  
Rna Polymerization ◽  
Synthetic Approaches

<p>A mechanism of nucleoside triphosphorylation would have been critical in an evolving “RNA world” to provide high-energy substrates for reactions such as RNA polymerization. However, synthetic approaches to produce ribonucleoside triphosphoates (rNTPs) have suffered from conditions such as high temperatures or high pH that lead to increased RNA degradation, as well as substrate production that cannot sustain replication. We demonstrate that cyclic trimetaphosphate (cTmp) can react with nucleosides to form rNTPs under mild, prebiotically-relevant conditions, with second-order rate constants ranging from 1.7 x 10<sup>–6</sup> to 6.5 x 10<sup>–6</sup> M<sup>–1</sup> s<sup>–1</sup>. The ATP reaction shows a linear dependence on pH and Mg<sup>2+</sup>, and an enthalpy of activation of 88 ± 4 kJ/mol. At millimolar nucleoside and cTmp concentrations, the rNTP production rate is sufficient to facilitate RNA synthesis by both T7 RNA polymerase and a polymerase ribozyme. We suggest that the optimized reaction of cTmp with nucleosides may provide a viable connection between prebiotic nucleotide synthesis and RNA replication.</p>

Annulations leading to diene systems. Total syntheses of the dolastane-type diterpenoids (±)-(5S,12R,14S)-dolasta-1(15),7,9-trien-14-ol and (±)-amijitrienol

1992 ◽  
Vol 70 (4) ◽  
pp. 1204-1220 ◽  
Author(s):  
Edward Piers ◽  
Richard W. Friesen
Keyword(s):  
Aldol Condensation ◽  
Ring Closure ◽  
Starting Material ◽  
Target Compound ◽  
One Pot ◽  
Stereoselective Reduction ◽  
Total Syntheses ◽  
Reductive Transformation ◽  
The One ◽  
Key Steps

Alkylation of the substituted cycloalkanones 14a–d and 30 with (Z)-1-bromo-4-methyl-3-trimethylstannyl-2-pentene (13) produced compounds 15a–d and 33, which were readily converted into the corresponding enol trifluoromethane-sulfonates (triflates) 16a–d and 34. Intramolecular Pd(O)-catalyzed coupling of the vinylstannane and enol triflate functions in 16a–d and 34 provided the dienes 17a–d and 35. The annulation product 35 served as a suitable starting material for the total syntheses of the dolastane diterpenoids (±)-(5S,12R,14S)-dolasta-1(15),7,9-trien-14-ol (2) and (±)-amijitrienol (3). The key steps of the synthesis of (±)-2 involved the stereoselective methylation of the ketone 44 (readily derived from 35) to provide 46 and the Barbier type ring closure of 47 to provide the target compound. For the synthesis of (±)-3, the notable conversions included the reductive transformation of the diene 35 into the alkene 53, the aldol condensation of the ketone 54 with 4-trimethylstannyl-4-pentenal (55), the chemo- and stereoselective reduction of the dione 58, and the one-pot conversion of the keto vinylstannane 63 into the triene 65, via the intermediate 64.

scholarly journals Efficient Asymmetric Synthesis of Prostaglandin E1

2007 ◽  
Vol 62 (4) ◽  
pp. 556-560 ◽  
Author(s):  
Jae-Chul Jung ◽  
Oee-Sook Park
Keyword(s):  
Asymmetric Synthesis ◽  
Michael Addition ◽  
Prostaglandin E1 ◽  
Simple Synthesis ◽  
High Yield ◽  
Prostaglandin E ◽  
Magnesium Bromide ◽  
One Pot ◽  
Asymmetric Michael Addition ◽  
Key Steps

A simple synthesis of prostaglandin E1 (PGE1) is described. The key steps are an asymmetric Michael addition to establish the desired (R)-configurations at C8 and C12 of the 2- (trimethylsilyl)ethoxymethyl- (SEM) protected PGE1 and its one-pot deprotection with magnesium bromide in high yield. This method is potentially useful for the preparation of other modified prostaglandins.

scholarly journals Enzymatic RNA Production from NTPs Synthesized from Nucleosides and Trimetaphosphate

2021 ◽  
Author(s):  
Fabio Chizzolini ◽  
Alexandra Kent ◽  
Luiz F. M. Passalacqua ◽  
Andrej Lupták
Keyword(s):  
Rna Synthesis ◽  
Rna World ◽  
Rna Replication ◽  
High Energy ◽  
Rna Degradation ◽  
T7 Rna Polymerase ◽  
Nucleotide Synthesis ◽  
Enthalpy Of Activation ◽  
Rna Polymerization ◽  
Synthetic Approaches

<p>A mechanism of nucleoside triphosphorylation would have been critical in an evolving “RNA world” to provide high-energy substrates for reactions such as RNA polymerization. However, synthetic approaches to produce ribonucleoside triphosphoates (rNTPs) have suffered from conditions such as high temperatures or high pH that lead to increased RNA degradation, as well as substrate production that cannot sustain replication. We demonstrate that cyclic trimetaphosphate (cTmp) can react with nucleosides to form rNTPs under mild, prebiotically-relevant conditions, with second-order rate constants ranging from 1.7 x 10<sup>–6</sup> to 6.5 x 10<sup>–6</sup> M<sup>–1</sup> s<sup>–1</sup>. The ATP reaction shows a linear dependence on pH and Mg<sup>2+</sup>, and an enthalpy of activation of 88 ± 4 kJ/mol. At millimolar nucleoside and cTmp concentrations, the rNTP production rate is sufficient to facilitate RNA synthesis by both T7 RNA polymerase and a polymerase ribozyme. We suggest that the optimized reaction of cTmp with nucleosides may provide a viable connection between prebiotic nucleotide synthesis and RNA replication.</p>

Formal Synthesis of Actinoranone Using a Racemization-Free One-Pot Semipinacol Rearrangement/Wittig Reaction

2018 ◽  
Author(s):  
Martina Menger ◽  
Mathias Christmann
Keyword(s):  
Natural Product ◽  
Wittig Reaction ◽  
Reaction Sequence ◽  
One Pot ◽  
Formal Synthesis ◽  
Linear Sequence ◽  
Semipinacol Rearrangement ◽  
Key Steps

Here, we report a formal synthesis of the marine cytotoxic meroterpenoid actinoranone. Key steps include a racemization-free semipinacol rearrangement/Wittig reaction sequence and a chiral pool approach for the syntheses of the tetralone and the decalin fragments, respectively. The presented route provides access to the natural product in 14 steps in the longest linear sequence.

Chiron approach for the total synthesis of brevipolide M

Synlett ◽  
2022 ◽  
Author(s):  
Yang Liu ◽  
Ziyang Zhao ◽  
Chao Hu ◽  
Chuanfang Zhao ◽  
Jun Liu ◽  
...  
Keyword(s):  
Double Bond ◽  
Total Synthesis ◽  
Stereoselective Synthesis ◽  
Ring Closing Metathesis ◽  
One Pot ◽  
Double Bond Migration ◽  
Key Steps

An efficient stereoselective synthesis of brevipolide M was established in 13 linear steps and 17.8% overall yields base on chiron approach. The key steps of our synthesis involved tandem homologation / tetrahydrofuran cyclization and sequential ring-closing metathesis (RCM) / double-bond migration in one-pot processes.

scholarly journals Reverse C-glycosidase reaction provides C-nucleotide building blocks of xenobiotic nucleic acids

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Martin Pfeiffer ◽  
Bernd Nidetzky
Keyword(s):  
Synthetic Biology ◽  
Nucleic Acids ◽  
Enzymatic Reaction ◽  
Building Blocks ◽  
Cascade Reactions ◽  
Ring Closure ◽  
One Pot ◽  
Open Chain ◽  
Nucleotide Synthesis ◽  
Nucleotide Triphosphates

AbstractC-Analogues of the canonical N-nucleosides have considerable importance in medicinal chemistry and are promising building blocks of xenobiotic nucleic acids (XNA) in synthetic biology. Although well established for synthesis of N-nucleosides, biocatalytic methods are lacking in C-nucleoside synthetic chemistry. Here, we identify pseudouridine monophosphate C-glycosidase for selective 5-β-C-glycosylation of uracil and derivatives thereof from pentose 5-phosphate (d-ribose, 2-deoxy-d-ribose, d-arabinose, d-xylose) substrates. Substrate requirements of the enzymatic reaction are consistent with a Mannich-like addition between the pyrimidine nucleobase and the iminium intermediate of enzyme (Lys166) and open-chain pentose 5-phosphate. β-Elimination of the lysine and stereoselective ring closure give the product. We demonstrate phosphorylation-glycosylation cascade reactions for efficient, one-pot synthesis of C-nucleoside phosphates (yield: 33 – 94%) from unprotected sugar and nucleobase. We show incorporation of the enzymatically synthesized C-nucleotide triphosphates into nucleic acids by RNA polymerase. Collectively, these findings implement biocatalytic methodology for C-nucleotide synthesis which can facilitate XNA engineering for synthetic biology applications.

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