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Creators/Authors contains: "Krishnamurthy, Ramanarayanan"

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  1. Abstract

    The prebiotic origins of ribose, nucleosides, and eventually RNA are enduring questions whose answers are central to the RNA world hypothesis. The abiotic synthesis of sugars was first demonstrated over a century ago, but no known prebiotic reaction produces ribose (an aldose sugar) selectively and in good yield. In contrast, ribulose, and fructose (ketose sugars) and other monosaccharides are formed in high yield by several robust abiotic reactions. It is reported here that ketose sugars ‐ both ketopentoses and ketohexoes ‐ serve as precursors for the formation of ribosides and other aldosides, as demonstrated by glycoside‐forming reactions involving barbituric acid, a plausibly prebiotic nucleobase. Moreover, a one‐pot reaction of glyceraldehyde and barbituric acid was discovered which under mild conditions, and without special minerals or other catalysts, results in the formation of glycosides. These results reveal that an exclusive or high‐yielding generation of free ribose was not required for its incorporation into processes that provided the foundations for life.

     
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  2. Abstract

    The close synergy between peptides and nucleic acids in current biology is suggestive of a functional co-evolution between the two polymers. Here we show that cationic proto-peptides (depsipeptides and polyesters), either produced as mixtures from plausibly prebiotic dry-down reactions or synthetically prepared in pure form, can engage in direct interactions with RNA resulting in mutual stabilization. Cationic proto-peptides significantly increase the thermal stability of folded RNA structures. In turn, RNA increases the lifetime of a depsipeptide by >30-fold. Proto-peptides containing the proteinaceous amino acids Lys, Arg, or His adjacent to backbone ester bonds generally promote RNA duplex thermal stability to a greater magnitude than do analogous sequences containing non-proteinaceous residues. Our findings support a model in which tightly-intertwined biological dependencies of RNA and protein reflect a long co-evolutionary history that began with rudimentary, mutually-stabilizing interactions at early stages of polypeptide and nucleic acid co-existence.

     
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  3. Abstract

    The series of unnatural base pairs (UBPs) developed by the Romesberg lab, which pair via hydrophobic and packing interactions have been replicated, transcribed, and translated inside of a living organism. However, as to why these UBPs exhibit variable fidelity and efficiency when used in different contexts is not clear. In an effort to gain some insights, we investigated the thermal stability and pairing selectivity of the (d)NaM‐(d)TPT3 UBP in 11nt duplexes via UV spectroscopy and the effects on helical structure via CD spectroscopy. We observed that while the duplexes containing a UBP are less stable than fully natural duplexes, they are generally more stable than duplexes containing natural mispairs. This work provides the first insights connecting the thermal stability of the (d)NaM‐(d)TPT3 UBP to the molecular mechanisms for varying replication fidelity in different sequence contexts in DNA, asymmetrical transcription fidelity, and codon:anticodon interactions and can assist in future UBP development.

     
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  4. Abstract

    Polymerization of nucleic acids in biology utilizes 5′‐nucleoside triphosphates (NTPs) as substrates. The prebiotic availability of NTPs has been unresolved and other derivatives of nucleoside‐monophosphates (NMPs) have been studied. However, this latter approach necessitates a change in chemistries when transitioning to biology. Herein we show that diamidophosphate (DAP), in a one‐pot amidophosphorylation‐hydrolysis setting converts NMPs into the corresponding NTPs via 5′‐nucleoside amidophosphates (NaPs). The resulting crude mixture of NTPs are accepted by proteinaceous‐ and ribozyme‐polymerases as substrates for nucleic acid polymerization. This phosphorylation also operates at the level of oligonucleotides enabling ribozyme‐mediated ligation. This one‐pot protocol for simultaneous generation of NaPs and NTPs suggests that the transition from prebiotic‐phosphorylation and oligomerization to an enzymatic processive‐polymerization can be more continuous than previously anticipated.

     
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  5. Abstract

    Polymerization of nucleic acids in biology utilizes 5′‐nucleoside triphosphates (NTPs) as substrates. The prebiotic availability of NTPs has been unresolved and other derivatives of nucleoside‐monophosphates (NMPs) have been studied. However, this latter approach necessitates a change in chemistries when transitioning to biology. Herein we show that diamidophosphate (DAP), in a one‐pot amidophosphorylation‐hydrolysis setting converts NMPs into the corresponding NTPs via 5′‐nucleoside amidophosphates (NaPs). The resulting crude mixture of NTPs are accepted by proteinaceous‐ and ribozyme‐polymerases as substrates for nucleic acid polymerization. This phosphorylation also operates at the level of oligonucleotides enabling ribozyme‐mediated ligation. This one‐pot protocol for simultaneous generation of NaPs and NTPs suggests that the transition from prebiotic‐phosphorylation and oligomerization to an enzymatic processive‐polymerization can be more continuous than previously anticipated.

     
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  6. Abstract

    A reaction between two prebiotically plausible building blocks, hydantoin and glyoxylate, generates both the nucleobase orotate, a precursor of biological pyrimidines, and pyruvate, a core metabolite in the citric acid cycle and amino acid biosynthesis. The reaction proceeds in water to provide significant yields of the two widely divergent chemical motifs. Additionally, the reaction of thiohydantoin and glyoxylate produces thioorotate in high yield under neutral aqueous conditions. The use of an open‐chain thiohydantoin derivative also enables the potential pre‐positioning of a nucleosidic bond prior to the synthesis of an orotate nucleoside. The observation that diverse building blocks of modern metabolism can be produced in a single reaction pot, from common reactants under mild conditions, supports the plausibility of orthogonal chemistries operating at the origins of chemical evolution.

     
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  7. Abstract

    A reaction between two prebiotically plausible building blocks, hydantoin and glyoxylate, generates both the nucleobase orotate, a precursor of biological pyrimidines, and pyruvate, a core metabolite in the citric acid cycle and amino acid biosynthesis. The reaction proceeds in water to provide significant yields of the two widely divergent chemical motifs. Additionally, the reaction of thiohydantoin and glyoxylate produces thioorotate in high yield under neutral aqueous conditions. The use of an open‐chain thiohydantoin derivative also enables the potential pre‐positioning of a nucleosidic bond prior to the synthesis of an orotate nucleoside. The observation that diverse building blocks of modern metabolism can be produced in a single reaction pot, from common reactants under mild conditions, supports the plausibility of orthogonal chemistries operating at the origins of chemical evolution.

     
    more » « less