Structural interpretation of the effects of threo-nucleotides on nonenzymatic template-directed polymerization.

The prebiotic synthesis of ribonucleotides is likely to have been accompanied by the synthesis of noncanonical nucleotides including the threo-nucleotide building blocks of TNA. Here, we examine the ability of activated threo-nucleotides to participate in nonenzymatic template-directed polymerization. We find that primer extension by multiple sequential threo-nucleotide monomers is strongly disfavored relative to ribo-nucleotides. Kinetic, NMR and crystallographic studies suggest that this is due in part to the slow formation of the imidazolium-bridged TNA dinucleotide intermediate in primer extension, and in part because of the greater distance between the attacking RNA primer 3'-hydroxyl and the phosphate of the incoming threo-nucleotide intermediate. Even a single activated threo-nucleotide in the presence of an activated downstream RNA oligonucleotide is added to the primer 10-fold more slowly than an activated ribonucleotide. In contrast, a single activated threo-nucleotide at the end of an RNA primer or in an RNA template results in only a modest decrease in the rate of primer extension, consistent with the minor and local structural distortions revealed by crystal structures. Our results are consistent with a model in which heterogeneous primordial oligonucleotides would, through cycles of replication, have given rise to increasingly homogeneous RNA strands. © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.

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Wen Zhang, Seohyun Chris Kim, Chun Pong Tam, Victor S Lelyveld, Saikat Bala, John C Chaput, Jack W Szostak. Structural interpretation of the effects of threo-nucleotides on nonenzymatic template-directed polymerization. Nucleic acids research. 2021 Jan 25;49(2):646-656

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PMID: 33347562

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