Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 21, Issue 8, Pages -Publisher
MDPI
DOI: 10.3390/ijms21082882
Keywords
modified uridine; wobble modification; seleno-uridine; selenium; tRNA; anticodon; synonymous codons; translation regulation; decoding; new wobble base pair
Funding
- National Science Centre in Poland [UMO-2014/13/B/ST5/03979, UMO-2018/29/B/ST5/02509]
- Lodz University of Technology
- Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences
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5-Substituted 2-selenouridines (R5Se2U) are post-transcriptional modifications present in the first anticodon position of transfer RNA. Their functional role in the regulation of gene expression is elusive. Here, we present efficient syntheses of 5-methylaminomethyl-2-selenouridine (1, mnm5Se2U), 5-carboxymethylaminomethyl-2-selenouridine (2, cmnm5Se2U), and Se2U (3) alongside the crystal structure of the latter nucleoside. By using pH-dependent potentiometric titration, pKa values for the N3H groups of 1-3 were assessed to be significantly lower compared to their 2-thio- and 2-oxo-congeners. At physiological conditions (pH 7.4), Se2-uridines 1 and 2 preferentially adopted the zwitterionic form (ZI, ca. 90%), with the positive charge located at the amino alkyl side chain and the negative charge at the Se2-N3-O4 edge. As shown by density functional theory (DFT) calculations, this ZI form efficiently bound to guanine, forming the so-called new wobble base pair, which was accepted by the ribosome architecture. These data suggest that the tRNA anticodons with wobble R5Se2Us may preferentially read the 5 '-NNG-3 ' synonymous codons, unlike their 2-thio- and 2-oxo-precursors, which preferentially read the 5 '-NNA-3 ' codons. Thus, the interplay between the levels of U-, S2U- and Se2U-tRNA may have a dominant role in the epitranscriptomic regulation of gene expression via reading of the synonymous 3 '-A- and 3 '-G-ending codons.
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