Sulfur Modifications in tRNA: Function and Implications for Human Disease

General Method for Post-Synthetic Modification of Oligonucleotides Based on Oxidative Amination of 4-Thio-2′-deoxyuridine

“…The 4-thiouracil is a noncanonical nucleobase replacing the oxygen at the uracil 4-position with a sulfur, which acts as both a naturally occurring base in prokaryotic tRNAs , and metabolic label for studying RNA dynamics. , The aryl thiol, a resonance form of aromatic thioketone in 4-thiouracil, can be oxidized to sulfonate intermediates and further substituted by various nucleophiles such as alcohols, amines, and mercaptans. − This chemical reactivity of 4-thiouridine (s 4 U), the ribonucleosides of 4-thiouracil, has been utilized for the researches of RNA metabolism through s 4 U labeling and recording. , We speculate this reaction can also be adopted for modification of ONs with diverse chemical groups using the corresponding amines. The deoxyribonucleoside version of 4-thiouracil, 4-thio-2′-deoxyuridine (4SdU) can be incorporated into ONs through a well-developed solid-phase synthesis method, and 4SdU-containing ONs are commercially available from vendors. , Thus, we consider 4SdU may serve as a reactive handle for postsynthetic modification of ONs, and a series of functional amines can be derived to ONs via oxidative amination of 4SdU (Scheme ).…”

“…Design of General Method for Post-Synthetic Modification of 4SdU ON through Oxidative Amination. The 4-thiouracil is a noncanonical nucleobase replacing the oxygen at the uracil 4-position with a sulfur, which acts as both a naturally occurring base in prokaryotic tRNAs 37,38 metabolic label for studying RNA dynamics. 39,40 The aryl thiol, a resonance form of aromatic thioketone in 4-thiouracil, can be oxidized to sulfonate intermediates and further substituted by various nucleophiles such as alcohols, amines, and mercaptans.…”

Physical Chemistry of a Single tRNA-Modified Nucleoside Regulates Decoding of the Synonymous Lysine Wobble Codon and Affects Type 2 Diabetes

“…tRNAs are quite complex in their sequences especially mammalian tRNA having wobble codons, different modifications, and not all at the level of 100% complete. Including Cdkal1, over a dozen diseases have been associated with mutations in tRNA modification enzymes, revealing the importance of nucleoside modifications in tRNA function − Isoacceptor tRNAs modulate translation for various cell functions . However, all isoacceptor tRNAs whether modified in the anticodon loop differently and having various wobble codons are recognized by the one aminoacyl-tRNA synthetase …”

Recent Advances in Our Understanding of the Biosynthesis of Sulfur Modifications in tRNAs

“…The functions of sulfur modifications are briefly summarized in this section. For more detailed information, please refer to previous reviews ( Shigi, 2014 , 2016 ) and articles cited therein. Uridine at position 34 (the wobble base) of tRNAs for lysine, glutamic acid, and glutamine is almost universally modified to s 2 U derivatives, although the C5 carbon of uridine is also modified by functional groups that differ between species ( Elseviers et al, 1984 ).…”

“…The biosynthetic pathways underpinning sulfur modification of RNA in all domains of life share many aspects in common; hence research on bacteria can strengthen our understanding of this process in eukaryotes, including humans. Dysfunctional RNA modification, especially involving anticodons, can lead to diseases ( Shigi, 2016 ). Abnormalities in RNA modification are caused by three main factors: (1) mutations in genes encoding modification enzymes, (2) mutations in substrate tRNAs, and (3) alterations in metabolites acting as substrates.…”