Abstract
DNA (2′-deoxyribonucleic acid) and RNA (ribonucleic acid) play diverse functional roles in biology and disease. Despite being comprised primarily of only four cognate nucleobases, nucleic acids can adopt complex three-dimensional structures, and RNA in particular, can catalyze biochemical reactions to regulate a wide variety of biological processes. Such chemical versatility is due in part to the phenomenon of nucleobase tautomerism, whereby the bases can adopt multiple, yet distinct isomeric forms, known as tautomers. For nucleobases, tautomers refer to structural isomers that differ from one another by the position of protons. By altering the position of protons on nucleobases, many of which play critical roles for hydrogen bonding and base pairing interactions, tautomerism has profound effects on the biochemical processes involving nucleic acids. For example, the transient formation of minor tautomers during replication could generate spontaneous mutations. These mutations could arise from the stabilization of mismatches, in the active site of polymerases, in conformations involving minor tautomers that are indistinguishable from canonical base pairs. In this review, we discuss the evidence for tautomerism in DNA, and its consequences to the fidelity of DNA replication. Also reviewed are RNA systems, such as the riboswitches and self-cleaving ribozymes, in which tautomerism plays a functional role in ligand recognition and catalysis, respectively. We also discuss tautomeric nucleoside analogs that are efficacious as antiviral drug candidates such as molnupiravir for coronaviruses and KP1212 for HIV. The antiviral efficacy of these analogs is due, in part, to their ability to exist in multiple tautomeric forms and induce mutations in the replicating viral genomes. From a technical standpoint, minor tautomers of nucleobases are challenging to identify directly because they are rare and interconvert on a fast, millisecond to nanosecond, time scale. Nevertheless, many approaches including biochemical, structural, computational and spectroscopic methods have been developed to study tautomeric dynamics in RNA and DNA systems, and in antiviral nucleoside analogs. An overview of these methods and their applications is included here.
Highlights
Nucleic acid bases exhibit keto-enol and amino-imino prototropic tautomerism due to the presence of multiple solvent-exchangeable protons (Figure 1) (Watson and Crick, 1953; Topal and Fresco, 1976; Brown et al, 1989; Colominas et al, 1996; Mons et al, 2002)
Therapeutics based on tautomeric nucleoside analogs have proven effective as antiviral agents against a range of retro- and ribo-viruses, including influenza (Delang et al, 2018), hepatitisC-virus (HCV) (Crotty et al, 2001), human immunodeficiency virus (HIV) (Li et al, 2014) and coronaviruses, including COVID-19 (Figure 5) (Shannon et al, 2020; Kabinger et al, 2021)
The antiviral efficacy of these analogs stems from their ability to exist in multiple tautomeric or rotameric states, which help mutagenize the viral genomes to error catastrophe and even to viral population extinction
Summary
Nucleic acid bases exhibit keto-enol and amino-imino prototropic tautomerism due to the presence of multiple solvent-exchangeable protons (Figure 1) (Watson and Crick, 1953; Topal and Fresco, 1976; Brown et al, 1989; Colominas et al, 1996; Mons et al, 2002). The transient generation of minor tautomers in DNA allows stabilization of mismatches, in the polymerase active site, in conformations that are indistinguishable from the structures of canonical base pairs (Figure 4) (Watson and Crick, 1953; Topal and Fresco, 1976; Wang et al, 2011; Rangadurai et al, 2020) While assembling their double-helix model of DNA, James Watson and Francis Crick stumbled over the phenomenon of base tautomerism; their model required that the bases adopt specific tautomeric forms in order to base-pair, with the suggestion that alternate tautomers would lead to mispairing and spontaneous mutations. We will summarize the current, state-of-the-art methods for studying tautomerism in nucleic acids and in antiviral nucleoside analogs, and discuss the future directions of the field
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