Hydrolytic fitness of N‐glycosyl bonds: comparing the deglycosylation kinetics of modified, alternative, and native nucleosides

Abstract

Nature’s selection of the contemporary nucleobases in RNA and DNA continues to intrigue the origin of life community. While the prebiotic synthesis of the N-glycosyl bond has historically been a central area of investigation, variations in hydrolytic stabilities among the N-glycosyl bonds may have presented an additional selection pressure that contributed to nucleobase and nucleoside evolution. To experimentally probe this hypothesis, a systematic kinetic analysis of the hydrolytic deglycosylation reactions of modified, alternative and native nucleosides was undertaken. Rate constants were measured as a function of temperature (at pH 1) to produce Arrhenius and Eyring plots for extrapolation to 37°C and determination of thermodynamic activation parameters. Rate enhancements based on the differences in reaction rates of deoxyribo- and ribo-glycosidic bonds were found to vary under the same conditions. Rate constants of deoxynucleosides were also measured across the pH range of 1 – 3 (at 50°C), which highlighted how simple changes to the heterocycle alone can lead to significant variation in deglycosylation rates. The contemporary nucleosides exhibited the slowest deglycosylation rates in comparison to the non-native/alternative nucleosides, which we suggest as experimental support for nature’s selection of the fittest N-glycosyl bonds.

When nucleoside chemistry met hypervalent iodine reagents

“…The crystallographically determined Pd–Pd bond distance in 105 was 2.844 Å. This is comparable to the bond distances in cyclopalladated dimers obtained from 2-phenylpyridine (2.862 Å) and 2-p-tolylpyridine (2.857 Å), 38 and benzo[ h ]quinoline (2.84 Å). 39 Thus, Pd–Pd interaction may be important for the formation of a Pd III –Pd III bridged dimer 106 , and species such as these are implicated in N-directed C–H bond oxidations.…”

Spontaneous formation and base pairing of plausible prebiotic nucleotides in water

“…6 ). On the contrary, the canonical nucleosides and nucleotides of RNA are thermodynamically disfavoured (but kinetically stable) in water 29 .…”

Reviving the RNA World: An Insight into the Appearance of RNA Methyltransferases

“…The entire process could be chemically or photochemically driven, forming the basic units of ribonucleotides which, on polymerization with the help of a catalyst such as montmorillonite ( Ferris and Ertem, 1993 ), converted free ribonucleotides into a long chain of RNA ( Figure 1 ). Nature’s selection of contemporary bases in RNA might have been driven by modifications like N -glycosyl bonds that made the bases more resistant to hydrolysis ( Rios et al, 2014 ). The hallmark complexity of extant forms of life may trace their origin to the catalytic RNA and the appearance of methionine and other amino acids synthesized in the highly reactive primordial soup ( Van Trump and Miller, 1972 ; Keefe et al, 1995 ; Parker et al, 2011 ; Shechner and Bartel, 2011 ).…”