Selective prebiotic formation of RNA pyrimidine and DNA purine nucleosides

Xu, Jianfeng; Chmela, Václav; Green, Nicholas J.; Russell, DavidÂ A.; Janicki, Mikołaj J.; Góra, Robert W.; Szabla, Rafał; Bond, Andrew D.; Sutherland, JohnÂ D.

doi:10.1038/s41586-020-2330-9

Cited by 123 publications

(123 citation statements)

References 49 publications

(41 reference statements)

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“…Accordingly, the common ancestor of the two-β-barrel RNAPs could conceivably discriminate against 2'dNTPs and therefore likely evolved in the presence of both NTPs and 2'dNTPs. This inference lends credence to the hypothesis that proteins evolved in primordial lifeforms that already possessed both RNA and DNA 36,37 .…”

Section: Discussionsupporting

confidence: 64%

The mechanism of the nucleo-sugar selection by multi-subunit RNA polymerases

Mäkinen

Shin

Vieras

et al. 2020

Preprint

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AbstractRNA polymerases (RNAPs) synthesize RNA from NTPs, whereas DNA polymerases synthesize DNA from 2’dNTPs. DNA polymerases select against NTPs by using steric gates to exclude the 2’ OH, but RNAPs have to employ alternative selection strategies. In single-subunit RNAPs, a conserved Tyr residue discriminates against 2’dNTPs, whereas selectivity mechanisms of multi-subunit RNAPs remain hitherto unknown. Here we show that a conserved Arg residue uses a two-pronged strategy to select against 2’dNTPs in multi-subunit RNAPs. The conserved Arg interacts with the 2’OH group to promote NTP binding, but selectively inhibits incorporation of 2’dNTPs by interacting with their 3’OH group to favor the catalytically-inert 2’-endo conformation of the deoxyribose moiety. This deformative action is an elegant example of an active selection against a substrate that is a substructure of the correct substrate. Our findings provide important insights into the evolutionary origins of biopolymers and the design of selective inhibitors of viral RNAPs.

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Section: Discussionsupporting

confidence: 64%

The mechanism of the nucleo-sugar selection by multi-subunit RNA polymerases

Mäkinen

Shin

Vieras

et al. 2020

Preprint

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“…A recent one-pot report from Trapp and co-workers furnished deoxyribonucleosides following the aldol reaction between acetaldehyde and glyceraldehyde. 284 This nearly recapitulates one of the minor biosynthetic pathways for 2-deoxyribose-5-phosphate, via the aldol reaction of acetaldehyde and glyceraldehyde-3phosphate, suggesting that the point of entry of DNA into biochemical space could have dated back to prebiotic chemistry, 285,286 in line with the ideas of some biologists. 287…”

Section: Summary and Future Directionsmentioning

confidence: 71%

Nonenzymatic Metabolic Reactions and Life’s Origins

2020

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Prebiotic chemistry aims to explain how the biochemistry of life as we know it came to be. Most efforts in this area have focused on provisioning compounds of importance to life by multi-step synthetic routes that do not resemble biochemistry. However, gaining insight into why core metabolism uses the molecules, reactions, pathways, and overall organization that it does requires us to consider molecules not only as synthetic end goals. Equally important are the dynamic processes that build them up and break them down. This perspective has led many researchers to the hypothesis that the first stage of the origin of life began with the onset of a primitive non-enzymatic version of metabolism, initially catalyzed by naturally occurring minerals and metal ions. This view of life's origins has come to be known as "metabolism first". Continuity with modern metabolism would require a primitive version of metabolism to build and break down ketoacids, sugars, amino acids, and ribonucleotides in much the same way as the pathways that do it today. This review discusses metabolic pathways of relevance to the origin of life in a manner accessible to chemists, and summarizes experiments suggesting several pathways might have their roots in prebiotic chemistry. Finally, key remaining milestones for the protometabolic hypothesis are highlighted.

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“…Although new evidence may offer alternatives to the RNA World Hypothesis [5], which posits that DNA evolved later than RNA [6], the fact remains that for all life on earth, DNA biosynthesis is an add-on to RNA biochemistry, so that 2'-deoxyribonucleotides can only be made from ribonucleotides. Hence, DNA synthesis inevitably depletes the pool of ribonucleotide precursors that an RNA virus would need for copying its RNA for new virus production.…”

Section: Dna Biosynthesis Depletes the Pool Of Rna Precursors: A Critmentioning

confidence: 99%

RNA Viruses vs. DNA Synthesis: A General Viral Strategy That May Contribute to the Protective Antiviral Effects of Selenium

Taylor¹

2020

Preprint

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The biosynthesis of DNA inherently competes with RNA synthesis because it depends on the reduction of ribonucleotides (RNA precursors) to 2’-deoxyribonucleotides by ribonucleotide reductase (RNR). Hence, RNA viruses can increase viral RNA production in cells by partially blocking the synthesis of DNA, e.g. by downregulating the mammalian selenoprotein thioredoxin reductase (TR), which normally acts to sustain DNA synthesis by regenerating reduced thioredoxin, a hydrogen donor for RNR. Computational and preliminary experimental evidence supports the hypothesis that a number of pathogenic RNA viruses, including HIV-1, Ebola, Zika, some flu viruses, and SARS-CoV-2, target TR isoforms by antisense. TR knockdown would create a host antioxidant defect that could be partially rectified by increased selenium intake, or be exacerbated by selenium deficiency, contributing to viral pathogenesis. There are several non-selenium-dependent means that viruses might also exploit to slow DNA synthesis, such as targeting RNR itself, or components of the glutaredoxin system, which serves as a backup redox system for RNR. HIV-1 substantially downregulates glutathione synthesis, so it interferes with both the thioredoxin and glutaredoxin systems. Computational results suggest that, like Ebola, SARS-CoV-2 targets TR3 by antisense. TR3 is the only TR isoform that includes an N-terminal glutaredoxin domain, so antisense knockdown of TR3 may also affect both redox systems, favoring RNA synthesis. In contrast, some DNA viruses encode their own glutaredoxins, thioredoxin-like proteins and even RNR homologues – so they are doing just the opposite, favoring DNA synthesis. This is clear evidence that viruses can benefit from shifting the RNA:DNA balance to their advantage.

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Selective prebiotic formation of RNA pyrimidine and DNA purine nucleosides

Cited by 123 publications

References 49 publications

The mechanism of the nucleo-sugar selection by multi-subunit RNA polymerases

The mechanism of the nucleo-sugar selection by multi-subunit RNA polymerases

Nonenzymatic Metabolic Reactions and Life’s Origins

RNA Viruses vs. DNA Synthesis: A General Viral Strategy That May Contribute to the Protective Antiviral Effects of Selenium

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