The crystal structures of monomeric RNA-dependent RNA polymerases and reverse transcriptases of more than 20 different viruses are available in the Protein Data Bank. They all share the characteristic right-hand shape of DNA- and RNA polymerases formed by the fingers, palm and thumb subdomains, and, in many cases, “fingertips” that extend from the fingers towards the thumb subdomain, giving the viral enzyme a closed right-hand appearance. Six conserved structural motifs that contain key residues for the proper functioning of the enzyme have been identified in all these RNA-dependent polymerases. These enzymes share a two divalent metal-ion mechanism of polymerization in which two conserved aspartate residues coordinate the interactions with the metal ions to catalyze the nucleotidyl transfer reaction. The recent availability of crystal structures of polymerases of the Orthomyxoviridae and Bunyaviridae families allowed us to make pairwise comparisons of the tertiary structures of polymerases belonging to the four main RNA viral groups, which has led to a phylogenetic tree in which single-stranded negative RNA viral polymerases have been included for the first time. This has also allowed us to use a homology-based structural prediction approach to develop a general three-dimensional model of the Ebola virus RNA-dependent RNA polymerase. Our model includes several of the conserved structural motifs and residues described in other viral RNA-dependent RNA polymerases that define the catalytic and highly conserved palm subdomain, as well as portions of the fingers and thumb subdomains. The results presented here help to understand the current use and apparent success of antivirals, i.e. Brincidofovir, Lamivudine and Favipiravir, originally aimed at other types of polymerases, to counteract the Ebola virus infection.

Methionine sulfoxide reductases, enzymes that reverse the oxidation of methionine residues, have been described in a wide range of species. The reduction of the diastereoisomers of oxidized methionine is catalyzed by two different monomeric methionine sulfoxide reductases (MsrA and MsrB) and is best understood as an evolutionary response to high levels of oxygen either in the Earth's atmosphere or possibly in more localized environments. Phylogenetic analyses of these proteins suggest that their distribution is the outcome of a complex history including many paralogy and lateral gene transfer events.

Quantitative estimates of the gene complement of the last common ancestor of all extant organisms, that is, the cenancestor, may be hindered by ancient horizontal gene transfer events and polyphyletic gene losses, as well as by biases in genome databases and methodological artifacts. Nevertheless, most reports agree that the last common ancestor resembled extant prokaryotes. A significant number of the highly conserved genes are sequences involved in the synthesis, degradation, and binding of RNA, including transcription and translation. Although the gene complement of the cenancestor includes sequences that may have originated in different epochs, the extraordinary conservation of RNA-related sequences supports the hypothesis that the last common ancestor was an evolutionary outcome of the so-called RNA/protein world. The available evidence suggests that the cenancestor was not a hyperthermophile, but it is currently not possible to assess its ecological niche or its mode of energy acquisition and carbon sources. 361 LCA: last common ancestor RNA world: an evolutionary stage prior to proteins and DNA genomes during which life was based on catalytic and replicative RNAs

Twenty completely sequenced cellular genomes from the three major domains were analyzed using twice one-way BLAST searches in order to define the set of the most conserved protein-encoding sequences to characterize the gene complement of the last common ancestor of extant life. The resulting set is dominated by different putative ATPases, and by molecules involved in gene expression and RNA metabolism. DEAD-type RNA helicase and enolase genes, which are known to be part of the RNA degradosome, are as conserved as many transcription and translation genes. This suggests the early evolution of a control mechanism for gene expression at the RNA level, providing additional support to the hypothesis that during early cellular evolution RNA molecules played a more prominent role. Conserved sequences related to biosynthetic pathways include those encoding putative phosphoribosyl pyrophosphate synthase and thioredoxin, which participate in nucleotide metabolism. Although the information contained in the available databases corresponds only to a minor portion of biological diversity, the sequences reported here are likely to be part of an essential and highly conserved pool of proteins domains common to all organisms.

As of today, there is no antiviral for the treatment of the SARS-CoV-2 infection, and the development of a vaccine might take several months or even years. the structural superposition of the hepatitis c virus polymerase bound to sofosbuvir, a nucleoside analog antiviral approved for hepatitis c virus infections, with the SARS-coV polymerase shows that the residues that bind to the drug are present in the latter. Moreover, a multiple alignment of several SARS-CoV-2, SARS and MERS-related coronaviruses polymerases shows that these residues are conserved in all these viruses, opening the possibility to use sofosbuvir against these highly infectious pathogens.