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Inosine and the RNA World Theory

Kim et al. recently demonstrated that inosine serves as a guanosine substitute. Szostak’s research group tested if 8-oxo-purines could have acted as substrates in primordial RNA to test a new hypothesis of the RNA world theory. However, their results indicated that during their investigation inosine worked almost as well as guanosine. Therefore the researchers reported that inosine enabled RNA to replicate with high speed and few errors. Finally the researchers concluded that inosine could have served as a surrogate for guanosine in the early emergence of life and that the earliest forms of life (using A, U, C, and I) may have arisen from a different set of nucleobases than those found in modern life (now using A, U, C, and G).

Many biologists now also agree that bacterial cells cannot form from nonliving chemicals in one step. For life to arise from nonliving chemical in one step there must have been intermediate molecules, or at least "pre-cellular life forms." The leading contender of
various theories for the pre-cellular wolrd now is the RNA World Theory.

Figure 1: Itp complex of human inosine triphosphatase and inosine triphoshate.The crystal structure of human ITPA is shown in complex with its prime substrate ITP. These structures also revealed the site of the substrate and Mg2+ coordination. According to PubChem “Inosine is a purine nucleoside that has hypoxanthine linked by the N9 nitrogen to the C1 carbon of ribose. It is an intermediate in the degradation of purines and purine nucleosides to uric acid and pathways of purine salvage. It also occurs in the anticodon of certain transfer RNA molecules. Inosine is found associated with purine nucleoside phosphorylase deficiency and xanthinuria type I, which are inborn errors of metabolism." Inosine triphosphate pyrophosphohydrolase (ITPase; EC catalyzes the pyrophosphohydrolysis of inosine triphosphate (ITP) to inosine monophosphate (IMP).

The RNA world theory assumes that life on Earth originated from a mixture of self-replicating molecules that can store or code for information. Self-catalyzing molecules are known to undergo natural selection, and chemical experiments indicate that the RNA pyrimidine nucleotides, uridine, and cytosine, could have formed under primordial conditions. However, the formation of the purine nucleotides adenosine and guanosine under these conditions has cast the theory in doubt. Now Kim et al. suggest that RNA could have started with a different set of nucleotide bases. Instead of guanine, RNA could have relied on inosine.

As we know modern life needs three major components to function:  Proteins, DNA, and RNA. But unlike DNA molecules, RNA can fold in different conformations or folds permitting RNAs to carry out multiple specific functions in a cell. DNA needs protein for replication and proteins are coded for by DNA yet RNA can act as a code and as replication machinery.

Aptamers are an excellent example of code recognition molecules and ribozymes and self-splicing group I introns are an example for catalytic RNA molecules. Furthermore, DNA can be viewed as a modified RNA. Hence RNA is perceived as a precursor molecule to DNA. Also, self-catalyzing molecules can undergo natural selection. For example, ribozymes are RNA molecules that can catalyze or accelerate chemical reactions similar to protein-based enzymes.

Compared to DNA sequences RNA sequences are aligned or compared differently since sequence variations in RNA maintain base-pairing pattern. Therefore alignment of RNA sequences will exhibit covariation at interacting base pairs. Also, RNA specifying genes will have conserved regions reflecting a common ancestry.

Inosine is present in tRNAs in three different positions, at position 34 in both eukaryotes and prokaryotes, and position 34 is the first nucleotide position of the anticodon loop.

Adenosine-to-inosine (A-to-I) RNA editing is a prevalent mode of transcription modification in higher eukaryotes. Adenosine deaminases acting on RNA (ADARs) proteins catalyze the reaction. Also, A-to-I editing adds another layer of gene regulation in RNA metabolisms, including RNA folding, processing, localization, and degradation. Furthermore, A-to-I editing events in exonic regions contribute to proteome diversity since the translational machinery decodes inosine as guanosine. However, the precise regulatory mechanisms for this critical cellular process are not yet fully understood. In addition, it is also known that primers with an inosine chain at the 5′-terminus improve the reliability of single nucleotide polymorphism (SNP) analysis when using the PCR-amplified product length polymorphism method.


Seohyun Chris Kim, Derek K. O’Flaherty, Lijun Zhou, Victor S. Lelyveld, Jack W. Szostak; Inosine, but none of the 8-oxo-purines, is a plausible component of a primordial version of RNA. Proceedings of the National Academy of Sciences Dec 2018, 115 (52) 13318-13323;  DOI: 10.1073/pnas.1814367115.


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