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Review
. 2021 Apr 19;12(4):600.
doi: 10.3390/genes12040600.

Inosine in Biology and Disease

Sundaramoorthy Srinivasan  1 , Adrian Gabriel Torres  1 , Lluís Ribas de Pouplana  1   2
Affiliations
Review

Inosine in Biology and Disease

Sundaramoorthy Srinivasan et al. Genes (Basel). .

Abstract

The nucleoside inosine plays an important role in purine biosynthesis, gene translation, and modulation of the fate of RNAs. The editing of adenosine to inosine is a widespread post-transcriptional modification in transfer RNAs (tRNAs) and messenger RNAs (mRNAs). At the wobble position of tRNA anticodons, inosine profoundly modifies codon recognition, while in mRNA, inosines can modify the sequence of the translated polypeptide or modulate the stability, localization, and splicing of transcripts. Inosine is also found in non-coding and exogenous RNAs, where it plays key structural and functional roles. In addition, molecular inosine is an important secondary metabolite in purine metabolism that also acts as a molecular messenger in cell signaling pathways. Here, we review the functional roles of inosine in biology and their connections to human health.

Keywords: RNA modification; adenosine deaminase acting on RNAs; deamination; inosine; translation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Molecular inosine. (A) The N9 nitrogen of hypoxanthine is linked to the C1 carbon of ribose to form inosine. (B) Adenosine deaminases hydrolyze the amino group at C6 of adenosine to form inosine.
Figure 2
Figure 2
Purine metabolism. Inosine acts as a central intermediate in purine anabolic and catabolic pathways.
Figure 3
Figure 3
Inosine base pairing. (A) Inosine modified tRNAAla with the anticodon IGC base-pairs with its synonymous codons GCA, GCC, and GCU. (B) Hydrogen bonding of inosine with adenosine, cytosine, and uracil.
Figure 4
Figure 4
Substrate diversity of tRNA-specific deaminases. In bacteria, tRNAArgACG is a well-established A34 substrate for homodimeric TadA. * Inosine modified tRNALeuAAG is also found in a few prokaryotes such as O. oeni [65]. In eukaryotes, diverse A34 tRNAs serve as substrates for heterodimeric ADAT2/3 where the population of G34 tRNAs is limited. The expansion of A34 tRNA diversity co-evolved with multisubstrate specificity in ADATs. (The anticodons are boxed, and the corresponding amino acids are one-letter-abbreviated).
Figure 5
Figure 5
A-to-I editing in tRNAs. Adenosines at positions 34, 37, and 57 of tRNAs can be modified to inosines. The A34-to-I34 modification is observed in bacteria and eukaryotes and is catalyzed by the enzymes TadA and ADAT2/3, respectively. ADAT1 catalyzes A37-to-I37 modification in eukaryotic tRNAAla. I57 modification was observed in archaeal tRNAIle. Adenosines at positions 37 and 57 are modified to methylated forms of inosine.
Figure 6
Figure 6
A-to-I editing in mRNAs. The effects of A-to-I editing in different regions of a hypothetical mRNA are shown. Inosine modification in the coding regions may result in protein recoding. Inosines from the untranslated regions modulate the secondary structure of mRNA, thus affecting the localization, stability, and splicing.
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