2′-O-methyltransferase

General information on 2′-O-methyltransferase

2′-O-methyltransferase is an enzyme responsible for mRNAs ribose 2′-O-methylation in eukaryotic cells and many viruses. Methylation of viral RNAs is an important for their genome replication and evasion of innate recognition of viral RNAs by the cellular sensors of the target cell. 2′-O-methyltransferases are highly conserved among the viruses that replicate in the cytoplasm of higher eukaryotes. In many viruses, 2′-O-methyltransferases is essential for the viral particle to automatically change their mRNAs. Furthermore, 2′-O methylation of cap structures contributes to the sensing of non-self RNA and restriction of viral replication and pathogenesis.
2′-O-methyltransferase enzymatic activity leads to the methylation of the 5′-cap structure of viral RNAs which is essential in the case of coronavirus. COVID is caused severe acute respiratory syndrome coronavirus (SARS-CoV-2). Coronavirus family of viruses are typically single-stranded (+) RNA viruses. They replicate in the cytoplasm. The methylation of the viral RNA is mediated by nonstructural protein 14 (nsp14) and nonstructural protein 16 (nsp16). The two proteins have distinct roles. nsp14 protein acts as an N7-(guanine)-methyltransferase (MTase) whereas nsp16 protein acts as a s-adenosylmethionine-dependent (nucleoside-2′-O)-methyltransferase. The nsp16 proteins show strong homology among different coronaviruses such as SARS-CoV-2, bat-coronavirus, SARS and middle east respiratory syndrome-related coronavirus (MERS).
Nsp16 is involved in several biological processes such as viral signal transduction, nucleic acid processing, chromatin remodeling, metabolism, detoxification, and mRNA capping. However, nsp16 protein is active as an adenosylmethionine-dependent (nucleoside-2′-O)-methyltransferase only in the presence of its activation partner, nonstructural protein 10 (nsp10). Nsp10 protein is a co-factor of the nsp16 2′-O-MTase that is believed to acts as a buttress to support the pocket involved in S-adenosyl-L-methionine. 2′-O methylation is a strategy pathogenic viruses use to to produce mRNA with 5′-ends that mimic host cellular mRNAs. As such, 2′-O-MTase is a potential target for the development of a vaccine.