Guanylylation

Guanylylation is the covalent attachment of a GMP moiety to a substrate, catalyzed by guanylyltransferases, using GTP as the donor and releasing pyrophosphate. The guanylyl group is transferred to nucleophilic sites on proteins or to the 5' end of RNA, forming a guanylylated substrate.

In RNA biology, guanylylation is best known as the key step in the formation of the 5' cap on eukaryotic mRNA. A guanylyltransferase transfers GMP from GTP to the 5' end of a nascent transcript, creating a cap structure (GpppN), which is subsequently methylated to form the mature cap (m7GpppN). The cap enhances mRNA stability and promotes translation initiation and efficient export from the nucleus. Similar capping strategies are found in some viruses.

In proteins, guanylylation may also occur as a post-translational modification, wherein GMP is covalently attached to specific amino acid residues by guanylyltransferases. This modification can modulate protein activity, interactions, or localization. In some pathogenic systems, guanylylation of host proteins by bacterial or viral enzymes alters signaling pathways to favor infection.

Mechanistically, guanylylation typically involves formation of an enzyme–GMP intermediate and transfer of GMP to the substrate, powered by the hydrolysis of GTP to pyrophosphate. The scope of guanylylation extends beyond RNA capping and includes regulatory protein modifications, with ongoing research to delineate substrates and functional outcomes.