RNA CAPPING ENZYME AND DNA-LIGASE - A SUPERFAMILY OF COVALENT NUCLEOTIDYL TRANSFERASES

mRNA capping entails GMP transfer from GTP to a 5' diphosphate RNA end to form the structure G(5')ppp(5')N. A similar reaction involving AMP transfer to the 5' monophosphate end of DNA or RNA occurs during stra nd joining by polynucleotide ligases, In both cases, nucleotidyl trans fer occurs through a covalent lysyl-NMP intermediate. Sequence conserv ation among capping enzymes and ATP-dependent ligases in the vicinity of the active site lysine (KxDG) and at five other co-linear motifs su ggests a common structural basis for covalent catalysis. Mutational st u- dies support this view. We propose that the cellular and DNA virus capping enzymes and ATP-dependent ligases constitute a protein superfa mily evolved from a common ancestral enzyme. Within this superfamily, the cellular capping enzymes display more extensive similarity to the ligases than they do to the poxvirus capping enzymes. Recent studies s uggest that eukaryotic RNA viruses have evolved alternative pathways o f cap metabolism catalysed by structurally unrelated enzymes that none theless employ a phosphoramidate intermediate. Comparative analysis of these enzymes, particularly at the structural level, should illuminat e the shared reaction mechanism while clarifying the basis for nucleot ide specificity and end recognition. The capping enzymes merit close a ttention as potential targets for antiviral therapy.