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 strand joining by polynucleotide ligases. In both cases, nucleotidyl transfer occurs through a covalent lysyl-NMP intermediate. Sequence conservation among capping enzymes and ATP-dependent ligases in the vicinity of the active site lysine (KxDG) and at five other co-linear motifs suggests a common structural basis for covalent catalysis. Mutational studies support this view. We propose that the cellular and DNA virus capping enzymes and ATP-dependent ligases constitute a protein superfamily 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 suggest that eukaryotic RNA viruses have evolved alternative pathways of cap metabolism catalysed by structurally unrelated enzymes that nonetheless employ a phosphoramidate intermediate. Comparative analysis of these enzymes, particularly at the structural level, should illuminate the shared reaction mechanism while clarifying the basis for nucleotide specificity and end recognition. The capping enzymes merit close attention as potential targets for antiviral therapy.
Shuman
S
S
Molecular Biology Program, Sloan-Kettering Institute, New York, New York 10021, USA.
Schwer
B
B
D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D005075:Biological Evolution; D017124:Conserved Sequence; D011088:DNA Ligases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004267:DNA Viruses / Q000201:enzymology / Q000235:genetics; D008969:Molecular Sequence Data; D009713:Nucleotidyltransferases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012315:RNA Caps / Q000378:metabolism; D012328:RNA Viruses / Q000201:enzymology / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D000098556:mRNA Guanylyltransferases
D012315:RNA Caps; D009713:Nucleotidyltransferases; D000098556:mRNA Guanylyltransferases; D011088:DNA Ligases