AdoMet-dependent methylation, DNA methyltransferases and base flipping

Twenty AdoMet-dependent methyltransferases (MTases) have been characterized structurally by X-ray crystallography and NMR. These include seven DNA MTa ses, five RNA MTases, four protein MTases and four small molecule MTases ac ting on the carbon, oxygen or nitrogen atoms of their substrates. The MTase s share a common core structure of a mixed seven-stranded P-sheet (6 down a rrow 7 up arrow 5 down arrow 4 down arrow 1 down arrow 2 down arrow 3 down arrow) referred to as an 'AdoMet-dependent MTase fold', with the exception of a protein arginine MTase which contains a compact consensus fold lacking the antiparallel hairpin strands (6 down arrow 7 up arrow). The consensus fold is useful to identify hypothetical MTases during structural proteomics efforts on unannotated proteins. The same core structure works for very di fferent classes of MTase including those that act on substrates differing i n size from small molecules (catechol or glycine) to macromolecules (DNA, R NA and protein). DNA MTases use a 'base flipping' mechanism to deliver a sp ecific base within a DNA molecule into a typically concave catalytic pocket . Base flipping involves rotation of backbone bonds in double-stranded DNA to expose an out-of-stack nucleotide, which can then be a substrate for an enzyme-catalyzed chemical reaction. The phenomenon is fully established for DNA MTases and for DNA base excision repair enzymes, and is likely to prov e general for enzymes that require access to unpaired, mismatched or damage d nucleotides within base-paired regions in DNA and RNA. Several newly disc overed MTase families in eukaryotes (DNA 5mC MTases and protein arginine an d lysine MTases) offer new challenges in the MTase field.