A rare geminal bismethylation represents the last step in the resistomycin biosynthetic pathway, as deduced from mutational analysis of the rem genes and isolation of the labile, pseudosymmetric bis-nor-resistomycin. A single enzyme, RemG, is capable of subsequently introducing both methyls into the unusual discoid substrate. This is supported by phylogenetic studies, which provide the first correlation of methyltransferase sequences with the site of methylation of polyphenols.