SalL, an enzyme that catalyzes the synthesis of SAM from L-methionine and 5′-chloro-5′-deoxyoadenosine, is shown to accept 5′-chloro-5′-deoxythienoadenosine as a substrate and facilitate the synthesis of a synthetic SAM analog with an unnatural nucleobase. This synthetic cofactor is demonstrated to replace SAM in the DNA methylation reaction with M.TaqI.