Diphthine synthase (), also known as diphthamide biosynthesis S-adenosylmethionine-dependent methyltransferase, participates in the modification of a specific histidine residue in elongation factor 2 (EF-2) of eukaryotes and archaea to diphthamide. It is required for the methylation step in dipthamide biosynthesis.This entry also includes diphthine methyl ester synthase () from Saccharomyces cerevisiae (a product of the DPH5 gene), which is an S-adenosyl-L-methionine-dependent methyltransferase that catalyzes methylations of a modified histidine residue in translation elongation factor 2 (EF-2), to form an intermediate called diphthine methyl ester: the second step of diphthamide biosynthesis [].