Eukaryotic elongation factor 2 (EEF2) catalyzes the GTP dependent ribosomal translocation step during translation elongation. This function requires the presence of a posttranslational modification, the conversion of histidine residue 715 to diphthamide (2' [3 carboxamido 3 (trimethylammonio)propyl] L histidine) (Van Ness et al. 1978). No other protein is known to undergo this modification. The diphthamide residue is also the target of ADP ribosylation catalyzed by diphtheria toxin, which inactivates EEF2 and leads to cell death (Collier 1975; Pappenheim 1977).
Diphthamide synthesis proceeds in four steps: the transfer of 3 amino 3 carboxypropyl group from S adenosylmethionine to histidine 715 of EEF2, the addition of four methyl groups to the 3 amino 3 carboxypropyl moiety, the demethylation of the methylated carboxylate group to form diphthine, and the amidation of the diphthine carboxyl group (Liu et al. 2004; Lin et al. 2014; Schaffrath et al. 2014; Su et al. 2013; Uthman et al. 2013).