Diphthamide biosynthesis 5 (DPH5)

Diphthamide biosynthesis 5 (DPH5) is an *S-adenosyl-L-methionine-dependent methyltransferase* involved in the biosynthetic pathway that generates **diphthamide**, a unique post-translational modification of a specific histidine residue in *translation elongation factor 2* (eEF2)[3][1]. Diphthamide is required for accurate protein synthesis and is highly conserved across eukaryotes and archaea[2][3]. DPH5 specifically catalyzes the trimethylation step (second step) of the pathway, converting an intermediate to "diphthine," which is subsequently amidated to generate diphthamide[1][4]. eEF2 modified with diphthamide is the critical *cellular target of diphtheria toxin and Pseudomonas exotoxin A*, which inactivate protein synthesis by ADP-ribosylation at this residue[2][3][1]. Mutations in DPH5 can cause resistance to these toxins and are also linked to rare neurodevelopmental disorders[3]. There are no approved drugs that target DPH5 directly, but the pathway is essential for cell viability and translational fidelity.

Other names

Diphthine methyl ester synthaseDiphthine synthaseDiphthamide biosynthesis methyltransferaseAD-018CGI-30HSPC143NEDSFFNPD015DPH5 homologProtein x 0011

Not applicable for direct inhibition; diphtheria toxin and Pseudomonas exotoxin A act by binding and modifying diphthamide on eEF2 (the product of the DPH5 pathway)