DIPHTHAMIDE is a unique posttranslationally modified histidine residue found only in translation elongation factor 2 (eEF-2). The role of diphthamide is still not understood. Mutant mice defective in its biosynthesis are retarded in growth and development, and almost always die before birth (
16648478),(
18765564). A potential role of diphthamide may be to protect ribosomes fom ribosome-inactivating proteins (such as ricin), which are widely distributed in nature (
18460012). The conversion of HIS to DIPHTHAMIDE is a complex process. It starts by the transfer of a 3-amino-3-carboxypropyl moiety from
S-adenosyl-L-methionine. Four different genes of (NCBI-TAX-4932) have been shown to be required for this step. Three of these genes, DPH1, DPH2 and DPH3, are believed to form a L-histidien:S-adenosyl-L-methionine 3-amino-3-carboxypropyl transferase complex (
15485916),(
8406038). The fourth gene, DPH4, is similar to DnaJ-type chaperones, and is assumed to be responsible for the proper folding of one or more of the other DPH proteins (
15485916). The next step, catalyzed by the DPH5 -encoded diphthine synthase, is the transfer of three methyl groups, donated by three molecules of
S-adenosyl-L-methionine, to form a DIPHTINE diphtine (
1508200). The last step is the amidation of DIPHTINE to DIPHTHAMIDE, catalyzed by an as-yet unidentified amidase. Diphthamide serves as the target for two important bacterial toxins - the diphtheria toxin (DT) and the Pseudomonas exotoxin A. Both toxins catalyze the transfer of ADP-ribose from NAD+ to diphthamide in eEF-2 on eEF-2, inactivating it and halting cellular protein synthesis, causing cell death (
15485916). By targeting this unique modified amino acid which does not exist in bacteria, these pathogens are able to shut down the eukaryotic protein synthesis machinery without jeopardizing their own system.