Synthesis of diphthamide-EEF2

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R-HSA-5358493
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Pathway
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Homo sapiens
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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).

Literature References
PubMed ID Title Journal Year
25352115 The Diphthamide Modification Pathway from Saccharomyces cerevisiae - Revisited

Schaffrath, R, Abdel-Fattah Mohamed, W, Klassen, R, Stark, MJ

Mol. Microbiol. 2014
721806 Isolation and properties of the trypsin-derived ADP-ribosyl peptide from diphtheria toxin-modified yeast elongation factor 2

Van Ness, BG, Howard, JB, Bodley, JW

J. Biol. Chem. 1978
23468660 The amidation step of diphthamide biosynthesis in yeast requires DPH6, a gene identified through mining the DPH1-DPH5 interaction network

Uthman, S, Bär, C, Scheidt, V, Liu, S, ten Have, S, Giorgini, F, Stark, MJ, Schaffrath, R

PLoS Genet. 2013
23971743 The biosynthesis and biological function of diphthamide

Su, X, Lin, Z, Lin, H

Crit. Rev. Biochem. Mol. Biol. 2013
24739148 Dph7 catalyzes a previously unknown demethylation step in diphthamide biosynthesis

Lin, Z, Su, X, Chen, W, Ci, B, Zhang, S, Lin, H

J. Am. Chem. Soc. 2014
20040 Diphtheria toxin

Pappenheimer, AM

Annu. Rev. Biochem. 1977
164179 Diphtheria toxin: mode of action and structure

Collier, RJ

Bacteriol Rev 1975
15485916 Identification of the proteins required for biosynthesis of diphthamide, the target of bacterial ADP-ribosylating toxins on translation elongation factor 2

Liu, S, Milne, GT, Kuremsky, JG, Fink, GR, Leppla, SH

Mol. Cell. Biol. 2004
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