Diphthamide Explained

Diphthamide is a post-translationally modified histidine amino acid found in archaeal and eukaryotic elongation factor 2 (eEF-2).

Dipthamide is named after the toxin produced by the bacterium Corynebacterium diphtheriae, which targets diphthamide. Besides this toxin, it is also targeted by exotoxin A from Pseudomonas aeruginosa.^[1] It is the only target of these toxins.

Structure and biosynthesis

Diphthamide is proposed to be a 2-[3-carboxyamido-3-(trimethylammonio)propyl]histidine. Though this structure has been confirmed by X-ray crystallography, its stereochemistry is uncertain.^[2]

Diphthamide is biosynthesized from histidine and S-adenosyl methionine (SAM). The side chain bound to imidazole group and all methyl groups come from SAM. The whole synthesis takes place in three steps:

• transfer of 3-amino-3-carboxylpropyl group from SAM
• transfer of three methyl groups from SAM – synthesis of diphtine
• amidation – synthesis of diphthamide

In eukaryotes, this biosynthetic pathway contains a total of 7 genes (Dph1-7).

Biological function

Diphthamide ensures translation fidelity.^[3]

The presence or absence of diphthamide is known to affect NF-κB or death receptor pathways.^[4]

Notes and References

1. Liu S, Wiggins JF, Sreenath T, Kulkarni AB, Ward JM, Leppla SH . Dph3, a small protein required for diphthamide biosynthesis, is essential in mouse development . Molecular and Cellular Biology . 26 . 10 . 3835–3841 . May 2006 . 16648478 . 1488998 . 10.1128/MCB.26.10.3835-3841.2006 .
2. Jørgensen R, Merrill AR, Andersen GR . The life and death of translation elongation factor 2 . Biochemical Society Transactions . 34 . Pt 1 . 1–6 . February 2006 . 16246167 . 10.1042/BST20060001 .
3. Su X, Lin Z, Lin H . The biosynthesis and biological function of diphthamide . Critical Reviews in Biochemistry and Molecular Biology . 48 . 6 . 515–521 . 2013-11-01 . 23971743 . 4280834 . 10.3109/10409238.2013.831023 .
4. Stahl S, da Silva Mateus Seidl AR, Ducret A, Kux van Geijtenbeek S, Michel S, Racek T, Birzele F, Haas AK, Rueger R, Gerg M, Niederfellner G, Pastan I, Brinkmann U . 6 . Loss of diphthamide pre-activates NF-κB and death receptor pathways and renders MCF7 cells hypersensitive to tumor necrosis factor . Proceedings of the National Academy of Sciences of the United States of America . 112 . 34 . 10732–10737 . August 2015 . 26261303 . 4553792 . 10.1073/pnas.1512863112 . free . 2015PNAS..11210732S .