Diphthamide is a post-translationally modified

histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

found in archaeal and eukaryotic elongation factor 2 (eEF-2). Dipthamide is named after the toxin produced by the bacterium ''

Corynebacterium diphtheriae ''Corynebacterium diphtheriae'' is a Gram-positive pathogenic bacterium that causes diphtheria. It is also known as the Klebs–Löffler bacillus because it was discovered in 1884 by German bacteriologists Edwin Klebs (1834–1912) and Friedrich ...

'', which targets diphthamide. Besides this toxin, it is also targeted by exotoxin A from ''

Pseudomonas aeruginosa ''Pseudomonas aeruginosa'' is a common Bacterial capsule, encapsulated, Gram-negative bacteria, Gram-negative, Aerobic organism, aerobic–facultative anaerobe, facultatively anaerobic, Bacillus (shape), rod-shaped bacteria, bacterium that can c ...

''. It is the only target of these toxins.

Structure and biosynthesis

Diphthamide is proposed to be a 2- -carboxyamido-3-(trimethylammonio)propylistidine. Though this structure has been confirmed by

X-ray crystallography X-ray crystallography is the experimental science of determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to Diffraction, diffract in specific directions. By measuring th ...

, its stereochemistry is uncertain. Diphthamide is biosynthesized from histidine and ''S''-adenosyl methionine (SAM). The side chain bound to

imidazole Imidazole (ImH) is an organic compound with the formula . It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. It can be classified as a heterocycle, specifically as a diazole. Many natural products, ...

group and all methyl groups come from SAM. The whole synthesis takes place in three steps: * transfer of 3-amino-3-carboxypropyl group from SAM * transfer of three methyl groups from SAM – synthesis of diphtine *

amidation In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent any group, typically organyl groups or hydrogen atoms. The amide group is called a p ...

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

Biological function

Diphthamide ensures

translation Translation is the communication of the semantics, meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The English la ...

fidelity. The presence or absence of diphthamide is known to affect

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...

or death receptor pathways.

References

{{Reflist Amino acids Imidazoles Quaternary ammonium compounds Post-translational modification Zwitterions