Diphthamide

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Diphthamide
Diphthamide.png
Names
IUPAC name
2-Amino-3-[2-(3-carbamoyl-3-trimethylammonio-propyl)-3H-imidazol-4-yl]propanoate
Identifiers
75645-22-6 YesY
ChemSpider 4942856 YesY
Jmol 3D model Interactive image
Interactive image
PubChem 6438375
Properties
C13H23N5O3
Molar mass 297.354 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

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

It is usually found at position H715 in mammalian eEF2 (H699 in yeast). This residue is modified by the protein encoded by the DPH1 (OVCA1) gene. Dph1 knockout mice are inviable while heterozygotes develop diverse types of carcinomas and sarcomas. In humans, DH1 is frequently found mutated in ovarian cancer. Loss of heterozygosity has taken place in 50% of benign tumours, and 90% of end-stage ovarian tumours.

It is an ADP-ribosylated[clarification needed] by diphtheria toxin, hence the name, which renders the elongation factor inactive. Nicotinamide adenine dinucleotide (NAD) serves as its ADP-ribosyl donor.[1] The inactivation of the elongation factor results in a halt in protein synthesis, which in turn leads to cell death.[2][3]

Diphthamide consists of seven genes namely DH1, DH2, DH3, DH4, DH5, DH6, and DH7.[clarification needed] According to research conducted by Sebastian Stahl et al., the loss of diphthamide or presence of unmodified eEF2 does not severely impact cell growth under normal conditions. However, animals with homozygous DPHko do not survive beyond embryonic stages, suggesting that the diphthamide may be necessary for development.[4]

Structure[edit]

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.[3]

Biological function[edit]

Diphthamide ensures translation fidelity.[5]

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

Biosynthesis[edit]

Diphthamide is biosynthesized from histidine and S-adenosyl methionine.[6]

References[edit]

  1. ^ Collier, R.J. (2001). "Understanding the mode of action of diphtheria toxin: a perspective on progress during the 20th century.". Toxicon. doi:10.1016/S0041-0101(01)00165-9. PMID 11595641. 
  2. ^ Honjo, T (1968). "Diphtheria toxin-dependent adenosine diphosphate ribosylation of aminoacyl transferase II and inhibition of protein synthesis". J. Biol. Chem. PMID 4297784. 
  3. ^ a b Jorgensen, R (2006). "The life and death of translation elongation factor 2.". Biochem Soc Trans. PMID 16246167. 
  4. ^ a b Stahl, Sebastian (2015). "Loss of diphthamide pre-activates NF-κB and death receptor pathways and renders MCF7 cells hypersensitive to tumor necrosis factor". Proc Natl Acad Sci U S A. doi:10.1073/pnas.1512863112. PMC 4553792. 
  5. ^ Su, Xiaoyang (2013). "THE BIOSYNTHESIS AND BIOLOGICAL FUNCTION OF DIPHTHAMIDE". Crit Rev Biochem Mol Biol. doi:10.3109/10409238.2013.831023. Retrieved December 21, 2015. 
  6. ^ Su, Xiaoyang; Lin, Zhewang; Lin, Hening (2013-11-01). "The biosynthesis and biological function of diphthamide". Critical Reviews in Biochemistry and Molecular Biology 48 (6): 515–521. doi:10.3109/10409238.2013.831023. ISSN 1040-9238. PMC 4280834. PMID 23971743.