Diphthamide

Diphthamide

Names
IUPAC name 2-Amino-3-[2-(3-carbamoyl-3-trimethylammonio-propyl)-3H-imidazol-4-yl]propanoate
Identifiers
CAS Number	75645-22-6 Y
ChemSpider	4942856 Y
Jmol 3D model	Interactive image Interactive image
PubChem	6438375
InChI InChI=1S/C13H23N5O3/c1-18(2,3)10(12(15)19)4-5-11-16-7-8(17-11)6-9(14)13(20)21/h7,9-10H,4-6,14H2,1-3H3,(H3-,15,16,17,19,20,21) Y Key: FOOBQHKMWYGHCE-UHFFFAOYSA-N Y InChI=1/C13H23N5O3/c1-18(2,3)10(12(15)19)4-5-11-16-7-8(17-11)6-9(14)13(20)21/h7,9-10H,4-6,14H2,1-3H3,(H3-,15,16,17,19,20,21) Key: FOOBQHKMWYGHCE-UHFFFAOYAN
SMILES C[N+](C)(C)C(CCC1=NC=C(N1)CC(C(=O)[O-])N)C(=O)N [O-]C(=O)C(N)Cc1cnc(n1)CCC(C(=O)N)[N+](C)(C)C
Properties
Chemical formula	C13H23N5O3
Molar mass	297.354 g/mol
Vapor pressure	{{{value}}}
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 by diphtheria toxin, hence the name, which renders the elongation factor inactive. Nicotinamide adenine dinucleotide (NAD) serves as its ADP-ribosyl donor. The inactivation of the elongation factor results in a halt in protein synthesis, which in turn leads to cell death.

Diphthamide consists of seven genes namely DH1, DH2, DH3, DH4, DH5, DH6, and DH7. 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.

Structure

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.

Biological function

Diphthamide ensures translation fidelity.

The presence or absence of diphthamide is known to affect Nf-kB or death receptor pathways.

Biosynthesis

Diphthamide is biosynthesized from histidine and S-adenosyl methionine.