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 ;
3D model (JSmol)	Interactive image; Interactive image;
ChemSpider	4942856 ;
PubChem CID	6438375;
UNII	86L3ZZ4408 ;
CompTox Dashboard (EPA)	DTXSID60904010 ;
	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) Key: FOOBQHKMWYGHCE-UHFFFAOYSA-N ; 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([nH]1)CCC(C(=O)N)[N ](C)(C)C;
Properties
Chemical formula	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). verify (what is ?) Infobox references

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.^[1] Besides this toxin, it is also targeted by exotoxin A from Pseudomonas aeruginosa.^[1]^[2] It is the only target of these toxins.^[2]

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.^[1]^[3]

Diphthamide is biosynthesized from histidine and S-adenosyl methionine (SAM).^[1] The side chain bound to imidazole group and all methyl groups come from SAM. The whole synthesis takes place in three steps:^[1]

transfer of 3-amino-3-carboxypropyl 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).^[1]

Biological function

Diphthamide ensures translation fidelity.^[1]

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

References

^ ^a ^b ^c ^d ^e ^f ^g Su X, Lin Z, Lin H (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. PMC 4280834. PMID 23971743.
^ ^a ^b Liu S, Wiggins JF, Sreenath T, Kulkarni AB, Ward JM, Leppla SH (May 2006). "Dph3, a small protein required for diphthamide biosynthesis, is essential in mouse development". Molecular and Cellular Biology. 26 (10): 3835–3841. doi:10.1128/MCB.26.10.3835-3841.2006. PMC 1488998. PMID 16648478.
^ Jørgensen R, Merrill AR, Andersen GR (February 2006). "The life and death of translation elongation factor 2". Biochemical Society Transactions. 34 (Pt 1): 1–6. doi:10.1042/BST20060001. PMID 16246167.
^ Stahl S, da Silva Mateus Seidl AR, Ducret A, Kux van Geijtenbeek S, Michel S, Racek T, et al. (August 2015). "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. Bibcode:2015PNAS..11210732S. doi:10.1073/pnas.1512863112. PMC 4553792. PMID 26261303.

[pmc4280834-1] ^ ^a ^b ^c ^d ^e ^f ^g Su X, Lin Z, Lin H (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. PMC 4280834. PMID 23971743.

[:2-2] Liu S, Wiggins JF, Sreenath T, Kulkarni AB, Ward JM, Leppla SH (May 2006). "Dph3, a small protein required for diphthamide biosynthesis, is essential in mouse development". Molecular and Cellular Biology. 26 (10): 3835–3841. doi:10.1128/MCB.26.10.3835-3841.2006. PMC 1488998. PMID 16648478.

[:0-3] Jørgensen R, Merrill AR, Andersen GR (February 2006). "The life and death of translation elongation factor 2". Biochemical Society Transactions. 34 (Pt 1): 1–6. doi:10.1042/BST20060001. PMID 16246167.

[:1-4] Stahl S, da Silva Mateus Seidl AR, Ducret A, Kux van Geijtenbeek S, Michel S, Racek T, et al. (August 2015). "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. Bibcode:2015PNAS..11210732S. doi:10.1073/pnas.1512863112. PMC 4553792. PMID 26261303.

[1]

[2]

[3]

[4]