:Diphthamide
{{chembox
| Watchedfields = changed
| verifiedrevid = 428011922
| ImageFile = diphthamide.png
| ImageSize = 200px
| IUPACName = 2-Amino-3-[2-(3-carbamoyl-3-trimethylammonio-propyl)-3H-imidazol-4-yl]propanoate
| OtherNames =
|Section1={{Chembox Identifiers
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4942856
| 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)
| InChIKey = FOOBQHKMWYGHCE-UHFFFAOYAN
| SMILES1 = [O-]C(=O)C(N)Cc1cnc([nH]1)CCC(C(=O)N)[N+](C)(C)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = FOOBQHKMWYGHCE-UHFFFAOYSA-N
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 75645-22-6
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 86L3ZZ4408
| PubChem = 6438375
| SMILES = C[N+](C)(C)C(CCC1=NC=C(N1)CC(C(=O)[O-])N)C(=O)N
}}
|Section2={{Chembox Properties
| C=13 | H=23 | N=5 | O=3
| MolarMass = 297.354 g/mol
| Appearance =
| Density =
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|Section3={{Chembox Hazards | MainHazards =
| FlashPt =
| AutoignitionPt =
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}}
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.{{cite journal | vauthors = Liu S, Wiggins JF, Sreenath T, Kulkarni AB, Ward JM, Leppla SH | title = Dph3, a small protein required for diphthamide biosynthesis, is essential in mouse development | journal = Molecular and Cellular Biology | volume = 26 | issue = 10 | pages = 3835–3841 | date = May 2006 | pmid = 16648478 | pmc = 1488998 | doi = 10.1128/MCB.26.10.3835-3841.2006 }} 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.{{cite journal | vauthors = Jørgensen R, Merrill AR, Andersen GR | title = The life and death of translation elongation factor 2 | journal = Biochemical Society Transactions | volume = 34 | issue = Pt 1 | pages = 1–6 | date = February 2006 | pmid = 16246167 | doi = 10.1042/BST20060001 }}
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-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).
Biological function
Diphthamide ensures translation fidelity.{{cite journal | vauthors = Su X, Lin Z, Lin H | title = The biosynthesis and biological function of diphthamide | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 48 | issue = 6 | pages = 515–521 | date = 2013-11-01 | pmid = 23971743 | pmc = 4280834 | doi = 10.3109/10409238.2013.831023 }}
The presence or absence of diphthamide is known to affect NF-κB or death receptor pathways.{{cite journal | vauthors = 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 | display-authors = 6 | title = Loss of diphthamide pre-activates NF-κB and death receptor pathways and renders MCF7 cells hypersensitive to tumor necrosis factor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 34 | pages = 10732–10737 | date = August 2015 | pmid = 26261303 | pmc = 4553792 | doi = 10.1073/pnas.1512863112 | doi-access = free | bibcode = 2015PNAS..11210732S }}