Chemistry:Diphthamide
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
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "The biosynthesis and biological function of diphthamide". Critical Reviews in Biochemistry and Molecular Biology 48 (6): 515–521. 2013-11-01. doi:10.3109/10409238.2013.831023. PMID 23971743.
- ↑ 2.0 2.1 "Dph3, a small protein required for diphthamide biosynthesis, is essential in mouse development". Molecular and Cellular Biology 26 (10): 3835–3841. May 2006. doi:10.1128/MCB.26.10.3835-3841.2006. PMID 16648478.
- ↑ "The life and death of translation elongation factor 2". Biochemical Society Transactions 34 (Pt 1): 1–6. February 2006. doi:10.1042/BST20060001. PMID 16246167.
- ↑ "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. August 2015. doi:10.1073/pnas.1512863112. PMID 26261303. Bibcode: 2015PNAS..11210732S.
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