2.1.1.314: diphthine methyl ester synthase
This is an abbreviated version!
For detailed information about diphthine methyl ester synthase, go to the full flat file.
Reaction
4 S-adenosyl-L-methionine + = 4 S-adenosyl-L-homocysteine +
Synonyms
diphthine methyltransferase, diphthine synthase, Dph5, S-adenosyl-L-methionine:elongation factor 2 methyltransferase
ECTree
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General Information
General Information on EC 2.1.1.314 - diphthine methyl ester synthase
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malfunction
metabolism
physiological function
complete inactivation of DPH1, DPH2, DPH4, and DPH5 generated viable cells without diphthamide. Reduced growth rates are observed for all clones with completely inactivated DPH5. These contain ACP-modified eEF2, which occurs only in DPH5-deficient cells and not in other variants
malfunction
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DPH5 gene overexpression causes growth defects in several dph mutant backgrounds. Higher-than-normal levels of Dph5 can inhibit the function of EF2, particularly when the translation factor is incompletely modified
malfunction
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growth inhibition by higher-than-normal Dph5 levels produced from DPH5 overexpression
the eukaryotic enzyme is part of the biosynthetic pathway of diphthamide
metabolism
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the eukaryotic enzyme is part of the biosynthetic pathway of diphthamide
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DPH1 and DPH5 are essential to generate diphthamide on eukaryotic translation elongation factor 2, the sole target of ADP-ribosylating toxins. DPH1 and DPH5-deficient MCF7 are therefore resistant to ADP-ribosylation and cytotoxicity inflicted by toxins that target eEF2-diphthamide
physiological function
Drosophila sp. (in: flies)
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Dph5 is required for gross translation activation and high dMyc protein level in RasV12 tumor-like hyperplasia. Dph5 is involved in the regulation of ribosome biogenesis genes. Diphthamidation is required for translation activation partly through the regulation of ribosome biogenesis in Ras-induced tumor-like hyperplasia model in Drosophila gut
physiological function
eukaryotic diphthine synthase, Dph5, is a promiscuous methyltransferase that catalyzes an extraordinary N,O-tetramethylation of 2-(3-carboxy-3-aminopropyl)-L-histidine to yield diphthine methyl ester. This compound is an intermediates in the biosynthesis of the post-translationally modified histidine residue diphthamide, a unique and essential residue part of the eukaryotic elongation factor 2 (eEF2)
physiological function
the diphthamide on human eukaryotic translation elongation factor 2 is the target of ADP ribosylating diphtheria toxin and Pseudomonas exotoxin A. This modification is synthesized by seven dipthamide biosynthesis proteins (DPH1-DPH7) and is conserved among eukaryotes and archaea. MCF7 breast cancer cell line-derived DPH gene knockout cells are generated to assess the impact of complete or partial inactivation on diphthamide synthesis and toxin sensitivity, and to address the biological consequence of diphthamide deficiency. Cells with heterozygous gene inactivation still contain predominantly diphthamide-modified eEF2 and are as sensitive to Pseudomonas exotoxin A and diphtheria toxin as parent cells. Thus, DPH gene copy number reduction does not affect overall diphthamide synthesis and toxin sensitivity. Complete inactivation of DPH1, DPH2, DPH4, and DPH5 generates viable cells without diphthamide. DPH1ko, DPH2ko, and DPH4ko harbor unmodified eEF2 and DPH5ko ACP-(diphthine-precursor)modified eEF2. Loss of diphthamide prevents ADP ribosylation of eEF2, renders cells resistant to Pseudomonas exotoxin A and diphtheria toxin, but does not affect sensitivity toward other protein synthesis inhibitors, such as saporin or cycloheximide. Cells without diphthamide (independent of which the DPH gene compromised) are presensitized toward nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-kappaB) and death-receptor pathways without crossing lethal thresholds. Loss of diphthamide renders cells hypersensitive toward TNF-mediated apoptosis
physiological function
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the enzyme is involved in modification of an invariant histidine (His-699 in yeast) residue in translation elongation factor 2 (EF2) with diphthamide. Diphthamide modified EF2 is important for translational accuracy and competitive cell growth in yeast
physiological function
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the enzyme is involved in the diphthamide modification pathway