Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
-
in the absence of ATP, S-adenosyl-L-methionine donates three methyl groups to form the trimethylamine and converts the intermediate intermediate to diphthine. The methyltransferase activity is specific for a single soluble cytosolic protein, translation elongation factor 2
-
-
?
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
-
in the absence of ATP, S-adenosyl-L-methionine donates three methyl groups to form the trimethylamine and converts the intermediate intermediate to diphthine. The methyltransferase activity is specific for a single soluble cytosolic protein, translation elongation factor 2
-
-
?
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
Drosophila sp. (in: flies)
-
-
-
-
?
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
Drosophila sp. (in: flies)
-
post-translational modification of eukaryotic elongation factor 2 (eEF2)
-
-
?
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
-
-
-
?
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
-
-
-
-
?
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
the eukaryotic enzyme is part of the biosynthetic pathway of diphthamide. The modification is sufficient to create diphtheria toxin sensitivity
diphthine methyl ester i.e. 2-[(3S)-3-carboxy methyl ester-3-(trimethylammonio)propyl]-L-histidine
-
?
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
the relevant histidine of elongation factor 2 is His699 in Saccharomyces cerevisiae
diphthine methyl ester i.e. 2-[(3S)-3-carboxy methyl ester-3-(trimethylammonio)propyl]-L-histidine
-
?
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
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)
-
-
?
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
-
in eukaryotes, the modification of an invariant histidine (His-699 in yeast) residue in translation elongation factor 2 (EF2) with diphthamide involves a conserved pathway encoded by the DPH1-DPH7 gene network. Diphthamide is the target for diphtheria toxin and related lethal ADP ribosylases, which collectively kill cells by inactivating the essential translocase function of EF2 during mRNA translation and protein biosynthesis
-
-
?
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
-
the enzyme is involved in the diphthamide modification pathway
-
-
?
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
homology modeling of the enzyme (Dph5) is carried out to provide the structure of Dph5, protein-protein docking and molecular dynamics to construct the Dph5-eukaryotic elongation factor 2 complex, and quantum mechanics/molecular mechanics calculations to outline a plausible mechanism. The calculations show that the methylation of N,O-tetramethylation of 2-(3-carboxy-3-aminopropyl)-L-histidine follows a typical SN2 mechanism, initiating with a complete methylation (trimethylation) at the N-position, followed by the single O-methylation. For each of the three N-methylation reactions, our calculations support a stepwise mechanism, which first involve proton transfer through a bridging water to a conserved aspartate residue D165, followed by a methyl transfer. Once fully methylated, the trimethyl amino group forms a weak electrostatic interaction with D165, which allows the carboxylate group of diphthine to attain the right orientation for the final methylation step to be accomplished
-
-
?
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
the eukaryotic enzyme is part of the biosynthetic pathway of diphthamide. The modification is sufficient to create diphtheria toxin sensitivity
diphthine methyl ester i.e. 2-[(3S)-3-carboxy methyl ester-3-(trimethylammonio)propyl]-L-histidine
-
?
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
the relevant histidine of elongation factor 2 is His699 in Saccharomyces cerevisiae
diphthine methyl ester i.e. 2-[(3S)-3-carboxy methyl ester-3-(trimethylammonio)propyl]-L-histidine
-
?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
Drosophila sp. (in: flies)
-
post-translational modification of eukaryotic elongation factor 2 (eEF2)
-
-
?
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
-
-
-
?
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
the eukaryotic enzyme is part of the biosynthetic pathway of diphthamide. The modification is sufficient to create diphtheria toxin sensitivity
diphthine methyl ester i.e. 2-[(3S)-3-carboxy methyl ester-3-(trimethylammonio)propyl]-L-histidine
-
?
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
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)
-
-
?
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
-
in eukaryotes, the modification of an invariant histidine (His-699 in yeast) residue in translation elongation factor 2 (EF2) with diphthamide involves a conserved pathway encoded by the DPH1-DPH7 gene network. Diphthamide is the target for diphtheria toxin and related lethal ADP ribosylases, which collectively kill cells by inactivating the essential translocase function of EF2 during mRNA translation and protein biosynthesis
-
-
?
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
-
the enzyme is involved in the diphthamide modification pathway
-
-
?
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2]
4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
the eukaryotic enzyme is part of the biosynthetic pathway of diphthamide. The modification is sufficient to create diphtheria toxin sensitivity
diphthine methyl ester i.e. 2-[(3S)-3-carboxy methyl ester-3-(trimethylammonio)propyl]-L-histidine
-
?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
malfunction
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
-
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
-
growth inhibition by higher-than-normal Dph5 levels produced from DPH5 overexpression
metabolism
the eukaryotic enzyme is part of the biosynthetic pathway of diphthamide
metabolism
-
the eukaryotic enzyme is part of the biosynthetic pathway of diphthamide
-
physiological function
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)
-
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
-
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
-
the enzyme is involved in the diphthamide modification pathway
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Moehring, J.M.; Moehring, T.J.
The post-translational trimethylation of diphthamide studied in vitro
J. Biol. Chem.
263
3840-3844
1988
Saccharomyces cerevisiae, Cricetulus griseus
brenda
Chen, J.Y.C.; Bodley, J.W.
Biosynthesis of diphthamide in Saccharomyces cerevisiae. Partial purification and characterization of a specific S-adenosylmethionine:elongation factor 2 methyltransferase
J. Biol. Chem.
263
11692-11696
1988
Saccharomyces cerevisiae (P32469), Saccharomyces cerevisiae ATCC 204508 (P32469)
brenda
Lin, Z.; Su, X.; Chen, W.; Ci, B.; Zhang, S.; Lin, H.
Dph7 catalyzes a previously unknown demethylation step in diphthamide biosynthesis
J. Am. Chem. Soc.
136
6179-6182
2014
Saccharomyces cerevisiae (P32469), Saccharomyces cerevisiae ATCC 204508 (P32469)
brenda
Tsuda-Sakurai, K.; Kimura, M.; Miura, M.
Diphthamide modification of eEF2 is required for gut tumor-like hyperplasia induced by oncogenic Ras
Genes Cells
25
76-85
2020
Drosophila sp. (in: flies)
brenda
Hoerberg, J.; Saenz-Mendez, P.; Eriksson, L.A.
QM/MM studies of Dph5 - a promiscuous methyltransferase in the eukaryotic biosynthetic pathway of diphthamide
J. Chem. Inf. Model.
58
1406-1414
2018
Saccharomyces cerevisiae (P32469)
brenda
Schaffrath, R.; Abdel-Fattah, W.; Klassen, R.; Stark, M.
The diphthamide modification pathway from Saccharomyces cerevisiae - revisited
Mol. Microbiol.
94
1213-1226
2016
Saccharomyces cerevisiae
brenda
Hawer, H.; tkr, K.; Arend, M.; Mayer, K.; Adrian, L.; Brinkmann, U.; Schaffrath, R.
Importance of diphthamide modified EF2 for translational accuracy and competitive cell growth in yeast
PLoS ONE
13
e0205870
2018
Saccharomyces cerevisiae
brenda
Stahl, S.; Da Silva Mateus Seidl, A.; Ducret, A.; Van Geijtenbeek, S.; Michel, S.; Racek, T.; Birzele, F.; Haas, A.; Rueger, R.; Gerg, M.; Niederfellner, G.; Pastan, I.; Brinkmann, U.
Loss of diphthamide pre-activates NF-kappaB and death receptor pathways and renders MCF7 cells hypersensitive to tumor necrosis factor
Proc. Natl. Acad. Sci. USA
112
10732-10737
2015
Homo sapiens (Q9H2P9)
brenda
Mayer, K.; Schrder, A.; Schnitger, J.; Stahl, S.; Brinkmann, U.
Influence of DPH1 and DPH5 protein variants on the synthesis of diphthamide, the target of ADPRibosylating toxins
Toxins
9
E78
2017
Homo sapiens (Q9H2P9)
brenda