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Information on EC 2.1.1.314 - diphthine methyl ester synthase and Organism(s) Saccharomyces cerevisiae and UniProt Accession P32469
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2.1.1.314 diphthine methyl ester synthaseIUBMB Comments
This eukaryotic enzyme is part of the biosynthetic pathway of diphthamide. Different from the archaeal enzyme, which performs only 3 methylations, producing diphthine (cf. EC 2.1.1.98). The relevant histidine of elongation factor 2 is His715 in mammals and His699 in yeast. The order of the 4 methylations is not known.
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The taxonomic range for the selected organisms is: Saccharomyces cerevisiae
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
4
+
=
4
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4
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4
+
diphthine methyl ester-[translation elongation factor 2]
Synonyms
diphthine methyltransferase, diphthine synthase, Dph5, S-adenosyl-L-methionine:elongation factor 2 methyltransferase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Dph5
S-adenosyl-L-methionine:elongation factor 2 methyltransferase
ambiguous
PATHWAY SOURCE
PATHWAYS
-
-
SYSTEMATIC NAME
IUBMB Comments
S-adenosyl-L-methionine:2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2] methyltransferase (diphthine methyl ester-[translation elongation factor 2]-forming)
This eukaryotic enzyme is part of the biosynthetic pathway of diphthamide. Different from the archaeal enzyme, which performs only 3 methylations, producing diphthine (cf. EC 2.1.1.98). The relevant histidine of elongation factor 2 is His715 in mammals and His699 in yeast. The order of the 4 methylations is not known.
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
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]
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]
-
-
-
-
?
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
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
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]
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
-
-
?
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
the eukaryotic enzyme is part of the biosynthetic pathway of diphthamide
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)
malfunction
physiological function
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
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
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Moehring, J.M.; Moehring, T.J.
The post-translational trimethylation of diphthamide studied in vitro
J. Biol. Chem.
263
3840-3844
1988
Cricetulus griseus, Saccharomyces cerevisiae
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)
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)
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)
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
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