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Literature summary for 2.1.1.314 extracted from

  • Hoerberg, J.; Saenz-Mendez, P.; Eriksson, L.A.
    QM/MM studies of Dph5 - a promiscuous methyltransferase in the eukaryotic biosynthetic pathway of diphthamide (2018), J. Chem. Inf. Model., 58, 1406-1414 .
    View publication on PubMed
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Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[translation elongation factor 2] Saccharomyces cerevisiae 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-homocysteine + diphthine methyl ester-[translation elongation factor 2]
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Organism

Organism UniProt Comment Textmining
Saccharomyces cerevisiae P32469
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Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[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) Saccharomyces cerevisiae 4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
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4 S-adenosyl-L-methionine + 2-[(3S)-3-carboxy-3-aminopropyl]-L-histidine-[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 Saccharomyces cerevisiae 4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
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Synonyms

Synonyms Comment Organism
diphthine synthase
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 Saccharomyces cerevisiae
Dph5
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 Saccharomyces cerevisiae

General Information

General Information Comment Organism
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) Saccharomyces cerevisiae