| Superclasses: | Biosynthesis → Amino Acid Biosynthesis → Modification of Amino Acid Within Proteins |
Pathway Summary from MetaCyc: (Citate)
"Diphthamide is a unique posttranslationally modified histidine residue found only in translation elongation factor 2 ( elongation factor 2). This factor is found in archaebacteria and in all eukaryotes, but not in eubacteria, and is conserved from archaebacteria to humans. The role of diphthamide is still not understood. Mutants defective in its biosynthesis are viable in yeast, but mutant mice are retarded in growth and development, and almost always die before birth [Liu06a, Webb08]. A potential role of diphthamide may be to protect ribosomes fom ribosome-inactivating proteins (such as ricin), which are widely distributed in nature [Gupta08].
"Diphthamide is a unique posttranslationally modified histidine residue found only in translation elongation factor 2 ( elongation factor 2). This factor is found in archaebacteria and in all eukaryotes, but not in eubacteria, and is conserved from archaebacteria to humans. The role of diphthamide is still not understood. Mutants defective in its biosynthesis are viable in yeast, but mutant mice are retarded in growth and development, and almost always die before birth [Liu06a, Webb08]. A potential role of diphthamide may be to protect ribosomes fom ribosome-inactivating proteins (such as ricin), which are widely distributed in nature [Gupta08].
The conversion of
L-histidine to
Diphthamide is a complex process.
It starts by the transfer of a 3-amino-3-carboxypropyl moiety from S-adenosyl-L-methionine.
Four different genes of Saccharomyces cerevisiae have been shown to be required for this step. Three of these genes, DPH1, DPH2 and DPH3, are believed to form a 2-(3-amino-3-carboxypropyl)histidine synthase complex [Mattheakis93, Liu04d]. "
DPH1, https://www.uniprot.org/uniprot/Q9BZG8
2-(3-amino-3-carboxypropyl)histidine synthase subunit 1
DPH2 , https://www.uniprot.org/uniprot/Q9BQC3
2-(3-amino-3-carboxypropyl)histidine synthase subunit 2
DPH3, ZCSL2, DESR1, CSL-type zinc finger-containing protein 2
DPH3 homolog on Zn tai Fe sitova.
https://www.uniprot.org/uniprot/Q96FX2
DPH4 , DnaJC4
https://www.uniprot.org/uniprot/Q6P3W2.
"The fourth gene, DPH4, is similar to DnaJ-type chaperones,DnaJC24.
and is assumed to be responsible for the proper folding of one or more of the other DPH proteins [Liu04d].
It starts by the transfer of a 3-amino-3-carboxypropyl moiety from S-adenosyl-L-methionine.
Four different genes of Saccharomyces cerevisiae have been shown to be required for this step. Three of these genes, DPH1, DPH2 and DPH3, are believed to form a 2-(3-amino-3-carboxypropyl)histidine synthase complex [Mattheakis93, Liu04d]. "
DPH1, https://www.uniprot.org/uniprot/Q9BZG8
2-(3-amino-3-carboxypropyl)histidine synthase subunit 1
DPH2 , https://www.uniprot.org/uniprot/Q9BQC3
2-(3-amino-3-carboxypropyl)histidine synthase subunit 2
DPH3, ZCSL2, DESR1, CSL-type zinc finger-containing protein 2
DPH3 homolog on Zn tai Fe sitova.
https://www.uniprot.org/uniprot/Q96FX2
DPH4 , DnaJC4
https://www.uniprot.org/uniprot/Q6P3W2.
"The fourth gene, DPH4, is similar to DnaJ-type chaperones,DnaJC24.
and is assumed to be responsible for the proper folding of one or more of the other DPH proteins [Liu04d].
The next step, catalyzed by the
DPH5-encoded
diphthine synthase, is the transfer of three methyl groups, donated by three molecules of
S-adenosyl-L-methionine, to form a
diphtine residue
[Mattheakis92]. DPH5: Diphtine methylester synthase"
(DPH7, Diphtine methyl transferase).
" DPH6
The last step is the amidation of diphtine to diphthamide, catalyzed by the DPH6-encoded diphthine—ammonia ligase [Su12a].
(DPH7, Diphtine methyl transferase).
" DPH6
The last step is the amidation of diphtine to diphthamide, catalyzed by the DPH6-encoded diphthine—ammonia ligase [Su12a].
Diphthamide serves as the target for two important bacterial toxins - the
diphtheria toxin (DT) and the Pseudomonas
endotoxin A. Both toxins catalyze the transfer of
ADP-D-ribose from NAD+ to
a diphthamide-[translation elongation factor 2] on eEF-2, inactivating it and halting cellular protein synthesis, causing cell death
[Liu04d].
By targeting this unique modified amino acid which does not exist in
bacteria, these pathogens are able to shut down the eukaryotic protein
synthesis machinery without jeopardizing their own system.
Locations of Mapped Genes.."
...
(Lisätietoa DPH5, DPH6 ja DPH7 entsyymeistä)
DPH5, Diphtine methylester synthase
Aliases for DPH5 Gene
This gene encodes a component of the diphthamide
synthesis pathway. Diphthamide is a post-translationally modified
histidine residue found only on translation elongation factor 2. It is
conserved from archaebacteria to humans, and is targeted by diphtheria
toxin and Pseudomonas exotoxin A to halt cellular protein synthesis. The
yeast and Chinese hamster homologs of this protein catalyze the
trimethylation of the histidine residue on elongation factor 2,
resulting in a diphthine moiety that is subsequently amidated to yield
diphthamide. Multiple transcript variants encoding different isoforms
have been found for this gene. [provided by RefSeq, Jul 2008]
GeneCards Summary for DPH5 Gene
DPH5 (Diphthamide Biosynthesis 5) is a Protein Coding gene.
Diseases associated with DPH5 include Diphtheria.
Among its related pathways are Metabolism of proteins and Gamma carboxylation, hypusine formation and arylsulfatase activation.
Gene Ontology (GO) annotations related to this gene include methyltransferase activity and diphthine synthase activity.
UniProtKB/Swiss-Prot Summary for DPH5 Gene
S-adenosyl-L-methionine-dependent
methyltransferase that catalyzes four methylations of the modified
target histidine residue in translation elongation factor 2 (EF-2), to
form an intermediate called diphthine methyl ester. The four successive
methylation reactions represent the second step of diphthamide
biosynthesis. DPH5_HUMAN,Q9H2P9DPH6 , Diphtine - Ammonia ligase (ATPBD4)
Aliases for DPH6 Gene
- Protein DPH6 Homolog 3 4
- ATP Binding Domain 4 2 3
- ATPBD4 3 4
- DPH6 Homolog (S. Cerevisiae) 2
- DPH6 Homolog 3
GeneCards Summary for DPH6 Gene
DPH6 (Diphthamine Biosynthesis 6) is a Protein Coding gene.
Diseases associated with DPH6 include Spastic Paraplegia 11, Autosomal Recessive.
Among its related pathways are Metabolism of proteins and *Gamma carboxylation, hypusine formation and *arylsulfatase activation.
Gene Ontology (GO) annotations related to this gene include diphthine-ammonia ligase activity.( *K-vitamiinin funktioalue) https://pathcards.genecards.org/card/gamma_carboxylation_hypusine_formation_and_arylsulfatase_activation
UniProtKB/Swiss-Prot Summary for DPH6 Gene
Amidase that catalyzes the last step of diphthamide biosynthesis using ammonium and ATP. Diphthamide biosynthesis consists in the conversion of an L-histidine residue in the translation elongation factor (EEF2) to diphthamide (By similarity). DPH6_HUMAN,Q7L8W6 Additional gene information for DPH6 Gene
https://www.uniprot.org/uniprot/Q7L8W6
Amidase that catalyzes the last step of diphthamide biosynthesis using ammonium and ATP. Diphthamide biosynthesis consists in the conversion of an L-histidine residue in the translation elongation factor (EEF2) to diphthamide (By similarity). DPH6_HUMAN,Q7L8W6 Additional gene information for DPH6 Gene
https://www.uniprot.org/uniprot/Q7L8W6
DPH7, Diphtine methyl transferase
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