Tulos:
https://biocyc.org/HUMAN/NEW-IMAGE?type=PATHWAY&object=PWY-6482
Pathway Summary from MetaCyc:
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].
The fourth gene,
DPH4, is similar to DnaJ-type chaperones, 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]. 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:
| Superclasses: | Biosynthesis → Amino Acid Biosynthesis → Modification of Amino Acid Within Proteins |
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