Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Combined Automated Annotation using Multiple IEA Methods
Diphthamide biosynthesis requires an organic radical generated by an iron-sulphur enzyme
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The Dph2 enzyme in Pyrococcus horikoshii uses a [4Fe-4S] cluster to generate an organic radical from SAM for diphthamide biosynthesis
"Diphthamide biosynthesis requires an organic radical generated by an iron-sulphur enzyme"
Organometallic and radical intermediates reveal mechanism of diphthamide biosynthesis
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The diphthamide biosynthetic enzyme generates an organometallic intermediate with an iron-carbon bond between ACP and the [4Fe-4S] cluster, followed by a product-like radical on eEF2
"Diphthamide biosynthesis involves a carbon-carbon bond-forming reaction catalyzed by a radical S-adenosylmethionine (SAM) enzyme that cleaves a carbon-sulfur (C-S) bond in SAM to generate a 3-amino-3-carboxypropyl (ACP) radical"
Dph3 is an electron donor for Dph1-Dph2 in the first step of eukaryotic diphthamide biosynthesis
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Dph3 (KTI11) serves as the physiological electron donor to reduce the [4Fe-4S] cluster in the Dph1-Dph2 complex
"Yeast Dph1 and Dph2 form a complex (Dph1-Dph2) that is equivalent to the homodimer of PhDph2 and is sufficient to catalyze the first step in vitro in the presence of dithionite as the reductant"
Dph3 enables aerobic diphthamide biosynthesis by donating one iron atom to transform a [3Fe-4S] to a [4Fe-4S] cluster in Dph1-Dph2
Diphthamide-deficiency syndrome -- a novel human developmental disorder and ribosomopathy
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Biallelic DPH2 mutations cause diphthamide-deficiency syndrome with intellectual disability, seizures, and developmental abnormalities
"The gene products DPH1 and DPH2 are components of a heterodimeric enzyme complex that mediates the first step of the posttranslational diphthamide modification on the nonredundant eukaryotic translation elongation factor 2 (eEF2)"
DPH1 and DPH2 variants that confer susceptibility to diphthamide deficiency syndrome in human cells and yeast models
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DPH2 variants H105P and C341Y abolish diphthamide biosynthesis, confirmed in human cells and yeast functional assays
"Ten additional human DPH1...and two DPH2 (H105P, C341Y) variants showed reduced functionality and hence are deficiency-susceptibility alleles"
Diphthamide deficiency promotes association of eEF2 with p53 to induce p21 expression and neural crest defects
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Diphthamide deficiency causes eEF2 to dissociate from ribosomes and associate with p53, driving p21-mediated growth arrest and neural crest defects
"DPH1 depletion facilitates dissociation of eEF2 from ribosomes and association with p53 to promote transcription of the cell cycle inhibitor p21, resulting in inhibited proliferation"
Diphthamide -- a conserved modification of eEF2 with clinical relevance
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Comprehensive review of diphthamide as a conserved eEF2 modification affecting translational fidelity, viral susceptibility, and human disease
"Diphthamide, a complex modification on eukaryotic translation elongation factor 2 (eEF2), assures reading-frame fidelity during translation"
BioReason SFT reasoning trace for dph2 (Danio rerio)
Falcon deep research for zebrafish dph2 (Danio rerio, A4QN59)
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No zebrafish-specific primary studies naming UniProt A4QN59 or zgc:162269 were retrieved; functional assignments are based on highly conserved, mechanistically characterized eukaryotic/archaeal DPH2 homologs given the strong conservation of the diphthamide biosynthesis pathway from archaea to humans.
"I did ...not... find zebrafish-specific primary studies explicitly naming UniProt A4QN59 or zgc:162269; therefore, organism-specific phenotypes or expression patterns for zebrafish are not asserted here. Functional statements are based on ...highly conserved, mechanistically characterized eukaryotic/archaeal DPH2 homologs..."
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Dph2, with Dph1, catalyzes the first committed step of diphthamide biosynthesis - transfer of the 3-amino-3-carboxypropyl (ACP) group from SAM onto the imidazole C2 of a conserved eEF2 histidine.
"DPH2 (together with DPH1) functions in the ...first committed step... of diphthamide biosynthesis: transfer of a ...3-amino-3-carboxypropyl (ACP)... group derived from ...S-adenosylmethionine (SAM/AdoMet)... onto the ...C2 of the imidazole ring... of a conserved eEF2 histidine"
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The Dph1-Dph2 catalytic module is a non-canonical radical-SAM enzyme that uses Fe-S clusters but does not employ the canonical CX3CX2C motif and generates an ACP radical rather than the classical 5'-deoxyadenosyl radical.
"it uses Fe–S clusters but does ...not... rely on the canonical ...CX3CX2C... motif and does ...not... generate the classical 5′-deoxyadenosyl radical; instead it generates an ...ACP radical... from SAM cleavage that is then used to functionalize eEF2 histidine"
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Diphthamide on eEF2 supports translational fidelity and suppresses spurious -1 frameshifting; in mammalian cells its loss perturbs RRM1 translation and elevates DNA replication stress.
"Mature diphthamide on eEF2 supports translational fidelity and suppresses spurious -1 frameshifting; deficiency perturbs translation of proteins such as RRM1 and elevates DNA replication stress"
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Dph2 acts in the cytosol on cytosolic eEF2; experimental cytosolic localization of Arabidopsis DPH2 (interacting with DPH1) supports this expectation for the conserved complex.
"Arabidopsis DPH2 localizes to the cytosol and physically interacts with DPH1..., consistent with a cytosolic biosynthetic complex acting on cytosolic eEF2"