ArticleJournal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry2019
The asymmetric function of Dph1-Dph2 heterodimer in diphthamide biosynthesis.
Article in Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 35 citations in OpenAlex.
- Diphthamide synthesis is linked to the eEF2-client chaperone machinery.FEBS letters · 2025Article
- Functional Integrity of Radical SAM Enzyme Dph1•Dph2 Requires Non-Canonical Cofactor Motifs with Tandem Cysteines.Biomolecules · 2024Article
- Article
- Yeast geneMicrobial cell (Graz, Austria) · 2023Article
- DPH1 and DPH2 variants that confer susceptibility to diphthamide deficiency syndrome in human cells and yeast models.Disease models & mechanisms · 2023Article
- Discovery of 2-(furan-2-ylmethylene)hydrazine-1-carbothioamide derivatives as novel inhibitors of SARS-CoV-2 main protease.European journal of medicinal chemistry · 2022Article
- Translational fidelity and growth of Arabidopsis require stress-sensitive diphthamide biosynthesis.Nature communications · 2022Article
- Iron-sulfur clusters as inhibitors and catalysts of viral replication.Nature chemistry · 2022Review
- Dph3 Enables Aerobic Diphthamide Biosynthesis by Donating One Iron Atom to Transform a [3Fe-4S] to a [4Fe-4S] Cluster in Dph1-Dph2.Journal of the American Chemical Society · 2021Article
- Iron in Translation: From the Beginning to the End.Microorganisms · 2021Review
- Identification of 11 candidate structured noncoding RNA motifs in humans by comparative genomics.BMC genomics · 2021Article
- Diphthamide-deficiency syndrome: a novel human developmental disorder and ribosomopathy.European journal of human genetics : EJHG · 2020Article
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7 authors at 3 institutions in 2 countries.
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Abstract
Diphthamide, the target of diphtheria toxin, is a post-translationally modified histidine residue found in archaeal and eukaryotic translation elongation factor 2 (EF2). In the first step of diphthamide biosynthesis, a [4Fe-4S] cluster-containing radical SAM enzyme, Dph1-Dph2 heterodimer in eukaryotes or Dph2 homodimer in archaea, cleaves S-adenosylmethionine and transfers the 3-amino-3-carboxypropyl group to EF2. It was demonstrated previously that for the archaeal Dph2 homodimer, only one [4Fe-4S] cluster is necessary for the in vitro activity. Here, we demonstrate that for the eukaryotic Dph1-Dph2 heterodimer, the [4Fe-4S] cluster-binding cysteine residues in each subunit are required for diphthamide biosynthesis to occur in vivo. Furthermore, our in vitro reconstitution experiments with Dph1-Dph2 mutants suggested that the Dph1 cluster serves a catalytic role, while the Dph2 cluster facilitates the reduction of the Dph1 cluster by the physiological reducing system Dph3/Cbr1/NADH. Our results reveal the asymmetric functional roles of the Dph1-Dph2 heterodimer and may help to understand how the Fe-S clusters in radical SAM enzymes are reduced in biology.
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