DPH5 Gene

Name	diphthamide biosynthesis 5
Description	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]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Diphthamide is a unique post‐translationally modified histidine residue found exclusively on eukaryotic and archaeal translation elongation factor 2 (eEF2). Its synthesis proceeds through a multistep pathway that, in yeast, requires a set of proteins designated Dph1–Dph5 plus additional factors responsible for the final amidation step. DPH5 encodes a specific S‑adenosylmethionine–dependent methyltransferase that mediates the second step in diphthamide biosynthesis by catalyzing the sequential mono‐, di‐, and tri‑methylation of the substrate intermediate (diphthine). Structural and biochemical studies have shown that DPH5 is a “promiscuous” methyltransferase capable of performing an extraordinary N, O‑tetramethylation reaction on 2-(3‑carboxy‑3‑aminopropyl)-l‑histidine, thereby converting it into its methylated ester form—a modification that is critical for rendering eEF2 sensitive to ADP‑ribosylating toxins such as diphtheria toxin. Inactivation or mutation of DPH5 leads to the production of an incompletely modified eEF2 that is resistant to such toxins and has been linked to defects in embryonic development, neurodevelopmental delays, and aberrant cellular signaling. Moreover, studies in model organisms indicate that alterations in DPH5 activity not only impact translational fidelity but may also contribute to tumor progression. Collectively, these results underscore the essential role of DPH5 in ensuring proper diphthamide formation on eEF2, thereby maintaining the fidelity of protein synthesis and modulating cellular responses to environmental and pathological challenges."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Shihui Liu, G Todd Milne, Jeffrey G Kuremsky, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of the proteins required for biosynthesis of diphthamide, the target of bacterial ADP-ribosylating toxins on translation elongation factor 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.24.21.9487-9497.2004"}], "href": "https://doi.org/10.1128/MCB.24.21.9487-9497.2004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15485916"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15485916"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "J Y Chen, J W Bodley "}, {"type": "b", "children": [{"type": "t", "text": "Biosynthesis of diphthamide in Saccharomyces cerevisiae. Partial purification and characterization of a specific S-adenosylmethionine:elongation factor 2 methyltransferase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (1988)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "3042777"}], "href": "https://pubmed.ncbi.nlm.nih.gov/3042777"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Johanna Hörberg, Patricia Saenz-Mendez, Leif A Eriksson "}, {"type": "b", "children": [{"type": "t", "text": "QM/MM Studies of Dph5 - A Promiscuous Methyltransferase in the Eukaryotic Biosynthetic Pathway of Diphthamide."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Chem Inf Model (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/acs.jcim.8b00217"}], "href": "https://doi.org/10.1021/acs.jcim.8b00217"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29927239"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29927239"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Xuling Zhu, Jungwoo Kim, Xiaoyang Su, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reconstitution of diphthine synthase activity in vitro."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi100812h"}], "href": "https://doi.org/10.1021/bi100812h"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20873788"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20873788"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Shanow Uthman, Christian Bär, Viktor Scheidt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The amidation step of diphthamide biosynthesis in yeast requires DPH6, a gene identified through mining the DPH1-DPH5 interaction network."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1003334"}], "href": "https://doi.org/10.1371/journal.pgen.1003334"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23468660"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23468660"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Kayoko Tsuda-Sakurai, Masaki Kimura, Masayuki Miura "}, {"type": "b", "children": [{"type": "t", "text": "Diphthamide modification of eEF2 is required for gut tumor-like hyperplasia induced by oncogenic Ras."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Cells (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/gtc.12742"}], "href": "https://doi.org/10.1111/gtc.12742"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31828897"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31828897"}]}]}]}
Synonyms	CGI-30, NPD015, AD-018, HSPC143
Proteins	DPH5_HUMAN
NCBI Gene ID	51611
API
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Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

DPH5 has 5,027 functional associations with biological entities spanning 8 categories (molecular profile, organism, chemical, disease, phenotype or trait, functional term, phrase or reference, structural feature, cell line, cell type or tissue, gene, protein or microRNA) extracted from 108 datasets.

Click the + buttons to view associations for DPH5 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

DPH5 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of DPH5 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of DPH5 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of DPH5 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of DPH5 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of DPH5 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of DPH5 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of DPH5 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of DPH5 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of DPH5 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of DPH5 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of DPH5 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with DPH5 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with DPH5 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of DPH5 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of DPH5 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of DPH5 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with DPH5 gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CM4AI KOLF21J CRISPRi Gene Perturbation Atlas	gene perturbations changing expression of DPH5 gene from the CM4AI KOLF21J CRISPRi Gene Perturbation Atlas dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of DPH5 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with DPH5 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with DPH5 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of DPH5 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with DPH5 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Disease Associations	diseases associated with DPH5 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of DPH5 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by DPH5 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with DPH5 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with DPH5 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with DPH5 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with DPH5 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	DrugBank Drug Targets	interacting drugs for DPH5 protein from the curated DrugBank Drug Targets dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at DPH5 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of DPH5 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of DPH5 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing DPH5 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GDSC Cell Line Gene Expression Profiles	cell lines with high or low expression of DPH5 gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with DPH5 gene in literature-supported statements describing functions of genes from the GeneRIF Biological Term Annotations dataset.
	GeneSigDB Published Gene Signatures	PubMedIDs of publications reporting gene signatures containing DPH5 from the GeneSigDB Published Gene Signatures dataset.
	GEO Signatures of Differentially Expressed Genes for Diseases	disease perturbations changing expression of DPH5 gene from the GEO Signatures of Differentially Expressed Genes for Diseases dataset.
	GEO Signatures of Differentially Expressed Genes for Gene Perturbations	gene perturbations changing expression of DPH5 gene from the GEO Signatures of Differentially Expressed Genes for Gene Perturbations dataset.