2010 Feb;38(2):491-500.
Functional Significance of eIF5A and Its Hypusine Modification in Eukaryotes
Affiliations
- PMID: 19997760
- PMCID: PMC2829442
- DOI: 10.1007/s00726-009-0408-7
Abstract
The unusual basic amino acid, hypusine
[N(epsilon)-(4-amino-2-hydroxybutyl)-lysine], is a modified lysine with
the addition of the 4-aminobutyl moiety from the polyamine spermidine.
This naturally occurring amino acid is a product of a unique
posttranslational modification that occurs in only one cellular protein,
eukaryotic translation initiation factor 5A (eIF5A, eIF-5A).
Hypusine is synthesized exclusively in this protein by two sequential enzymatic steps involving deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH). The deoxyhypusine/hypusine synthetic pathway has evolved in archaea and eukaryotes, and eIF5A, DHS and DOHH are highly conserved suggesting a vital cellular function of eIF5A. Gene disruption and mutation studies in yeast and higher eukaryotes have provided valuable information on the essential nature of eIF5A and the deoxyhypusine/hypusine modification in cell growth and in protein synthesis. In view of the extraordinary specificity and functional significance of hypusine-containing eIF5A in mammalian cell proliferation, eIF5A and the hypusine biosynthetic enzymes are novel potential targets for intervention in aberrant cell proliferation.
Aliases for DHPS Gene
DHPS Gene: This gene encodes a protein that is required for
the formation of hypusine, a unique amino acid formed by the
posttranslational modification of only one protein, eukaryotic
translation initiation factor 5A. The encoded protein catalyzes the
first step in hypusine formation by transferring the butylamine moiety
of spermidine to a specific lysine residue of the eukaryotic translation
initiation factor 5A precursor, forming an intermediate deoxyhypusine
residue. Alternatively spliced transcript variants encoding multiple
isoforms have been observed for this gene. [provided by RefSeq, May
2011]
Hypusine is synthesized exclusively in this protein by two sequential enzymatic steps involving deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH). The deoxyhypusine/hypusine synthetic pathway has evolved in archaea and eukaryotes, and eIF5A, DHS and DOHH are highly conserved suggesting a vital cellular function of eIF5A. Gene disruption and mutation studies in yeast and higher eukaryotes have provided valuable information on the essential nature of eIF5A and the deoxyhypusine/hypusine modification in cell growth and in protein synthesis. In view of the extraordinary specificity and functional significance of hypusine-containing eIF5A in mammalian cell proliferation, eIF5A and the hypusine biosynthetic enzymes are novel potential targets for intervention in aberrant cell proliferation.
DHPS (19p13.13)
https://www.genecards.org/cgi-bin/carddisp.pl?gene=DHPS&keywords=DHPSAliases for DHPS Gene
GeneCards Summary for DHPS Gene
DHPS (Deoxyhypusine Synthase) is a Protein Coding gene.
Diseases associated with DHPS include Neurodevelopmental Disorder With Seizures And Speech And Walking Impairment and Pneumocystosis.
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 deoxyhypusine synthase activity.
An important paralog of this gene is ENSG00000285589.
UniProtKB/Swiss-Prot Summary for DHPS Gene
Catalyzes the NAD-dependent oxidative cleavage
of spermidine and the subsequent transfer of the butylamine moiety of
spermidine to the epsilon-amino group of a critical lysine residue of
the eIF-5A precursor protein to form the intermediate deoxyhypusine
residue (PubMed:30661771). This is the first step of the
post-translational modification of that lysine into an unusual amino
acid residue named hypusine. Hypusination is unique to mature eIF-5A
factor and is essential for its function. DHYS_HUMAN,P49366.
Protein attributes for DHPS Gene
Size: 369 amino acids Molecular mass: 40971 Da
Cofactor Name=NAD(+); Xref=ChEBI:CHEBI:57540;
Quaternary structure: Homotetramer formed by a dimer of dimers.
Miscellaneous: [Isoform Short]: Inactive.
SequenceCaution: Sequence=AL520040; Type=Frameshift; Evidence={ECO:0000305};
DOHH ( 19p13.3) NM_031304.5 → NP_112594.1 deoxyhypusine hydroxylase
https://www.genecards.org/cgi-bin/carddisp.pl?gene=DOHH&keywords=DOHH
GeneCards Summary for DOHH Gene
Aliases for DOHH Gene
External Ids for DOHH Gene: This gene encodes a metalloenzyme that catalyzes
the last step in the conversion of lysine to the unique amino acid
hypusine in eukaryotic initiation factor 5A. The encoded protein
hydroxylates deoxyhypusine to form hypusine in the mature eukaryotic
initiation factor 5A protein. Alternative splicing results in multiple
transcript variants.[provided by RefSeq, Feb 2009]
GeneCards Summary for DOHH Gene
DOHH (Deoxyhypusine Hydroxylase) is a Protein Coding gene.
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 binding and deoxyhypusine monooxygenase activity.
UniProtKB/Swiss-Prot Summary for DOHH Gene: Catalyzes the hydroxylation of the
N(6)-(4-aminobutyl)-L-lysine intermediate produced by deoxyhypusine
synthase/DHPS on a critical lysine of the eukaryotic translation
initiation factor 5A/eIF-5A. This is the second step of the
post-translational modification of that lysine into an unusual amino
acid residue named hypusine (PubMed:16533814, PubMed:16371467,
PubMed:19706422). Hypusination is unique to mature eIF-5A factor and is
essential for its function (By similarity). DOHH_HUMAN,Q9BU89
Protein attributes for DOHH Gene
Size:302 amino acids. Molecular mass: 32904 Da. Cofactor: Name=Fe(2+); Xref=ChEBI:CHEBI:29033; Quaternary structure: No Data Available
DOI: 10.1016/j.str.2015.03.002
DOI: 10.1016/j.str.2015.03.002
Highlights
- Spectroscopic studies demonstrate extreme longevity of hDOHH peroxo intermediate
- Crystal structures of hDOHH were solved in two forms, peroxo and glycerol complex
- The diiron core environment explains the unusual stability of the peroxo intermediate
- A docking experiment provides a plausible model for deoxyhypusine binding to hDOHH
The polyamine-hypusine pathway. The most common polyamines are putrescine, spermidine and spermine, which are predominantly derived from the amino acids ornithine and methionine. One of the polyamines, spermidine, is used as the substrate to synthesize a unique amino acid coined hypusine, which is covalently linked to the lysine-50 residue of eIF5A. In cancer cells, ornithine decarboxylase 1 (ODC1), the enzyme catalyzing the first step of polyamine biosynthesis, is often up-regulated, especially in Myc-driven malignant cancers, which in turn, increases levels of polyamines. As a result, the levels of polyamines are elevated in cancer cells. 2-difluoromethylornithine (DFMO) is suicide inhibitor of ODC1 and has shown impressive efficacy in several clinical cancer prevention trials, including colon and prostate cancer. Hypusination of eIF5A is mediated by two enzymes, DHPS and DOHH. Hypusination is conserved among all eukaryotes. MAT methionine adenosyltransferase, SAM S-adenosyl-l-methionine, AMD1 AdoMet decarboxylase, SRM spermidine synthase, SMS spermine synthase, SMO spermine oxidase, SSAT spermidine/ spermine N1-acetyltransferase, PAO polyamine oxidase
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