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Information on EC 2.5.1.46 - deoxyhypusine synthase and Organism(s) Homo sapiens and UniProt Accession P49366
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2.5.1.46 deoxyhypusine synthaseIUBMB Comments
The eukaryotic initiation factor eIF5A contains a hypusine residue that is essential for activity. This enzyme catalyses the first reaction of hypusine formation from one specific lysine residue of the eIF5A precursor. The reaction occurs in four steps: NAD+-dependent dehydrogenation of spermidine (1a), formation of an enzyme-imine intermediate by transfer of the 4-aminobutylidene group from dehydrospermidine to the active site lysine residue (Lys329 for the human enzyme; 1b), transfer of the same 4-aminobutylidene group from the enzyme intermediate to the e1F5A precursor (1c), reduction of the e1F5A-imine intermediate to form a deoxyhypusine residue (1d). Hence the overall reaction is transfer of a 4-aminobutyl group. For the plant enzyme, homospermidine can substitute for spermidine and putrescine can substitute for the lysine residue of the eIF5A precursor. Hypusine is formed from deoxyhypusine by the action of EC 1.14.99.29, deoxyhypusine monooxygenase.
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Word Map
- 2.5.1.46
- polyamine
- gc7
- homospermidine
-
pyrrolizidine
- n1-guanyl-1,7-diaminoheptane
-
nepsilon-4-amino-2-hydroxybutyllysine
-
aminobutylation
-
hypusine-containing
- 1,7-diaminoheptane
-
deoxyhypusine-containing
- butylamine
-
polyamine-derived
-
eif-4d
- medicine
- 1,3-diaminopropane
- triamine
-
wolff
- drug development
- analysis
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Archaea, Bacteria, Eukaryota
The expected taxonomic range for this enzyme is: Archaea, Bacteria, Eukaryota
Reaction Schemes
hide(Overall reactions are displayed. Show all >>)
Synonyms
deoxyhypusine synthase, dhs34, cpdhs, pf3d7_1412600, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
deoxyhypusine synthase (Caulobacter crescentus gene CC0359)
-
-
-
-
deoxyhypusine synthase (Halobacterium strain NRC-1 gene dhs)
-
-
-
-
deoxyhypusine synthase (human clone 30649 gene DHPS subunit reduced)
-
-
-
-
deoxyhypusine synthase (Nicotiana tabacum gene DHS1)
-
-
-
-
deoxyhypusine synthase (Senecio vernalis gene DHS1)
-
-
-
-
DHS
synthase, deoxyhypusine
-
-
-
-
DHS
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
aminobutyl group transfer
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
[eIF5A-precursor]-lysine:spermidine 4-aminobutyltransferase (propane-1,3-diamine-forming)
The eukaryotic initiation factor eIF5A contains a hypusine residue that is essential for activity. This enzyme catalyses the first reaction of hypusine formation from one specific lysine residue of the eIF5A precursor. The reaction occurs in four steps: NAD+-dependent dehydrogenation of spermidine (1a), formation of an enzyme-imine intermediate by transfer of the 4-aminobutylidene group from dehydrospermidine to the active site lysine residue (Lys329 for the human enzyme; 1b), transfer of the same 4-aminobutylidene group from the enzyme intermediate to the e1F5A precursor (1c), reduction of the e1F5A-imine intermediate to form a deoxyhypusine residue (1d). Hence the overall reaction is transfer of a 4-aminobutyl group. For the plant enzyme, homospermidine can substitute for spermidine and putrescine can substitute for the lysine residue of the eIF5A precursor. Hypusine is formed from deoxyhypusine by the action of EC 1.14.99.29, deoxyhypusine monooxygenase.
CAS REGISTRY NUMBER
COMMENTARY
127069-31-2
deoxyhypusine synthase
171041-87-5
human clone 30649 gene DHPS subunit reduced
253180-41-5
Nicotiana tabacum gene DHS1
259168-76-8
Senecio vernalis gene DHS1
302492-11-1
Halobacterium strain NRC-1 gene dhs
332963-67-4
Caulobacter crescentus gene CC0359
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
[eIF5A-precursor]-L-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
1-ethylspermidine + [eIF5A-precursor]-lysine
[eIF5A-precursor]-deoxyhypusine + ?
-
-
-
?
1-methylspermidine + [eIF5A-precursor]-lysine
[eIF5A-precursor]-deoxyhypusine + ?
-
-
-
?
8-ethylspermidine + [eIF5A-precursor]-lysine
[eIF5A-precursor]-ethyldeoxyhypusine + ?
-
-
-
?
8-methylspermidine + [eIF5A-precursor]-lysine
[eIF5A-precursor]-methyldeoxyhypusine + ?
-
-
-
?
aminopropylcadaverine + [eIF5A-precursor]-lysine
[eIF5A-precursor]-homodeoxyhypusine + ?
-
-
-
?
homospermidine + [eIF5A-precursor]-lysine
[eIF5A-precursor]-deoxyhypusine + ?
-
-
-
?
N-(3-aminopropyl)-1,4-diamino-cis-but-2-ene + putrescine
(1Z)-N4-(4-aminobutyl)but-1-ene-1,4-diamine + 1,3-diaminopropane
-
-
-
?
N-(3-aminopropyl)-1,4-diamino-cis-but-2-ene + [eIF5A-precursor]-lysine
?
-
-
-
?
N-(3-aminopropyl)-1,4-diamino-trans-but-2-ene + putrescine
(1E)-N4-(4-aminobutyl)but-1-ene-1,4-diamine + 1,3-diaminopropane
-
-
-
?
N-(3-aminopropyl)-1,4-diamino-trans-but-2-ene + [eIF5A-precursor]-lysine
?
-
-
-
?
[eIF5A-1-precursor]-lysine + spermidine
[eIF5A-1-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
-
-
?
[eIF5A-2-precursor]-lysine + spermidine
[eIF5A-2-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
[eIF5A-precursor]-lysine + (R)-3-methylspermidine
?
enzyme DHS prefers the (R)- over the (S)-enantiomer as a substrate
-
-
?
[eIF5A-precursor]-lysine + (R)-3-methylspermidine
?
no activity with the (S)-enantiomer
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
i.e. [eIF5A-precursor]-N6-(4-aminobutyl)lysine
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
first step in the biosynthesis of hypusine
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
overall reaction
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
formation of [N(epsilon)-(4-amino-2-hydroxybutyl)lysine]
-
-
?
[eIF5A-precursor]-lysine + 2-methylspermidine
?
-
the S-enantiomer of 2-MeSpd, which supports long-term growth, is a good substrate for DHS in vitro, whereas the R isomer is not
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
-
-
ir
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
i.e. [eIF5A-precursor]-N6-(4-aminobutyl)lysine
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
i.e. [eIF5A-precursor]-N6-(4-aminobutyl)lysine
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
i.e. [eIF5A-precursor]-N6-(4-aminobutyl)lysine
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
i.e. [eIF5A-precursor]-N6-(4-aminobutyl)lysine
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
i.e. [eIF5A-precursor]-N6-(4-aminobutyl)lysine
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
i.e. [eIF5A-precursor]-N6-(4-aminobutyl)lysine
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
i.e. [eIF5A-precursor]-N6-(4-aminobutyl)lysine
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
i.e. [eIF5A-precursor]-N6-(4-aminobutyl)lysine
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
i.e. [eIF5A-precursor]-N6-(4-aminobutyl)lysine
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
i.e. [eIF5A-precursor]-N6-(4-aminobutyl)lysine
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
reversal of reaction in presence of NAD+
i.e. [eIF5A-precursor]-N6-(4-aminobutyl)lysine
r
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
first step in the biosynthesis of hypusine
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
posttranslational activation of eIF-5A which has a specialized role in proliferation and in serum starvation-induced apoptosis in endothelial cells
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
bovine enzyme is approximately 26times as effective as the human enzyme in catalyzing the reaction
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
DHS catalyzes a NAD-dependent cleavage between N4 and C5 of spermidine and the transfer of the butylamine moiety to the ?-amino group of a specific lysine residue of the eIF5A precursor, eIF5A(Lys), to form the deoxyhypusine residue. The enzyme is modification is strictly specific for one single lysine residue of the cellular protein eukaryotic initiation factor 5A (eIF5A) and does not work on short peptides
1,3-diaminopropane is released as a byproduct from spermidine cleavage
-
?
additional information
?
-
(R)-3-methylspermidine competes with spermidine for cellular uptake less efficiently than the (S)-3-methylspermidine
-
-
?
additional information
?
-
(R)-3-methylspermidine competes with spermidine for cellular uptake less efficiently than the (S)-3-methylspermidine
-
-
?
additional information
?
-
-
as racemic mixtures, only 2-MeSpd and 3-MeSpd support long-term growth (9-18 days) of spermidine-depleted DU-145 cells, whereas gamma-MeSpd and omega-MeSpd do not
-
-
?
additional information
?
-
-
development of a radioactive assay method for detection of spermidine incorporation into eIF5A, overview
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
additional information
?
-
-
as racemic mixtures, only 2-MeSpd and 3-MeSpd support long-term growth (9-18 days) of spermidine-depleted DU-145 cells, whereas gamma-MeSpd and omega-MeSpd do not
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
first step in the biosynthesis of hypusine
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
-
-
-
ir
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
first step in the biosynthesis of hypusine
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
-
posttranslational activation of eIF-5A which has a specialized role in proliferation and in serum starvation-induced apoptosis in endothelial cells
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
NADH
there is a measurable release of enzyme-bound NADH in the absence of eIF5A precursor. The NADH:DHS ratio is around 6
NAD+
-
one enzyme tetramer can bind up to four each of NAD+ and spermidine, the binding of spermidine being dependent on NAD+
NAD+
-
the NADH generated in the first step of the reaction remains enzyme-associated during the reaction and the hydride ion generated by the oxidation of spermidine is preserved for the reduction of the eIF5A-imine intermediate
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
6-bromo-N-(1H-indol-4-yl)-1-benzothiophene-2-carboxamide
the 6'-bromo substituent is necessary for binding to DHPS
N''-guanyl-1,7-diaminoheptane
i.e. GC7, almost complete inhibition at 20 microM in both one-step and two-step assays
1,7-Diaminoheptane
-
inhibits generation of spermidine from [eIF5A-precursor]-deoxyhypusine
1-amino-7-guanidinoheptane
-
competitive, inhibits binding of spermidine to the enzyme
GC7
-
a specific DHS-inhibitor, inhibits DHS by competitive replacement of its native spermidine substrate. Inhibition of DHS by GC7 induces antiproliferative effects in vitro. The compound shows a strong antiproliferative effect in glioblastoma cell lines in vitro, while normal human astrocytes are not affected, and it causes p53 dependent premature senescence, a permanent cell cycle arrestin U-MG 87 cells
N,N'-bis[3,5-bis[1(aminoiminomethyl)-hydrazoethyl]phenyl]decanediamide-tetrahydrochloride
-
i.e. CNI-1493
N,N'-bis[3,5-bis[1(aminoiminomethyl)-hydrazoethyl]phenyl]dodecanediamide-tetrahydrochloride
-
i.e. DHSI-15
N1-ethylspermidine
-
inhibits generation of spermidine from [eIF5A-precursor]-deoxyhypusine
N1-methylspermidine
-
inhibits generation of spermidine from [eIF5A-precursor]-deoxyhypusine
spermidine
-
inhibits generation of spermidine from [eIF5A-precursor]-deoxyhypusine
additional information
no growth inhibition by alpha-difluoromethylornithine, an inhibitor of polyamine biosynthesis, and (R)-3-methylspermidine, while the the combination of alpha-difluoromethylornithine with a racemate or (S)-3-methylspermidine causes cessation of cell growth. Cells treated with racemic 3-MeSpd accumulat intracellularly mainly (S)-3-methylspermidine, but not DHS substrate (R)-3-methylspermidine, explaining the inability of the racemate to support long-term growth
-
N1-guanyl-1,7-diaminoheptane
-
inhibits generation of spermidine from [eIF5A-precursor]-deoxyhypusine
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.141
(R)-3-methylspermidine
pH and temperature not specified in the publication
0.019
(S)-3-methylspermidine
pH and temperature not specified in the publication
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
-
DHS is ubiquitously expressed in CD34+ cellss from patients with chronic myeloid leukemia and acute myeloid leukemia
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
DHS enzyme inhibition by N1-guanyl-1,7-diaminoheptane results in a significant decrease in tumor formation in vivo. In patients with esophageal squamous cell carcinoma, overexpression of gene DHPS in ESCC tumors is significantly associated with worse recurrence-free survival, and correlated with distant metastasis. Although the mRNA levels of RhoA in DHPS-knockdown cells do not change, RhoA protein levels significantly decrease compared with control
physiological function
malfunction
-
inhibition of DHS by GC7 induces antiproliferative effects in vitro. GC7 treatment induces premature senescence in U87-MG cells, co-treatment of glioblastoma cells with TMZ/BCNU and GC7 has an additive antiproliferative effect
metabolism
-
deoxyhypusine synthase catalyzes a step in hypusine sythesis, a unique mmoified lysine derivative of eukaryotic translation initiation factor 5A, eIF5A
physiological function
additional information
physiological function
hypusine is formed from spermidine, a metabolite of polyamine metabolism, by the sequential action of two catalytic enzymes, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). These enzymes have an important role in post-translational modification of eukaryotic translation factor 5A (eIF5A), which functions in protein synthesis. The hypusine cascade contributes to cell proliferation and embryogenesis by the regulation of translation elongation in healthy cells. DHPS-mediated hypusine-modification of eukaryotic translation factor 5A facilitates the translation of RhoA, resulting in the activation of the RhoA signaling pathway and leading to not only increased cell motility, invasion and metastasis of cancer cells in vitro, but also increased tumor growth in vivo. DHPS regulates the expression and activation of RhoA, DHPS may regulate the organization of F-actin through the increase in RhoA protein level. Hypusinated eIF5A may regulate tumor growth and metastasis via the RhoA signaling pathway
physiological function
the eukaryotic translation initiation factor 5A (eIF5A) is essential for cell proliferation, becoming functionally active only after post-translational conversion of a specific Lys to hypusine catalyzed by deoxyhypusine synthase, the rate-limiting enzyme of this two-step process
physiological function
-
deoxyhypusine synthase catalyzes the synthesis of deoxyhypusine [N?-(4-aminobutyl)-lysine], the first step in the post-translational synthesis of an unusual amino acid hypusine [N?-(4-amino-2-hydroxybutyl)-lysine]
physiological function
-
eukaryotic translation initiation factor 5A, eIF5A, is a small acidic protein and the only cellular protein that contains the unique modified lysine, hypusine [N1-(4-amino-2-hydroxybutyl)lysine]. Hypusine is formed by the post-translational modification of one specific lysine residue of the eIF5A precursor, eIF5A(Lys), in two consecutive enzymatic steps. The first enzyme, deoxyhypusine synthase, DHS, catalyzes the transfer of the aminobutyl moiety from the polyamine spermidine to form an intermediate, deoxyhypusine [N1-(4-aminobutyl)lysine] residue, which is subsequently hydroxylated by deoxyhypusine hydroxylase
physiological function
-
hypusine modification is an irreversible protein modification and naturally occurring eIF5A exists predominantly as the hypusinated form. Deoxyhypusine synthase catalyzes the transfer of the aminobutyl moiety from spermidine to a specific lysine of the eIF5A precursor to form the deoxyhypusine [N?-(4-aminobutyl)lysine] intermediate. Hypusine is formed from deoxyhypusine by the action of EC 1.14.99.29, deoxyhypusine monooxygenase
additional information
the inability of racemic 3-methylspermidine and (S)-3-methylspermidine to support DU-145 cells growth due to the fact that only the (R)-isomer is a substrate of DHS, but this isomer, (R)-3-methylspermidine, competes with spermidine for cellular uptake and is less efficient than the (S)-3-methylspermidine, which results in accumulation of inactive (S)-3-methylspermidine in the cell. Synthesis of (S)-3-methylspermidine and (R)-3-methylspermidine, overview
additional information
-
inhibition of eIF5A by siRNA or DHS-inhibitors in combination with Imatinib exerts synergistic cytotoxic effects on BCR-ABL positive cell lines
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). DHYS_HUMAN
369
0
40971
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
tetramer
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
at 2.2 A a new form II crystal of the deoxyhypusine synthase:NAD holoenzyme is grown at low ionic strength and pH 8.0, near the optimal pH for enzymatic activity
in complex with inhibitors 6-bromo-N-(1H-indol-4-yl)-1-benzothiophene-2-carboxamide and N''-guanyl-1,7-diaminoheptane. Presence of 6-bromo-N-(1H-indol-4-yl)-1-benzothiophene-2-carboxamide induces a dramatic conformational change in DHPS
structures of the apoprotein, as well as ligand-bound states at 1.41 to 1.69 A resolution. Polyamines namely spermine and putrescine bind DHS in a similar manner as spermidine. Spermine may to some extent serve as an alternative DHS substrate. No conformational changes occur in the DHS structure upon spermidine binding. A conserved ball-and-chain motif is indispensable to assembling a functional DHS tetramer
vapor diffusion in hanging drops, crystal structure of the enzyme-NAD complex at 2.2 A resolution
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
N173S
recurrent missense variant identified with likely gene disrupting variant (c.1014+1G>A, c.912_917delTTACAT [p.Tyr305_Ile306del]), or c.1A>G [p.Met1] in unrelated individuals having similar neurodevelopmental features that include global developmental delay and seizures. Two of four affected females have short stature. The c.1014+1G>A variant causes aberrant splicing. Recombinant p.Asn173Ser or p.Tyr305_Ile306del protein show reduced (20%) or absent in vitro activity, respectively. The p.Tyr305_Ile306del and p.Asn173Ser variants result in reduced hypusination of eIF5A compared to wild-type DHPS enzyme
H288A
additional information
additional information
variant recombinant proteins with i. a truncation of 48 or 97 NH2-terminal amino acids, ii. A truncation of 39 COOH-terminal amino acids, or iii. An internal deletion (ASp262-Ser317) are inactive. A chimeric protein consisting of the complete human sequence and 16 amino acids of the yeast sequence, Gln197-Asn212, not present in the human enzyme, inserted between Glu193 and Gln194 exhibit moderate activity
additional information
-
variant recombinant proteins with i. a truncation of 48 or 97 NH2-terminal amino acids, ii. A truncation of 39 COOH-terminal amino acids, or iii. An internal deletion (ASp262-Ser317) are inactive. A chimeric protein consisting of the complete human sequence and 16 amino acids of the yeast sequence, Gln197-Asn212, not present in the human enzyme, inserted between Glu193 and Gln194 exhibit moderate activity
additional information
DHPS gene silencing by transfection of DHPS-specific short hairpin RNA (shRNA) in LM-pGL4.5 cells
additional information
-
DHPS gene silencing by transfection of DHPS-specific short hairpin RNA (shRNA) in LM-pGL4.5 cells
additional information
during purification and crystallization, residue C177 is is covalently modified to a 2-mercaptoethanol adduct
additional information
-
during purification and crystallization, residue C177 is is covalently modified to a 2-mercaptoethanol adduct
additional information
-
DHS knock-down by stable lentiviral expression of shRNAs in G55T2 and U87-MG cells
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli, the deduced amino acid sequence shows a high degree of identity to that of yeast enzyme and to the known sequences of tryptic peptides from the rat and Neurospora enzymes
gene DHPS, DHPS is a metastasis-associated gene within the specific amplification at chromosome 19p13.2p13.13 in HOC313-LM cells, quantitative RT-PCR expressionanalysis
DHS DNA and amino acid seuence determination and analysis, functional coexpression with human deoxyhypusine hydroxylase and human eukaryotic translation initiation factor 5A in Escherichia coli strain BL21(DE3)pLys that produces eIF5A(Hpu), overview
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
analysis
DHS activity can be determined by coupling the first phase reaction with the NADH-Glo assay in which the generation of luminescence is dependent on NADH derived from the DHS partial reaction. The non-radioactive DHS/NADH-Glo coupled assay is highly specific, sensitive and reproducible and can be configured for high throughput screening of small molecule libraries
medicine
medicine
elevated mRNA levels of the target enzymes deoxyhypusine synthase (DHPS) and ornithine decarboxylase (ODC) correlate with poor prognosis in a large cohort of neuroblastoma tumors. The DHPS inhibitor GC7 (N1-guanyl-1,7-diaminoheptane) and the ODC inhibitor alpha-difluoromethylornithine (DFMO) are target-specific and in combination induce synergistic effects in neuroblastomas at concentrations that are not individually cytotoxic. The drug combination induces caspase 3/7/9, but not caspase 8-mediated apoptosis, in neuroblastoma cells. Hypusinated eIF5A levels and intracellular spermidine levels correlate directly with drug treatments
medicine
recurrent missense variant p.Asn173Ser is identified with likely gene disrupting variant (c.1014+1G>A, c.912_917delTTACAT [p.Tyr305_Ile306del]), or c.1A>G [p.Met1?] in unrelated individuals having similar neurodevelopmental features that include global developmental delay and seizures. Two of four affected females have short stature. The c.1014+1G>A variant causes aberrant splicing. Recombinant p.Asn173Ser or p.Tyr305_Ile306del protein show reduced (20%) or absent in vitro activity, respectively. The p.Tyr305_Ile306del and p.Asn173Ser variants result in reduced hypusination of eIF5A compared to wild-type DHPS enzyme
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Wolff, E.C.; Folk, J.E.; Park, M.H.
Enzyme-substrate intermediate formation at lysine 329 of human deoxyhypusine synthase
J. Biol. Chem.
272
15865-15871
1997
Homo sapiens
Chen, K.Y.; Liu, A.Y.C.
Biochemistry and function of hypusine formation on eukaryotic initiation factor 5A
Biol. Signals
6
105-109
1997
Homo sapiens, Neurospora crassa
Wolff, E.C.; Wolff.J.; Park, M.H.
Deoxyhypusine synthase generates and uses bound NADH in a transient hydride transfer mechanism
J. Biol. Chem.
275
9170-9177
2000
Homo sapiens
Joe, Y.A.; Wolff, E.C.; Park, M.H.
Cloning and expression of human deoxyhypusine synthase cDNA: structure-function studies with the recombinant enzyme and mutant proteins
J. Biol. Chem.
270
22386-22392
1995
Homo sapiens (P49366), Homo sapiens
Lee, C.H.; Um, P.Y.; Park, M.H.
Structure-function studies of human deoxyhypusine synthase: identification of amino acid residues critical for the binding of spermidine and NAD
Biochem. J.
355
841-849
2001
Homo sapiens
Lee, C.H.; Park, M.H.
Human deoxyhypusine synthase: interrelationship between binding of NAD and substrates
Biochem. J.
352
851-857
2000
Homo sapiens
-
Lee, Y.B.; Joe, Y.A.; Wolff, E.C.; Dimitriadis, E.K.; Park, M.H.
Complex formation between deoxyhypusine synthase and its protein substrate, the eukaryotic translation initiation factor 5A (eIF5A) precursor
Biochem. J.
340
273-281
1999
Homo sapiens
-
Liao, D.I.; Wolff, E.C.; Park, M.H.; Davies, D.R.
Crystal structure of the NAD complex of human deoxyhypusine synthase: an enzyme with a ball-and-chain mechanism for blocking the active site
Structure
6(1)
23-32
1998
Homo sapiens
-
Joe, Y.A.; Wolff, E.C.; Lee, Y.B.; Park, M.H.
Enzyme-substrate intermediate at a specific lysine residue is required for deoxyhypusine synthesis. The role of Lys329 in human deoxyhypusine synthase
J. Biol. Chem.
272
32679-32685
1997
Homo sapiens
Klier, H.; Csonga, R.; Steinkasserer, A.; Woehl, T.; Lottspeich, F.; Eder, J.
Purification and characterization of human deoxyhypusine synthase from HeLa cells
FEBS Lett.
364
207-210
1995
Homo sapiens
Kang, K.R.; Kim, J.S.; Chang, S.II; Park, M.H.; Kim, Y.W.; Lim, D.; Lee, S.Y.
Deoxyhypusine synthase is phosphorylated by protein kinase C in vivo as well as in vitro
Exp. Mol. Med.
34
489-495
2002
Cricetulus griseus, Gallus gallus, Homo sapiens, Saccharomyces cerevisiae
Lee, Y.; Kim, H.K.; Park, H.E.
Park, M.H.; Joe, Y.A.: Effect of N1-guanyl-1,7-diaminoheptane, an inhibitor of deoxyhypusine synthase, on endothelial cell growth, differentiation and apoptosis
Mol. Cell. Biochem.
237
69-76
2002
Homo sapiens
Park, J.H.; Wolff, E.C.; Folk, E.C.; Park, M.H.
Reversal of the deoxyhypusine synthesis reaction. Generation of spermidine or homospermidine from deoxyhypusine by deoxyhypusine synthase
J. Biol. Chem.
278
32683-32691
2003
Homo sapiens
Clement, P.M.; Henderson, C.A.; Jenkins, Z.A.; Smit-McBride, Z.; Wolff, E.C.; Hershey, J.W.; Park, M.H.; Johansson, H.E.
Identification and characterization of eukaryotic initiation factor 5A-2
Eur. J. Biochem.
270
4254-4263
2003
Homo sapiens
Umland, T.C.; Wolff, E.C.; Park, M.H.; Davies, D.R.
A new crystal structure of deoxyhypusine synthase reveals the configuration of the active enzyme and of an enzyme-NAD-inhibitor ternary complex
J. Biol. Chem.
279
28697-28705
2004
Homo sapiens (P49366), Homo sapiens
Huang, J.K.; Tsai, S.; Huang, G.H.; Gowda, P.G.; Walzer, A.M.; Wen, L.
Higher activity of recombinant bovine deoxyhypusine synthase vs. human deoxyhypusine synthase
Protein Expr. Purif.
35
32-38
2004
Bos taurus (Q6EWQ6), Bos taurus, Homo sapiens
Park, J.; Dias, C.; Lee, S.; Valentini, S.; Sokabe, M.; Fraser, C.; Park, M.
Production of active recombinant eIF5A: Reconstitution in E. coli of eukaryotic hypusine modification of eIF5A by its coexpression with modifying enzymes
Protein Eng. Des. Sel.
24
301-309
2011
Homo sapiens
Hyvoenen, M.T.; Keinaenen, T.A.; Khomutov, M.; Simonian, A.; Vepsaelaeinen, J.; Park, J.H.; Khomutov, A.R.; Alhonen, L.; Park, M.H.
Effects of novel C-methylated spermidine analogs on cell growth via hypusination of eukaryotic translation initiation factor 5A
Amino Acids
42
685-695
2012
Homo sapiens
Ziegler, P.; Chahoud, T.; Wilhelm, T.; Paellman, N.; Braig, M.; Wiehle, V.; Ziegler, S.; Schroeder, M.; Meier, C.; Kolodzik, A.; Rarey, M.; Panse, J.; Hauber, J.; Balabanov, S.; Bruemmendorf, T.H.
Evaluation of deoxyhypusine synthase inhibitors targeting BCR-ABL positive leukemias
Invest. New Drugs
30
2274-2283
2012
Homo sapiens, Mus musculus
Wolff, E.C.; Lee, S.B.; Park, M.H.
Assay of deoxyhypusine synthase activity
Methods Mol. Biol.
720
195-205
2011
Homo sapiens
Preukschas, M.; Hagel, C.; Schulte, A.; Weber, K.; Lamszus, K.; Sievert, H.; Paellmann, N.; Bokemeyer, C.; Hauber, J.; Braig, M.; Balabanov, S.
Expression of eukaryotic initiation factor 5A and hypusine forming enzymes in glioblastoma patient samples: implications for new targeted therapies
PLoS ONE
7
e43468
2012
Homo sapiens
Hyvoenen, M.T.; Khomutov, M.; Petit, M.; Weisell, J.; Kochetkov, S.N.; Alhonen, L.; Vepsaelaeinen, J.; Khomutov, A.R.; Keinaenen, T.A.
Enantiomers of 3-methylspermidine selectively modulate deoxyhypusine synthesis and reveal important determinants for spermidine transport
ACS Chem. Biol.
10
1417-1424
2015
Homo sapiens (P49366)
Muramatsu, T.; Kozaki, K.I.; Imoto, S.; Yamaguchi, R.; Tsuda, H.; Kawano, T.; Fujiwara, N.; Morishita, M.; Miyano, S.; Inazawa, J.
The hypusine cascade promotes cancer progression and metastasis through the regulation of RhoA in squamous cell carcinoma
Oncogene
35
5304-5316
2016
Homo sapiens (P49366), Homo sapiens
Khomutov, M.; Keinanen, T.; Hyvonen, M.; Weisell, J.; Vepsalainen, J.; Alhonen, L.; Kochetkov, S.; Khomutov, A.
Enantioselective synthesis of (R)- and (S)-3-methylspermidines
Russ. J. Bioorg. Chem.
41
548-553
2015
Homo sapiens (P49366)
-
Ganapathi, M.; Padgett, L.R.; Yamada, K.; Devinsky, O.; Willaert, R.; Person, R.; Au, P.B.; Tagoe, J.; McDonald, M.; Karlowicz, D.; Wolf, B.; Lee, J.; Shen, Y.; Okur, V.; Deng, L.; LeDuc, C.A.; Wang, J.; Hanner, A.; Mirmira, R.G.; Park, M.H.; Mastracci, T.L.; Chung, W.K.
Recessive rare variants in deoxyhypusine synthase, an enzyme involved in the synthesis of hypusine, are associated with a neurodevelopmental disorder
Am. J. Hum. Genet.
104
287-298
2019
Homo sapiens (P49366)
Park, M.H.; Mandal, A.; Mandal, S.; Wolff, E.C.
A new non-radioactive deoxyhypusine synthase assay adaptable to high throughput screening
Amino Acids
49
1793-1804
2017
Homo sapiens (P49366), Homo sapiens
Schultz, C.R.; Geerts, D.; Mooney, M.; El-Khawaja, R.; Koster, J.; Bachmann, A.S.
Synergistic drug combination GC7/DFMO suppresses hypusine/spermidine-dependent eIF5A activation and induces apoptotic cell death in neuroblastoma
Biochem. J.
475
531-545
2018
Homo sapiens (P49366)
Wator, E.; Wilk, P.; Grudnik, P.
Half way to hypusine-structural basis for substrate recognition by human deoxyhypusine synthase
Biomolecules
10
522
2020
Homo sapiens (P49366), Homo sapiens
Tanaka, Y.; Kurasawa, O.; Yokota, A.; Klein, M.G.; Ono, K.; Saito, B.; Matsumoto, S.; Okaniwa, M.; Ambrus-Aikelin, G.; Morishita, D.; Kitazawa, S.; Uchiyama, N.; Ogawa, K.; Kimura, H.; Imamura, S.
Discovery of novel allosteric inhibitors of deoxyhypusine synthase
J. Med. Chem.
63
3215-3226
2020
Homo sapiens (P49366)
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