Information on EC 2.5.1.46 - deoxyhypusine synthase

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
2.5.1.46
-
RECOMMENDED NAME
GeneOntology No.
deoxyhypusine synthase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
dehydrospermidine + [enzyme]-lysine = N-(4-aminobutylidene)-[enzyme]-lysine + propane-1,3-diamine
show the reaction diagram
(1b)
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-
-
N-(4-aminobutylidene)-[eIF5A-precursor]-lysine + NADH + H+ = [eIF5A-precursor]-deoxyhypusine + NAD+
show the reaction diagram
(1d)
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-
-
N-(4-aminobutylidene)-[enzyme]-lysine + [eIF5A-precursor]-lysine = N-(4-aminobutylidene)-[eIF5A-precursor]-lysine + [enzyme]-lysine
show the reaction diagram
(1c)
-
-
-
spermidine + NAD+ = dehydrospermidine + NADH
show the reaction diagram
(1a)
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-
[eIF5A-precursor]-lysine + spermidine = [eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
show the reaction diagram
first reaction; 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 second reaction being catalysed by EC 1.14.99.29, deoxyhypusine monooxygenase. The reaction of this enzyme occurs in four steps: i. NAD-dependent dehydrogenation of spermidine, ii. 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, iii. transfer of the same 4-aminobutylidene group from the enzyme intermediate to the eIF5A precursor, iv. reduction of the eIF5A-imine intermediate to form a deoxyhypusine residue. 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
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-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
aminobutyl group transfer
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-
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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 hide
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
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
ecotype Columbia
-
-
Manually annotated by BRENDA team
cv. Westar
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-
Manually annotated by BRENDA team
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-
-
Manually annotated by BRENDA team
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-
Manually annotated by BRENDA team
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Manually annotated by BRENDA team
DHS34; DHSL20 is a DHS-like gene from chromosome 20 and DHS34, a DHS gene from chromosome 34
SwissProt
Manually annotated by BRENDA team
gene Dhps
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-
Manually annotated by BRENDA team
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Manually annotated by BRENDA team
strain KCY307
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-
Manually annotated by BRENDA team
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SwissProt
Manually annotated by BRENDA team
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-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
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
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
1-ethylspermidine + putrescine
homospermidine + ?
show the reaction diagram
-
-
-
?
1-ethylspermidine + [eIF5A-precursor]-lysine
[eIF5A-precursor]-deoxyhypusine + ?
show the reaction diagram
-
-
-
?
1-methylspermidine + putrescine
homospermidine + ?
show the reaction diagram
-
-
-
?
1-methylspermidine + [eIF5A-precursor]-lysine
[eIF5A-precursor]-deoxyhypusine + ?
show the reaction diagram
-
-
-
?
8-ethylspermidine + putrescine
ethylhomospermidine + ?
show the reaction diagram
-
-
-
?
8-ethylspermidine + [eIF5A-precursor]-lysine
[eIF5A-precursor]-ethyldeoxyhypusine + ?
show the reaction diagram
-
-
-
?
8-methylspermidine + putrescine
methylhomospermidine + ?
show the reaction diagram
-
-
-
?
8-methylspermidine + [eIF5A-precursor]-lysine
[eIF5A-precursor]-methyldeoxyhypusine + ?
show the reaction diagram
-
-
-
?
aminopropylcadaverine + [eIF5A-precursor]-lysine
[eIF5A-precursor]-homodeoxyhypusine + ?
show the reaction diagram
-
-
-
?
caldine + putrescine
spermidine + ?
show the reaction diagram
-
-
-
?
homospermidine + putrescine
homospermidine + ?
show the reaction diagram
homospermidine + [eIF5A-precursor]-lysine
[eIF5A-precursor]-deoxyhypusine + ?
show the reaction diagram
-
-
-
?
N-(3-aminopropyl)-1,4-diamino-cis-but-2-ene + putrescine
(1Z)-N4-(4-aminobutyl)but-1-ene-1,4-diamine + 1,3-diaminopropane
show the reaction diagram
-
-
-
?
N-(3-aminopropyl)-1,4-diamino-cis-but-2-ene + [eIF5A-precursor]-lysine
?
show the reaction diagram
-
-
-
?
N-(3-aminopropyl)-1,4-diamino-trans-but-2-ene + putrescine
(1E)-N4-(4-aminobutyl)but-1-ene-1,4-diamine + 1,3-diaminopropane
show the reaction diagram
-
-
-
?
N-(3-aminopropyl)-1,4-diamino-trans-but-2-ene + [eIF5A-precursor]-lysine
?
show the reaction diagram
-
-
-
?
spermidine
1,3-diaminopropane + DELTA1-pyrroline
show the reaction diagram
spermidine + putrescine
homospermidine + ?
show the reaction diagram
[eIF5A-1-precursor]-lysine + spermidine
[eIF5A-1-precursor]-deoxyhypusine + propane-1,3-diamine
show the reaction diagram
[eIF5A-2-precursor]-lysine + spermidine
[eIF5A-2-precursor]-deoxyhypusine + propane-1,3-diamine
show the reaction diagram
-
-
-
-
?
[eIF5A-precursor] + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
show the reaction diagram
[eIF5A-precursor]-lysine + 2-methylspermidine
?
show the reaction diagram
[eIF5A-precursor]-lysine + 3-methylspermidine
?
show the reaction diagram
-
-
-
-
?
[eIF5A-precursor]-lysine + 4-methylspermidine
?
show the reaction diagram
-
-
-
-
?
[eIF5A-precursor]-lysine + homospermidine
[eIF5A-precursor]-deoxyhypusine + putrescine
show the reaction diagram
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
[eIF5A-precursor]-lysine + 2-methylspermidine
?
show the reaction diagram
-
-
-
-
?
[eIF5A-precursor]-lysine + 3-methylspermidine
?
show the reaction diagram
-
-
-
-
?
[eIF5A-precursor]-lysine + spermidine
[eIF5A-precursor]-deoxyhypusine + propane-1,3-diamine
show the reaction diagram
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1,3-Diaminopropane
1,7-Diaminoheptane
1,8-diaminooctane
1,9-diaminononane
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-
1-(3-aminopropyl)-4-aminomethylpiperidine
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1 mM, less than 50% inhibition
1-amino-7-guanidinoheptane
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competitive, inhibits binding of spermidine to the enzyme
1-aminooctane
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1 mM, less than 50% inhibition
1-methylspermidine
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0.184 mM, 50% inhibition
2-methylspermidine
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-
3-methylspermidine
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-
4-methylspermidine
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-
6,6'-difluorospermidine
6-fluorospermidine
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0.048 mM, 50% inhibition
7,7-Difluorospermidine
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1 mM, less than 50% inhibition
aminopropylcadaverine
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inhibition of deoxyhypusine synthesis
caldine
CNI-1493
deoxyspergualin
GC7
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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
guazatine
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-
hirudonine
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-
Homospermidine
-
inhibition of deoxyhypusine synthesis
N,N'-bis-benzyldiaminooctane
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1 mM, less than 50% inhibition
N,N'-bis[3,5-bis[1(aminoiminomethyl)-hydrazoethyl]phenyl]decanediamide-tetrahydrochloride
N,N'-bis[3,5-bis[1(aminoiminomethyl)-hydrazoethyl]phenyl]dodecanediamide-tetrahydrochloride
N-(2-cyanoethyl)-1,3-diaminopropane
-
1 mM, less than 50% inhibition
N-(3-aminopropyl)-1,3-diaminopropane
-
1 mM, less than 50% inhibition
N-(3-aminopropyl)-1,4-diamino-cis-but-2-ene
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N-(3-aminopropyl)-1,4-diamino-trans-but-2-ene
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-
N-(3-aminopropyl)-cadaverine
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-
N-(3-aminopropyl)-cis-1,4-diaminocyclohexane
-
1 mM, less than 50% inhibition
N-(3-aminopropyl)-N'-methylbutane-1,4-diamine
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-
N-(3-aminopropyl)-trans-1,4-diaminocyclohexane
-
1 mM, less than 50% inhibition
N-(3-cyanopropyl)-1,3-diaminopropane
-
1 mM, less than 50% inhibition
N-butyl-1,3-diaminopropane
-
1 mM, less than 50% inhibition
N-guanyl-1,7-diaminoheptane
shows only little inhibitory effect on the leishmanial recombinant DHS34
N1,N3-bis-guanyl-1,3-diaminopropane
-
1 mM, less than 50% inhibition
N1,N3-bis-tert-butyloxycarbonylspermidine
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1 mM, less than 50% inhibition
N1,N6-bis-guanyl-1,6-diaminohexane
-
-
N1,N7-bis-allylcaldine
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1 mM, less than 50% inhibition
N1,N7-bis-benzylcaldine
-
1 mM, less than 50% inhibition
N1,N7-bis-dimethylcaldine
-
1 mM, less than 50% inhibition
N1,N7-bis-guanyl-1,7-diaminoheptane
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-
N1,N7-bis-guanylcaldine
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N1,N8-bis-guanyl-1,8-diaminooctane
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N1-acetylspermidine
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1 mM, less than 50% inhibition
N1-ethylspermidine
N1-guanyl-1,3-diaminopropane
-
1 mM, less than 50% inhibition
N1-guanyl-1,7-diaminoheptane
N1-guanyl-1,8-diaminooctane
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-
N1-guanylcaldine
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-
N1-guanylspermine
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-
N1-methylspermidine
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inhibits generation of spermidine from [eIF5A-precursor]-deoxyhypusine
N3-ethylspermidine
-
1 mM, less than 50% inhibition
N4-(3-aminopropyl)-4-methylpentane-1,4-diamine
-
1 mM, less than 50% inhibition
N4-acetylspermidine
-
1 mM, less than 50% inhibition
N4-benzoylspermidine
-
1 mM, less than 50% inhibition
N4-benzylspermidine
-
1 mM, less than 50% inhibition
N4-bromoacetylspermidine
-
1 mM, less than 50% inhibition
N4-methylcaldine
-
1 mM, less than 50% inhibition
putrescine
-
1 mM, less than 50% inhibition
spermidine
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0954 - 0.1058
1,3-Diaminopropane
0.00177
eIF5A
-
-
0.00008 - 1.12
eIF5A-precursor
-
0.0193
homospermine
-
-
-
0.0048 - 0.81
NAD+
0.0015 - 0.203
putrescine
0.001 - 0.028
spermidine
0.0015
[eIF5A-1-precursor]-lysine
-
pH 9.5, 37C
0.0083
[eIF5A-2-precursor]-lysine
-
pH 9.5, 37C
0.0066 - 0.0086
[eIF5A-precursor]-deoxyhypusine
0.00177
[eIF5A-precursor]-lysine
pH 9.2, 37C, recombinant DHS34
additional information
additional information
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0022
eIF5A-precursor
Senecio vernalis
-
+ spermidine
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0129
1,3-Diaminopropane
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-
0.0009
1,7-Diaminoheptane
-
-
0.00191
1,8-diaminooctane
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-
0.00752
1,9-diaminononane
-
-
0.012
guazatine
-
-
0.00489
hirudonine
-
-
0.035
N1,N6-bis-guanyl-1,6-diaminohexane
-
-
0.0017
N1,N7-bis-guanyl-1,7-diaminoheptane
-
-
0.1545
N1,N7-bis-guanylcaldine
-
-
0.00565
N1,N8-bis-guanyl-1,8-diaminooctane
-
-
0.0000097 - 0.01
N1-guanyl-1,7-diaminoheptane
0.00024
N1-guanyl-1,8-diaminooctane
-
-
0.00074
N1-guanylcaldine
-
-
0.00033
N1-guanylspermine
-
-
0.00649
spermidine
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-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.0000096
low specific activity of DHS34 could be due to the fact that one of the NAD+ binding regions in the DHS34 is present in the big long insertion when compared with human deoxyhypusine synthase
0.000137
-
-
0.00325
-
-
0.0034
with donor homospermidine
0.0091
with donor homospermidine
0.0101
-
with acceptor eIF5A-prcursor
0.0211
with donor spermidine
0.0442
-
with acceptor putrescine
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
9 - 9.5
-
optimum for spermidine-binding
9.3
-
glycine-NaOH buffer
9.5
-
assay at
9.5 - 9.6
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-
9.6
assay at; assay at
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
8.5 - 11
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pH 8.5: about 45% of maximal activity, pH 11.0: about 50% of maximal activity
8.8 - 9.9
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pH 8.8: about 35% of maximal activity, pH 9.9: about 60% of maximal activity
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
20 - 37
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20C: about 75% of maximal activity, 37C: about 25% of maximal activity
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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DHS is ubiquitously expressed in primary mouse cells and murine cell lines
Manually annotated by BRENDA team
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young or old, low level
Manually annotated by BRENDA team
additional information
-
DHS is ubiquitously expressed in CD34+ cellss from patients with chronic myeloid leukemia and acute myeloid leukemia
Manually annotated by BRENDA team
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
41000
-
SDS-PAGE
42000
predicted from cDNA
48000
-
SDS-PAGE
66000
predicted from cDNA
137000
gel filtration; recombinant DHS34, gel filtration
144000 - 180000
-
gel filtration, sedimentation equilibrium centrifugation
150000
-
gel filtration
165000 - 172000
-
gel filtration sedimentation equilibrium centrifugation
180000 - 190000
-
gel filtration
180000
gel filtration
190000
gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
tetramer
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
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
vapor diffusion in hanging drops, crystal structure of the enzyme-NAD complex at 2.2 A resolution
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TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
4
-
1 h, 35% loss of activity, NAD+ protects
65
-
15 min, almost complete loss of activity, NAD+ protects
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
freeze-thawing of the partially purified enzyme inactivates, no stabilization by glycerol
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
; recombinant enzyme
recombinant enzyme
-
recombinant His-tagged DHSL20 and DHS34 from Escherichia coli by metal affinity chromatography; using Ni-NTA chromatography; using Ni-NTA chromatography
using Ni-NTA chromatography
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
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
-
DHS gene, DNA and amino acid sequence determination and analysis
DHSL20 is a DHS-like gene from chromosome 20 and DHS34, a DHS gene from chromosome 34, DNA and amino acid sequence determination and analysis, sequence comparisons and phylogenetic analysis, expression of His-tagged DHSL20 and DHS34 in Escherichia coli; expressed in Escherichia coli as a His-tagged fusion protein; expressed in Escherichia coli as a His-tagged fusion protein
expressed as a C-terminal his-tagged fusion protein
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
subcloning of bovine and human DHS gene, overexpression in Escherichia coli
transgenic canola lines with suppressed DHS expression were obtained by introducing a transgene expressing antisense 3'-UTR canola deoxyhypusine synthase cDNA under the regulation of the constitutive cauliflower mosaic virus 35S (CaMV-35S) promoter
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
D238A
-
NAD-site mutant, less than 5% activity of wild-type
D243A
-
spermidine-site mutant, no spermidine-binding
D313A
-
unable to bind eIF5A-precursor, no synthesis of deoxyhypusine
D316A
-
spermidine-site mutant, no spermidine-binding
D342A
-
NAD-site mutant, less than 5% activity of wild-type
E137A
-
NAD-site mutant, less than 5% activity of wild-type
E323A
-
spermidine-site mutant, no spermidine-binding
G283A
-
NAD-site mutant, activity similar to wild-type
K305A
-
spermidine-site mutant with retained avtivity
K329A
-
spermidine-site mutant, 18-24% spermidine binding capacity
K329R
-
no activity
S317A
-
NAD-site mutant, activity similar to wild-type
T308A
-
NAD-site mutant, activity similar to wild-type
W327A
-
spermidine-site mutant, no spermidine-binding
L344K
mutant enzyme is still devoid of any DHS activity, suggesting that other differences in amino acid sequences also contribute to its inactivity
K308A
-
very low reaction rate
K308R
-
low reaction rate
K308R/K350E
-
no activity
K308R/K350P
-
no activity
K308R/K350R
-
no activity
K350A
-
no activity
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
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