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Information on EC 2.5.1.16 - spermidine synthase and Organism(s) Plasmodium falciparum and UniProt Accession Q8II73

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EC Tree
IUBMB Comments
The enzymes from the plant Glycine max and from mammalia are highly specific for putrescine as the amine acceptor [2,7]. The enzymes from the bacteria Escherichia coli and Thermotoga maritima prefer putrescine but are more tolerant towards other amine acceptors, such as spermidine and cadaverine [5,6]. cf. EC 2.5.1.22 (spermine synthase) and EC 2.5.1.23 (sym-norspermidine synthase).
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Plasmodium falciparum
UNIPROT: Q8II73
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The taxonomic range for the selected organisms is: Plasmodium falciparum
The enzyme appears in selected viruses and cellular organisms
Synonyms
spermidine synthase, aminopropyltransferase, spds2, spdsyn, spd synthase, mdspds1, spermidine synthase 1, pgspd, putrescine aminopropyltransferase, spermidine synthetase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
aminopropyltransferase
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aminopropyltransferase spermidine synthase
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putrescine aminopropyltransferase
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spermidine synthetase
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synthase, spermidine
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
S-adenosyl 3-(methylsulfanyl)propylamine + putrescine = S-methyl-5'-thioadenosine + spermidine
show the reaction diagram
reaction mechanism involving a gate-keeping loop, active site and substrate binding structures and involved residues, structure-function relationship analysis by molecular dynamics simulations of a homology model
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
aminopropyl group transfer
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-
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SYSTEMATIC NAME
IUBMB Comments
S-adenosyl 3-(methylthio)propylamine:putrescine 3-aminopropyltransferase
The enzymes from the plant Glycine max and from mammalia are highly specific for putrescine as the amine acceptor [2,7]. The enzymes from the bacteria Escherichia coli and Thermotoga maritima prefer putrescine but are more tolerant towards other amine acceptors, such as spermidine and cadaverine [5,6]. cf. EC 2.5.1.22 (spermine synthase) and EC 2.5.1.23 (sym-norspermidine synthase).
CAS REGISTRY NUMBER
COMMENTARY hide
37277-82-0
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SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
S-adenosyl 3-(methylthio)propylamine + putrescine
S-methyl-5'-thioadenosine + spermidine
show the reaction diagram
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-
-
?
putrescine + S-adenosylmethioninamine
spermidine + 5'-methylthioadenosine
show the reaction diagram
-
-
-
?
S-adenosylmethioninamine + putrescine
5'-S-methyl-5'-thioadenosine + spermidine
show the reaction diagram
S-adenosylmethioninamine + putrescine
S-methyl-5'-thioadenosine + spermidine
show the reaction diagram
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-
-
-
?
spermidine + S-adenosylmethioninamine
spermine + 5'-methylthioadenosine
show the reaction diagram
in contrast to mammalian spermidine synthases, spermidine can replace to some extent putrescine as the aminopropyl acceptor
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-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
S-adenosyl 3-(methylthio)propylamine + putrescine
S-methyl-5'-thioadenosine + spermidine
show the reaction diagram
-
-
-
?
S-adenosylmethioninamine + putrescine
5'-S-methyl-5'-thioadenosine + spermidine
show the reaction diagram
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spermidine plays an important role in the activation of the eukaryotic translation initiation factor and cell proliferation
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-
?
S-adenosylmethioninamine + putrescine
S-methyl-5'-thioadenosine + spermidine
show the reaction diagram
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-
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-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
4-methylaniline
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benzimidazol-(2-yl)pentan-1-amine
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S-adenosyl-1,8-diamino-3-thio-octane
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1-Aminooxy-3-aminopropane
poor inhibition
1H-benzimidazol-5-yl(4-[(2Z)-3-phenylprop-2-en-1-yl]piperazin-1-yl)methanone
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identified by a five-step structure-based virtual screening procedure as a binder to spermidine synthase active site. Binds reversibly to the active site and partially competes with binding of methylthioadenosine
2-mercaptoethylamine
poor inhibition
2-[(6-amino-5,9-dihydro-4H-purin-8-yl)sulfanyl]acetamide
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identified by a five-step structure-based virtual screening procedure as a binder to spermidine synthase active site. Binds reversibly to the active site and competes with binding of methylthioadenosine
5'-methylthioadenosine
feedback inhibition
5-(1H-benzimidazol-2-yl)pentan-1-amine
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identified by a five-step structure-based virtual screening procedure as a binder to spermidine synthase active site. Binds reversibly to the active site
5-amino-1-pentene
50% inhibition at 6.5 microM
Cyclohexylamine
50% inhibition at 19.7 microM
decarboxylated S-adenosylhomocysteine
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Dicyclohexylamine
poor inhibition
methyl (2E)-2-(4-hydroxy-3-methoxybenzylidene)hydrazinecarbimidothioate
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identified by a five-step structure-based virtual screening procedure as a binder to spermidine synthase active site. Binds reversibly to the active site and partially competes with binding of methylthioadenosine
N-methyl-6-(piperidin-1-yl)hexan-1-amine
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identified by a five-step structure-based virtual screening procedure as a binder to spermidine synthase active site. Binds reversibly to the active site
N-[2-(phenylsulfanyl)ethyl]-1H-benzotriazole-5-carboxamide
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identified by a five-step structure-based virtual screening procedure as a binder to spermidine synthase active site. Binds reversibly to the active site and partially competes with binding of methylthioadenosine
trans-4-Methylcyclohexylamine
additional information
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.052
putrescine
pH 7.0, 37°C
0.0353
S-adenosylmethioninamine
pH 7.0, 37°C
additional information
additional information
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molecular dynamics
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00018
trans-4-Methylcyclohexylamine
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0014
trans-4-Methylcyclohexylamine
Plasmodium falciparum
IC50 1.4 microM
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37000
2 * 37000, SDS-PAGE
70000
gel filtration
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
2 * 37000, SDS-PAGE
additional information
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structure-function relationship, overview
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
in complex with S-methyl-5'-thioadenosine and putrescine or inhibitors, hanging drop vapor diffusion method, using 0.1 M MES buffer pH 5.6, 0.1 M ammonium sulfate, 27% (w/v) PEG 3350
construction of a crystal structure homology model, PDB ID: Q9FS5, for the Plasmodium falciparum enzyme from crystal structure 1JQ3 and 1XJ5, structure-function relationship
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in apo form, in complex with S-adenosylmethioninamine in complex with and two inhibitors, S-adenosyl-1,8-diamino-3-thio-octane and trans-4-methylcyclohexylamine. Binding of S-adenosylmethioninamine stabilizes the conformation of the flexible gatekeeper loop of the enzyme and affects the conformation of the active-site amino acid residues, preparing the protein for binding of the second substrate. Inhibitor S-adenosyl-1,8-diamino-3-thio-octane essentially fills the entire active-site pocket, inhibitor trans-4-methylcyclohexylamine only occupies part of it
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
D196N
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site-directed mutagenesis, the mutant activity is reduced by 89% compared to the wild-type enzyme
S197A
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site-directed mutagenesis, the mutant activity is reduced by 24% compared to the wild-type enzyme
Y102A
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site-directed mutagenesis, the mutant activity is reduced by 91% compared to the wild-type enzyme
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
Ni-affinity column chromatography
metal affinity chromatography and gel filtration
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli BL21 (lambdaDE3) Rosetta Oxford cells
expression in Escherichia coli, without the first 29 amino acids of the N-terminal extension
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
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the enzyme is a drug target in the malaria parasite, Plasmodium falciparum, due to the vital role of spermidine in the activation of the eukaryotic translation initiation factor and cell proliferation
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Haider, N.; Eschbach, M.L.; Dias Sde, S.; Gilberger, T.W.; Walter, R.D.; Luersen, K.
The spermidine synthase of the malaria parasite Plasmodium falciparum: molecular and biochemical characterisation of the polyamine synthesis enzyme
Mol. Biochem. Parasitol.
142
224-236
2005
Plasmodium falciparum (Q9NFS5), Plasmodium falciparum
Manually annotated by BRENDA team
Burger, P.B.; Birkholtz, L.M.; Joubert, F.; Haider, N.; Walter, R.D.; Louw, A.I.
Structural and mechanistic insights into the action of Plasmodium falciparum spermidine synthase
Bioorg. Med. Chem.
15
1628-1637
2007
Plasmodium falciparum
Manually annotated by BRENDA team
Jacobsson, M.; Gaeredal, M.; Schultz, J.; Karlen, A.
Identification of Plasmodium falciparum spermidine synthase active site binders through structure-based virtual screening
J. Med. Chem.
51
2777-2786
2008
Plasmodium falciparum
Manually annotated by BRENDA team
Dufe, V.T.; Qiu, W.; Mueller, I.B.; Hui, R.; Walter, R.D.; Al-Karadaghi, S.
Crystal structure of Plasmodium falciparum spermidine synthase in complex with the substrate decarboxylated S-adenosylmethionine and the potent inhibitors 4MCHA and AdoDATO
J. Mol. Biol.
373
167-177
2007
Plasmodium falciparum
Manually annotated by BRENDA team
Seckute, J.; McCloskey, D.E.; Thomas, H.J.; Secrist, J.A.; Pegg, A.E.; Ealick, S.E.
Binding and inhibition of human spermidine synthase by decarboxylated S-adenosylhomocysteine
Protein Sci.
20
1836-1844
2011
Plasmodium falciparum, Thermotoga maritima, Homo sapiens (P19623), Homo sapiens
Manually annotated by BRENDA team
Sprenger, J.; Svensson, B.; Halander, J.; Carey, J.; Persson, L.; Al-Karadaghi, S.
Three-dimensional structures of Plasmodium falciparum spermidine synthase with bound inhibitors suggest new strategies for drug design
Acta Crystallogr. Sect. D
71
484-493
2015
Plasmodium falciparum (Q8II73), Plasmodium falciparum
Manually annotated by BRENDA team