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Information on EC 2.5.1.22 - spermine synthase and Organism(s) Homo sapiens and UniProt Accession P52788
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2.5.1.22 spermine synthaseIUBMB Comments
The enzyme from mammalia is highly specific for spermidine [2,3]. cf. EC 2.5.1.16 (spermidine synthase) and EC 2.5.1.23 (sym-norspermidine synthase).
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Word Map
- 2.5.1.22
- polyamine
- putrescine
- s-adenosylmethionine
- ornithine
- aminopropyltransferases
-
snyder-robinson
- alpha-difluoromethylornithine
- acaulis5
- thermospermine
- trans-4-methylcyclohexylamine
-
gyro
-
kyphoscoliosis
- agriculture
- adometdc
-
2.5.1.16
- medicine
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
Synonyms
spermine synthase, spmsyn, osspms1, spm synthase, spermidine aminopropyltransferase, spermine synthetase, spermine synthase 1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
aminopropyltransferase, spermidine
-
-
-
-
spermidine aminopropyltransferase
-
-
-
-
spermine synthetase
-
-
-
-
synthase, spermine
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
aminopropyl group transfer
-
-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
-
-, -
SYSTEMATIC NAME
IUBMB Comments
S-adenosyl 3-(methylthio)propylamine:spermidine 3-aminopropyltransferase
The enzyme from mammalia is highly specific for spermidine [2,3]. cf. EC 2.5.1.16 (spermidine synthase) and EC 2.5.1.23 (sym-norspermidine synthase).
CAS REGISTRY NUMBER
COMMENTARY
74812-43-4
-
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
S-adenosyl-L-methioninamine + spermidine
5'-methylthioadenosine + spermine
-
-
-
?
S-adenosylmethioninamine + spermidine
5'-methylthioadenosine + spermine + H+
Polyamine sythesis, addition of a second aminopropyl group to the N-10 position of spermidine. The active site with a bound spermidine molecule contains an Asp276 residue, which is in an ideal position to facilitate the deprotonation of the N-10 amino group of spermidine that attacks the C-atom of the aminopropyl group of decarboxylated S-adenosylmethionine
-
-
?
H2N(CH2)3NH(CH2)4NH2 + S-adenosyl 3-(methylthio)propylamine
H2N(CH2)3NH(CH2)4NH(CH2)3NH2 + S-methyl-5'-thioadenosine
-
-
-
-
?
S-adenosyl 3-(methylthio)propylamine + spermidine
S-methyl-5'-thioadenosine + spermine
-
-
-
-
?
S-adenosyl-L-methioninamine + spermidine
5'-methylthioadenosine + spermine
-
-
-
-
?
S-adenosyl 3-(methylthio)propylamine + spermidine
S-methyl-5'-thioadenosine + spermine
-
-
-
?
S-adenosyl 3-(methylthio)propylamine + spermidine
S-methyl-5'-thioadenosine + spermine
-
-
-
-
?
S-adenosylmethioninamine + spermidine
S-methyl-5'-thioadenosine + spermine
-
-
-
-
?
S-adenosylmethioninamine + spermidine
S-methyl-5'-thioadenosine + spermine
-
decarboxylated S-adenosylmethionine is an essential intermediate in the synthesis of polyamines
-
-
?
additional information
?
-
The predominant polyamines in mammalian cells are spermidine and spermine, these polyamines are made by the sequential addition of aminopropyl groups from decarboxylated S-adenosylmethionine.
-
-
?
additional information
?
-
-
levels of spermidine and spermine are not only regulated by activity of spermidine synthase and spermine synthase, but also by other factors, e.g. the level of aminopropyl donor substrate, overview
-
-
?
additional information
?
-
-
spermine synthase is clearly essential for normal development in humans
-
-
?
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
S-adenosylmethioninamine + spermidine
5'-methylthioadenosine + spermine + H+
Polyamine sythesis, addition of a second aminopropyl group to the N-10 position of spermidine. The active site with a bound spermidine molecule contains an Asp276 residue, which is in an ideal position to facilitate the deprotonation of the N-10 amino group of spermidine that attacks the C-atom of the aminopropyl group of decarboxylated S-adenosylmethionine
-
-
?
S-adenosyl 3-(methylthio)propylamine + spermidine
S-methyl-5'-thioadenosine + spermine
-
-
-
-
?
S-adenosylmethioninamine + spermidine
S-methyl-5'-thioadenosine + spermine
-
decarboxylated S-adenosylmethionine is an essential intermediate in the synthesis of polyamines
-
-
?
S-adenosyl 3-(methylthio)propylamine + spermidine
S-methyl-5'-thioadenosine + spermine
-
-
-
?
S-adenosyl 3-(methylthio)propylamine + spermidine
S-methyl-5'-thioadenosine + spermine
-
-
-
-
?
additional information
?
-
The predominant polyamines in mammalian cells are spermidine and spermine, these polyamines are made by the sequential addition of aminopropyl groups from decarboxylated S-adenosylmethionine.
-
-
?
additional information
?
-
-
levels of spermidine and spermine are not only regulated by activity of spermidine synthase and spermine synthase, but also by other factors, e.g. the level of aminopropyl donor substrate, overview
-
-
?
additional information
?
-
-
spermine synthase is clearly essential for normal development in humans
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
5'-methylthioadenosine
SpmSyn is strongly inhibited by 5'-methylthioadenosine. This inhibition does not have great importance in limiting spermine synthesis in vivo because 5'-methylthioadenosine is normally rapidly degraded by 5'-methylthioadenosine phosphorylase. Inhibition of this enzyme allows 5'-methylthioadenosine to accumulate with deleterious effects on polyamine content.
additional information
the spermine synthase-5'-methylthioadenosine structure provides a plausible explanation for the potent inhibition of the reaction by this product and the stronger inhibition of spermine synthase compared with spermidine synthase.
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0005
S-adenosyl 3-(methylthio)propylamine
-
wild type enzyme, at pH 7.5 and 37°C
0.0009
S-adenosyl 3-(methylthio)propylamine
-
mutant enzyme S165D/L175E/T178H/C206R, at pH 7.5 and 37°C
additional information
additional information
ratio of kcat/Km value of wild-type is 40000 for substrate spermidine, and 71000000 for S-adenosyl-L-methioninamine, respectively
-
additional information
additional information
-
ratio of kcat/Km value of wild-type is 40000 for substrate spermidine, and 71000000 for S-adenosyl-L-methioninamine, respectively
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
deletion of the N-terminal domain leads to a complete loss of spermine synthase activity, suggesting that dimerization may be required for activity
additional information
-
activity in vivo in wild-type and transgenic CAG/SpmS mice, polyamine contents, overview
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
from patients with Snyder-Robinson syndrome and non-affected individuals
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug target
spermine synthase and MYC cooperate to maintain colorectal cancer cell survival by repressing Bim expression. Combined inhibition of spermine synthase and MYC signaling may be an effective therapy for colorectal cancer
malfunction
metabolism
physiological function
spermine synthase is a key enzyme controlling the concentration of spermidine and spermine in the cell
malfunction
-
cells derived from patients with Snyder-Robinson syndrome, a rare X-linked recessive human disease caused by SMS gene mutations that greatly reduce the content of spermine synthase, show an increase in decarboxylated S-adenosylmethionine
physiological function
-
inverse relationship between the amount of spermine synthase protein and the content of decarboxylated S-adenosylmethionine. In mice lacking spermine synthase occurs a large increase in decarboxylated S-adenosylmethionine, dcAdoMet, overexpression of human spermine synthase reduces the amount of this nucleoside, Content of AdoMet and dcAdoMet in cultured lymphoblasts from control and Snyder-Robinson syndrome patients
malfunction
SMS single missense mutations cause the Snyder-Robinson Syndrome, SRS. Concerning mutability depending on structural micro-environment and involvement in the function and structural integrity of the SMS, the I150 site does not tolerate any mutation, while V132, despite its key position at the interface of SMS dimer, is quite mutable. The G56 site is still quite sensitive to charge residue replacement
malfunction
mutations in the spermine synthase gene are associated with Snyder Robinson mental retardation syndrome
metabolism
spermine synthase and MYC cooperate to maintain colorectal cancer cell survival by repressing Bim expression
metabolism
the enzyme is critical for maintaining the balance of spermine/spermidine in the cell
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). SPSY_HUMAN
366
0
41268
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
41000
-
2 * 41000, each monomer has three domains: an N-terminal domain, which contains most of the dimer contacts; a central domain made up of four beta-strands that serves as a lid for the C-terminal domain, and a C-terminal catalytic domain
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
homodimer
monomer
deletions of all or part of the N-terminal domain lead to the protein existing as a monomer as determined by gel filtration analysis and to virtually complete loss of activity
dimer
homodimer
2 identical subunits, each monomer has 3 domains: a C-terminal domain, which contains the active site, a central domain made up of 4 beta-strands and an N-terminal domain with structural similarity to S-adenosylmethionine decarboxylase. Dimerization occurs mainly through interactions between the N-terminal domains. The structures provide an outline of the active site and a plausible model for catalysis. The active site is similar to those of spermidine synthases but has a larger substrate-binding pocket able to accommodate longer substrates. Asp201 and 276, conserved in aminopropyltransferases, play a key part in the catalytic mechanism. By separate expression of both domains, enzymes are inactive and possess rigid tertiary structure, suggesting that human SpmSyn is a fusion protein.
dimer
-
2 * 41000, each monomer has three domains: an N-terminal domain, which contains most of the dimer contacts; a central domain made up of four beta-strands that serves as a lid for the C-terminal domain, and a C-terminal catalytic domain
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
analysis of X-ray crystal structure of the wild-type human SMS in complex with spermidine and 5-methylthioadenosine, PDB ID 3C6K, and folding free energy calculations, dimer structure analysis of wild-type and mutant enzymes, overview
in complex with 5'-methylthioadenosine and spermidine and with 5'-methylthioadenosine and spermine. Enzyme is a dimer of two identical subunits. Each monomer has three domains, a C-terminal domain, which contains the active site and is similar in structure to spermidine synthase, a central domain made up of four beta-strands, and an N-terminal domain with remarkable structural similarity to S-adenosylmethionine decarboxylase
Purified SpmSyn is crystallized as ternary complex in the presence of spermidine and 5'-methylthioadenosine or spermidine and 5'-methylthioadenosine using the hanging drop vapor diffusion method. The SpmSyn-5'-methylthioadenosine-spermidine complex is crystallized in 12% polyethylene glycol and 0.1 M MES (pH 6.5). The SpmSyn-5'-methylthioadenosine-spermine complex is crystallized in 18% polyethylene glycol, 0.1 M NaCl, and 0.1 M BisTris (pH 6.5). Crystals are soaked in the corresponding mother liquor supplemented with 20% glycerol as cryoprotectant before freezing in liquid nitrogen.
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D201A
D201N
D276N
DELTA347-366
truncation of the protein at position 346 removing the last 20 residues lead to a complete loss of activity
DELTA358-366A
smaller truncation of only 9 residues has a smaller effect but still reduced activity by 75%
E353Q
G191S
the mutation at a site far away from the active pocket affects the active site dynamics and thus the functionality of SpmSyn. This suggests that SpmSyn functionality is regulated by networks of interacting residues and thus expands the functional and structural importance beyond the amino acids directly involved in the catalysis
G56S
I150T
naturally occuring missense mutation involved in Snyder-Robinson Syndrome, the mutation affects dimer and monomer stability and perturb the hydrogen bond network of the functionally important amino acids
V132G
naturally occuring missense mutation involved in Snyder-Robinson Syndrome, the mutation affects dimer and monomer stability and perturb the hydrogen bond network of the functionally important amino acids
G56S
-
point mutation, leads to a large loss of spermine synthase activity, an inability to form dimers
I150T
-
point mutation, leads to a large loss of spermine synthase activity, an inability to form dimers
S165D/L175E/T178H/C206R
-
the mutant shows increased activity compared to the wild type enzyme
V132G
-
point mutation, leads to a large loss of spermine synthase activity, an inability to form dimers
additional information
D201A
mutation of Asp201 to Ala decreases the kcat/Km for decarboxylated S-adenosylmethionine by more than 100000fold
D201N
mutation of Asp201 to Asn decreases the kcat/Km for decarboxylated S-adenosylmethionine by more than 100000fold
D276N
alteration of this residue reduces the kcat/Km for spermidine by more than 200000fold
G56S
naturally occuring missense mutation involved in Snyder-Robinson Syndrome, the mutation affects dimer and monomer stability and perturb the hydrogen bond network of the functionally important amino acids
G56S
the mutation destabilizes the enzyme homodimer and thus abolishes enzymatic activity
additional information
deletion of the N-terminal domain leads to a complete loss of spermine synthase activity
additional information
-
deletion of the N-terminal domain leads to a complete loss of spermine synthase activity
additional information
-
enzyme overexpression in transgenic mice under control of a composite CMV-IE enhancer-chicken beta-actin promotor causes no deleterious effects, the mice show normal growth, fertility, and behaviour, the content of S-adenosylmethionine in transgenic mice is important for viability, overview
additional information
-
mutation p.G56S in the N-terminal region of spermine synthase greatly reduces spermine synthase activity and leads to severe epilepsy and cognitive impairment related to Snyder-Robinson X-linked recessive mental retardation syndrome
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
Cell lysate is loaded onto a HiTrap chelating column charged with Ni2+. The enzyme is eluted with an imidazole gradient (50-250 mM) at pH 8.0. The protein is loaded onto a Superdex 200 column equilibrated with 20 mM Tris-HCl and 150 mM NaCl. Thrombin is added to combined fractions containing SpmSyn to remove the His-tag. The protein is further purified to homogeneity by ion-exchange chromatography.
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
DNA fragment encoding human enzyme is amplified by PCR and subcloned into the pET28a-LIC vector downstream of the polyhistidine coding region. Enzyme is expressed in the Escherichia coli BL21-Codon Plus(DE3)-RIL strain by the addition of 1 mM isopropyl1-thio-beta-D-galactopyranoside. The N-terminally truncated SpmSyn mutants are generated by PCR and subcloned into the pET28a-LIC vector.
enzyme overexpression in transgenic mice under control of a composite CMV-IE enhancer-chicken beta-actin promotor, 4 separate founder CAG/SpmS mice are analysed: enzyme expression in all tissues, mostly highly increased compared to the wild-type mice, overview
-
expression of human spermine synthase in CAGSMS line 8 mice from a composite CMV-IE enhancer/chicken beta-actin promoter. Transgenic expression of spermine synthase in the Gy mice reverse all of the increases in dcAdoMet content and AdoMetDC
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
knockdown of the MYO5A gene reduces the expression of mRNA coding for spermine synthase. The amount of this transcript is also reduced in cells derived from a patient with Griscelli syndrome type 1. This suggests that, in addition to a direct physical interaction between the two proteins, myosin Va also modulates the transcription of the spermine synthase gene
MYO5A knockdown decreases the expression of spermine synthase gene and renders the distribution of spermine synthase protein diffuse, supporting a role for MyoVa in spermine synthase expression and targeting
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
-
mutation p.G56S in the N-terminal region of spermine synthase greatly reduces spermine synthase activity and leads to severe epilepsy and cognitive impairment related to Snyder-Robinson X-linked recessive mental retardation syndrome
medicine
-
Snyder-Robinson syndrome (SRS) mutations drastically reduce spermine synthase activity and cause mild-to-moderate mental retardation, and may lead to a variety of other characteristics including a marfanoid habitus, skeletal defects, osteoporosis, and facial asymmetry, as well as hypotonia and movement disorders
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Kajander, E.O.; Kauppinen, L.I.; Pajula, R.L.; Karkola, K.; Eloranta, T.O.
Purification and partial characterization of human polyamine synthases
Biochem. J.
259
879-886
1989
Homo sapiens
Korhonen, V.P.; Halmekyto, M.; Kauppinen, L.; Myohanen, S.; Wahlfors, J.; Keinanen, T.; Hyvonen, T.; Alhonen, L.; Eloranta, T.; Janne, J.
Molecular cloning of a cDNA encoding human spermine synthase
DNA Cell Biol.
14
841-847
1995
Homo sapiens
Ikeguchi, Y.; Wang, X.; McCloskey, D.E.; Coleman, C.S.; Nelson, P.; Hu, G.; Shantz, L.M.; Pegg, A.E.
Characterization of transgenic mice with widespread overexpression of spermine synthase
Biochem. J.
381
701-707
2004
Homo sapiens
Wu, H.; Min, J.; Zeng, H.; McCloskey, D.E.; Ikeguchi, Y.; Loppnau, P.; Michael, A.J.; Pegg, A.E.; Plotnikov, A.N.
Crystal structure of human spermine synthase: implications of substrate binding and catalytic mechanism
J. Biol. Chem.
283
16135-16146
2008
Homo sapiens (P52788), Homo sapiens
de Alencastro, G.; McCloskey, D.E.; Kliemann, S.E.; Maranduba, C.M.; Pegg, A.E.; Wang, X.; Bertola, D.R.; Schwartz, C.E.; Passos-Bueno, M.R.; Sertie, A.L.
New SMS mutation leads to a striking reduction in spermine synthase protein function and a severe form of Snyder-Robinson X-linked recessive mental retardation syndrome
J. Med. Genet.
45
539-543
2008
Homo sapiens
MacLean, H.E.; Chiu, W.S.; Notini, A.J.; Axell, A.; Davey, R.A.; McManus, J.F.; Ma, C.; Plant, D.R.; Lynch, G.S.; Zajac, J.D.
Impaired skeletal muscle development and function in male, but not female, genomic androgen receptor knockout mice
FASEB J.
22
2676-2689
2008
Homo sapiens (P52788)
Pegg, A.E.; Michael, A.J.
Spermine synthase
Cell. Mol. Life Sci.
67
113-121
2010
Homo sapiens, Monosiga brevicollis, Mus musculus, no activity in Caenorhabditis elegans, no activity in Hydra magnipapillata, Saccharomyces cerevisiae
Pegg, A.E.; Wang, X.; Schwartz, C.E.; McCloskey, D.E.
Spermine synthase activity affects the content of decarboxylated S-adenosylmethionine
Biochem. J.
433
139-144
2011
Homo sapiens, Mus musculus
Zhang, Z.; Norris, J.; Schwartz, C.; Alexov, E.
In silico and in vitro investigations of the mutability of disease-causing missense mutation sites in spermine synthase
PLoS ONE
6
e20373
2011
Homo sapiens (P52788)
Peng, Y.; Norris, J.; Schwartz, C.; Alexov, E.
Revealing the effects of missense mutations causing Snyder-Robinson syndrome on the stability and dimerization of spermine synthase
Int. J. Mol. Sci.
17
77
2016
Homo sapiens (P52788)
Zhang, Z.; Zheng, Y.; Petukh, M.; Pegg, A.; Ikeguchi, Y.; Alexov, E.
Enhancing human spermine synthase activity by engineered mutations
PLoS Comput. Biol.
9
e1002924
2013
Homo sapiens
Zhang, Z.; Martiny, V.; Lagorce, D.; Ikeguchi, Y.; Alexov, E.; Miteva, M.A.
Rational design of small-molecule stabilizers of spermine synthase dimer by virtual screening and free energy-based approach
PLoS ONE
9
e110884
2014
Homo sapiens (P52788), Homo sapiens
Dolce, L.G.; Silva-Junior, R.M.P.; Assis, L.H.P.; Nascimento, A.F.Z.; Araujo, J.S.; Meschede, I.P.; Espreafico, E.M.; de Giuseppe, P.O.; Murakami, M.T.
Myosin Va interacts with the exosomal protein spermine synthase
Biosci. Rep.
39
BSR20182189
2019
Homo sapiens (P52788)
Timson, D.J.
Myosin Va and spermine synthase partners in exosome transport
Biosci. Rep.
39
BSR20190326
2019
Homo sapiens (P52788)
Peng, Y.; Michonova, E.
Long-range effect of a single mutation in spermine synthase
J. Theor. Comput. Chem.
17
16135-16146
2018
Homo sapiens (P52788)
-
Guo, Y.; Ye, Q.; Deng, P.; Cao, Y.; He, D.; Zhou, Z.; Wang, C.; Zaytseva, Y.Y.; Schwartz, C.E.; Lee, E.Y.; Mark Evers, B.; Morris, A.J.; Liu, S.; She, Q.B.
Spermine synthase and MYC cooperate to maintain colorectal cancer cell survival by repressing Bim expression
Nat. Commun.
11
3243
2020
Homo sapiens (P52788)
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