Information on EC 3.5.4.10 - IMP cyclohydrolase

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The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea

EC NUMBER
COMMENTARY hide
3.5.4.10
-
RECOMMENDED NAME
GeneOntology No.
IMP cyclohydrolase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
IMP + H2O = 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
internal C-N condensation
-
-
H2O elimination
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
Biosynthesis of antibiotics
-
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Biosynthesis of secondary metabolites
-
-
inosine-5'-phosphate biosynthesis I
-
-
inosine-5'-phosphate biosynthesis II
-
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inosine-5'-phosphate biosynthesis III
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Metabolic pathways
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Purine metabolism
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purine metabolism
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SYSTEMATIC NAME
IUBMB Comments
IMP 1,2-hydrolase (decyclizing)
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CAS REGISTRY NUMBER
COMMENTARY hide
9013-81-4
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
-
-
Manually annotated by BRENDA team
enzyme is expressed at nearly constant levels in both nondiapausing and prediapausing adults and downregulated by temperature in diapausing beetles stored at 10C
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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
gene TM1249 or purH
SwissProt
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
-
impact of the ITGA2 gene polymorphism C807T on gastric cancer risk, overview. Increased risk of gastric cancer associated with the polymorphism is pronounced in rural subjects, but not in urban subjects
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
5-formamido-1-(5-phosphoribosyl)imidazole-4-carboxamide
?
show the reaction diagram
5-formamido-1-(5-phosphoribosyl)imidazole-4-carboxamide
IMP + H2O
show the reaction diagram
5-formamido-1-(5-phosphoribosyl)imidazole-4-carboxamide + H2O
?
show the reaction diagram
-
catalyzation of the final two steps of de novo purine biosynthesis pathway
-
-
?
5-formamidoimidazole-4-carboxamide
hypoxanthine + H2O
show the reaction diagram
5-formaminoimidazole-4-carboxamide ribonucleotide
IMP + H2O
show the reaction diagram
trans-alpha,beta-diformamido-beta-(5'-phosphoribosylamino)acrylamide
IMP + H2O
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
5-formamido-1-(5-phosphoribosyl)imidazole-4-carboxamide
?
show the reaction diagram
5-formamido-1-(5-phosphoribosyl)imidazole-4-carboxamide + H2O
?
show the reaction diagram
-
catalyzation of the final two steps of de novo purine biosynthesis pathway
-
-
?
additional information
?
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2'-deoxy-AMP
-
decreased IMP cyclohydrolase activity by 10-50%
2,2-dioxo-1,5-dihydroimidazo[4,5-c][1,2,6]thiadiazin-4(3H)-one
construction of 1,5-dihydroimidazo[4,5-c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide, the corresponding nucleoside, and the nucleoside monophosphate, as mimics of the tetrahedral intermediate in the cyclization reaction. All compounds are competitive inhibitors against IMPCH, but the simpler heterocycle has a completely different IMPCH binding mode, compared to the nucleosides, and is relocated to the phosphate binding pocket, the aromatic imidazole ring interacts with a helix dipole, inhibitor synthesis, binding structure, and mechanism of inhibition, overview
2-chloroinosine 5'-monophosphate
-
potent inhibitor
2-flouroinosine 5'-monophosphate
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IC50-value in cell culture 0.0049 mM; potent inhibitor
2-fluoroadenine arabinoside 5'-monophosphate
2-mercaptoinosine 5'-monophosphate
-
most potent competitive inhibitor, precursor of GMP in the purine pathway
5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside
-
decreased IMP cyclohydrolase activity by 10-50%
6-mercaptopurine riboside 5'-monophosphate
7-(3,4-dihydroxy-5-hydroxymethyltetrahydrofuran-2-yl)-2,2-dioxo-1,5-dihydroimidazo[4,5-c][1,2,6]thiadiazin-4(3H)-one
construction of 1,5-dihydroimidazo[4,5-c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide, the corresponding nucleoside, and the nucleoside monophosphate, as mimics of the tetrahedral intermediate in the cyclization reaction. All compounds are competitive inhibitors against IMPCH, but the simpler heterocycle has a completely different IMPCH binding mode, compared to the nucleosides, and is relocated to the phosphate binding pocket, the aromatic imidazole ring interacts with a helix dipole, inhibitor synthesis, binding structure, and mechanism of inhibition, overview
adenosine N1-oxide 5'-monophosphate
-
AMP
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decreased IMP cyclohydrolase activity by 10-50%
GMP
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decreased IMP cyclohydrolase activity by 10-50%
N-succino-AMP
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decreased IMP cyclohydrolase activity by 10-50%
N2-acetyl-2'deoxyguanosine 5'-monophosphate
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decreased IMP cyclohydrolase activity by 10-50%
N6-(carboxymethyl)adenosine 5'-monophosphate
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strong competitive inhibitor
phosphoric acid mono-[3,4-dihydroxy-5-(2,2,4-trioxo-1,5-dihydroimidazo[4,5-c][1,2,6]thiadiazin-7-yl)tetrahydrofuran-2-yl]methyl ester
construction of 1,5-dihydroimidazo[4,5-c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide, the corresponding nucleoside, and the nucleoside monophosphate, as mimics of the tetrahedral intermediate in the cyclization reaction. All compounds are competitive inhibitors against IMPCH, but the simpler heterocycle has a completely different IMPCH binding mode, compared to the nucleosides, and is relocated to the phosphate binding pocket, the aromatic imidazole ring interacts with a helix dipole, inhibitor synthesis, binding structure, and mechanism of inhibition, overview
xanthosine 5'-monophosphate
-
strong competitive inhibitor
additional information
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
KCl
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higher activity in buffers containing 50 mM
NaCl
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higher activity in buffers containing 150 mM
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1.28
5'-phosphoribosyl-5-formamido-4-imidazole carboxamide
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-
0.0009 - 0.115
5-Formamido-1-(5-phosphoribosyl)imidazole-4-carboxamide
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.014 - 8.6
5-Formamido-1-(5-phosphoribosyl)imidazole-4-carboxamide
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.13
1,5-dihydroimidazo[4,5-c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide
pH 7.4
0.23
7-(3,4-dihydroxy-5-hydroxymethyltetrahydrofuran-2-yl)-2,2-dioxo-1,5-dihydroimidazo[4,5-c][1,2,6]thiadiazin-4(3H)-one
about, pH 7.4
0.15
phosphoric acid mono-[3,4-dihydroxy-5-(2,2,4-trioxo-1,5-dihydroimidazo[4,5-c][1,2,6]thiadiazin-7-yl)tetrahydrofuran-2-yl]methyl ester
about, pH 7.4
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0049
2-flouroinosine 5'-monophosphate
Homo sapiens
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IC50-value in cell culture 0.0049 mM
0.0002
2-fluoroadenine arabinoside 5'-monophosphate
Homo sapiens
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IC50-value in cell culture 0.0002 mM
0.0075
6-mercaptopurine riboside 5'-monophosphate
Homo sapiens
-
IC50-value in cell culture 0.0075 mM
0.0000011
adenosine N1-oxide 5'-monophosphate
Homo sapiens
-
IC50-value in cell culture 0.0011 microM
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.44
purified recombinant mutant R31K
1.2
purified recombinant mutant Y59F
1.8
purified recombinant wild-type enzyme
2.8
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extract from Escherichia coli expression mutants after several pufification steps
5.09
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at 25C
32
purified recombinant mutant C61A
additional information
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7 - 7.8
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-
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5.49
sequence calculation
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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ALCL cell line TS, Sup-M2 cells, JB-6 cells, SU-DHL1 cells
Manually annotated by BRENDA team
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immunoprecipitated from
Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
UNIPROT
Methanothermobacter thermautotrophicus (strain ATCC 29096 / DSM 1053 / JCM 10044 / NBRC 100330 / Delta H)
Methanothermobacter thermautotrophicus (strain ATCC 29096 / DSM 1053 / JCM 10044 / NBRC 100330 / Delta H)
Methanothermobacter thermautotrophicus (strain ATCC 29096 / DSM 1053 / JCM 10044 / NBRC 100330 / Delta H)
Methanothermobacter thermautotrophicus (strain ATCC 29096 / DSM 1053 / JCM 10044 / NBRC 100330 / Delta H)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
21500
x * 21500, SDS-PAGE
22000
x * 22000, recombinant enzyme, SDS-PAGE
46000
-
8 * 46000, gel filtration
49700
1 * 49700, enzyme comprising residues 1-452, i.e. the IMP cyclohydrolase part of the bifunctional enzyme, SDS-PAGE
55746
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2 * 55746, open reading frame
62100
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2 * 62100, protein mobility assay
64200
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2 * 64200, open reading frame, polypeptide of 592 amino acids, 91% similar to human IMPCHase
64422
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2 * 64422, open reading frame, gel filtration
64425
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2 * 64425, open reading frame, polypeptide of 591 amino acids, 81% similar to chicken IMPCHase, truncation mutant, IMPCHase activity located within the NH2-terminal 223 amino acids
71000
-
2 * 71000, relative mobility in SDS-PAGE
350000
-
gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
monomer
1 * 49700, enzyme comprising residues 1-452, i.e. the IMP cyclohydrolase part of the bifunctional enzyme, SDS-PAGE
octamer
-
8 * 46000, gel filtration
tetramer
MthPurO has a four-layered alphabetabetaalpha core structure, showing an N-terminal nucleophile hydrolase fold. The active site is located at the deep pocket between two central beta-sheets and contains residues strictly conserved within PurOs, structure analysis, modelling, detailed overview
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
-
phophorylation increases enzyme activity
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
enzyme in complex with inhibitors, sitting drop vapor diffusion method, 22C, 10 mg/ml protein, mixing of equal volumes of protein and reservoir solutions, the latter containing 20% w/v PEG 8000, 0.2 M imidazole, pH 7.2, 5 mM dithiothreitol, X-ray diffraction structure determination and analysis at 2.0-2.7 A resolution
in complex with transformylase inhibitors BW1540 and BW2315
MthPurO in complex with either IMP or 5-aminoimidazole-4-carboxamide ribonucleotide, crystals from 30 mg/ml protein in 25-30% MPD, 0.2 M ammonium acetate, and 0.1 M sodium citrate buffer, pH 5.6, 0.001 ml protein solution is mixed with 0.001 ml of reservoir solution, equilibration against 0.5 mL reservoir solution, 24C, od-shaped crystals, 3-4 weeks, X-ray diffraction structure determination and analysis at 2.0 A and 2.6 A resolution, respectively, method optimization, molecular replacement and modelling; MthPurO in complex with either IMP or 5-aminoimidazole-4-carboxamide ribonucleotide, X-ray diffraction structure determination and analysis at 2.0 A and 2.6 A resolution, respectively
20 mg/ml purified recombinant enzyme in 20 mM Tris, pH 7.9, 150 mM NaCl, 0.25 mM TCEP, nanodroplet vapor diffusion method, the crystallization solution contains 20% w/v PEG 6000 and 0.1 M citrate pH 5.0, 10% v/v PEG 200 as a cryoprotectant, X-ray diffraction structure determination and anaylsis at 1.88 A resolution, modelling
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
50
-
up to
80
1 h, in air, no loss of activity
90
30 min, in air, 84% residual activity
100
30 min, in air, 30% residual activity
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
2 years at -25C
-
several months at -15C
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
154-fold
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780fold to apparent homogeneity
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expressed as glutathione-S-transferase fusion protein in Escherichia coli mutants
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from liver homogenate
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near to homogeneity from Escherichia coli expression mutants
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recombinant His-tagged enzyme from Escherichia coli by nickel affinity and anion exchange chromatography
recombinant His-tagged enzyme from Escherichia coli strain BL21 by cobalt affinity chromatography, elution with imidazole, to homogeneity; soluble recombinant wild-type and mutant enzymes from Escherichia coli strain BL21 by heat treatment for 15 min at 70C, and anion exchange chromatography, to homogeneity
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli
expression of His-tagged enzyme in Escherichia coli
gene ITGA2, genotyping of 614 male subjects, 1:1 ratio of gastric cancer patients and healthy controls, overview
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overexpression of His-tagged enzyme in Escherichia coli strain BL21; overexpression of wild-type and mutant enzymes in Escherichia coli strain BL21
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C807T
-
naturally occuring polymorphism involved in gastric cancer development
K246R
natural mutation observed in female infant patient with lack in transformylase activity and about 40% residual enzymic activity, showing massive excretion of 5-amino-4-imidazolecarboxamide riboside, dysmorphic features, severe neurological defects, and congenital blindness. Recombinant protein with K426R mutation completely lacks AICAR transformylase activity
Y104A/D125A
Y104F/D125A
C61A
site-directed mutagenesis, the mutant shows 8fold increased activity compared to the wild-type enzyme
E102Q
site-directed mutagenesis, inactive mutant
R31K
site-directed mutagenesis, the mutant shows 76% reduced activity compared to the wild-type enzyme
Y59F
site-directed mutagenesis, the mutant shows 34% reduced activity compared to the wild-type enzyme
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
the enzyme is a potential target for antineoplastic intervention, design of IMPCH inhibitors, overview
medicine
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determination of differentially expressed genes in HT-29 cells, both after short treatment with methotrexate and after the resistance to methotrexate has been established. Enzyme as well as survivin and inosine monophosphate dehydrogenase type II are upregulated
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