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Information on EC 1.1.1.42 - isocitrate dehydrogenase (NADP+) and Organism(s) Sus scrofa and UniProt Accession P33198
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1.1.1.42 isocitrate dehydrogenase (NADP+)IUBMB Comments
Requires Mn2+ or Mg2+ for activity. Unlike EC 1.1.1.41, isocitrate dehydrogenase (NAD+), oxalosuccinate can be used as a substrate. In eukaryotes, isocitrate dehydrogenase exists in two forms: an NAD+-linked enzyme found only in mitochondria and displaying allosteric properties, and a non-allosteric, NADP+-linked enzyme that is found in both mitochondria and cytoplasm . The enzyme from some species can also use NAD+ but much more slowly [6,7].
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proneural
The taxonomic range for the selected organisms is: Sus scrofa
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
isocitrate dehydrogenase 1, nadp-isocitrate dehydrogenase, nadp-dependent isocitrate dehydrogenase, isocitrate dehydrogenase-1, nadp-icdh, nadp-idh, nadp+-dependent isocitrate dehydrogenase, nadp-linked isocitrate dehydrogenase, nadp-specific isocitrate dehydrogenase, nadp+-specific isocitrate dehydrogenase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
CtIDP1
-
-
-
-
CtIDP2
-
-
-
-
IDH
-
-
-
-
IDP
-
-
-
-
isocitrate dehydrogenase (NADP)
-
-
-
-
isocitrate dehydrogenase (NADP-dependent)
-
-
-
-
isocitrate dehydrogenase (nicotinamide adenine dinucleotide phosphate)
-
-
-
-
NADP isocitric dehydrogenase
-
-
-
-
NADP+-linked isocitrate dehydrogenase
-
-
-
-
NADP+-specific ICDH
-
-
-
-
NADP-dependent isocitrate dehydrogenase
NADP-dependent isocitric dehydrogenase
-
-
-
-
NADP-linked isocitrate dehydrogenase
-
-
-
-
NADP-specific isocitrate dehydrogenase
-
-
-
-
oxalosuccinate decarboxylase
-
-
-
-
oxalsuccinic decarboxylase
-
-
-
-
PS-NADP-IDH
-
-
-
-
NADP-dependent isocitrate dehydrogenase
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
isocitrate + NADP+ = 2-oxoglutarate + CO2 + NADPH + H+
Ser95, Asn97, and Thr78 are important for the catalysis having distinguishable functions, overview
-
isocitrate + NADP+ = 2-oxoglutarate + CO2 + NADPH + H+
active site structure contains a well-ordered Mn2+-isocitrate complex, reaction mechanism
isocitrate + NADP+ = 2-oxoglutarate + CO2 + NADPH + H+
Tyr140 and Lys212 are required for catalytic activity, Tyr140 is the general acid that protonates the substrate after decarboxylation, Lys212 lowers as a positively charged residue the pK of the nearby ionizable group in the enzyme-substrate complex and stabilizes the carbanion formed initially on substrate decarboxylation
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
-
-
-
-
oxidative decarboxylation
-
-
-
-
reductive carboxylation
-
-
-
-
PATHWAY SOURCE
PATHWAYS
KEGG
-
-, -, -, -, -, -, -, -, -, -, -, -
SYSTEMATIC NAME
IUBMB Comments
isocitrate:NADP+ oxidoreductase (decarboxylating)
Requires Mn2+ or Mg2+ for activity. Unlike EC 1.1.1.41, isocitrate dehydrogenase (NAD+), oxalosuccinate can be used as a substrate. In eukaryotes, isocitrate dehydrogenase exists in two forms: an NAD+-linked enzyme found only in mitochondria and displaying allosteric properties, and a non-allosteric, NADP+-linked enzyme that is found in both mitochondria and cytoplasm [6]. The enzyme from some species can also use NAD+ but much more slowly [6,7].
CAS REGISTRY NUMBER
COMMENTARY
9028-48-2
-
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
isocitrate + NADP+
2-oxoglutarate + CO2 + NADPH + H+
-
Ser95, Asn97, and Thr78 are involved in substrate binding
-
-
?
additional information
?
-
-
His319 and His315 are not responsible for enzyme Fe2+-isocitrate cleavage
-
-
?
additional information
?
-
-
during oxidative stress, enzyme activity appears to be modulated through enzymatic glutathionylation and deglutathionylation
-
-
?
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
additional information
?
-
-
during oxidative stress, enzyme activity appears to be modulated through enzymatic glutathionylation and deglutathionylation
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
NADP+
-
Arg314 and the aromatic ring of Tyr316 are important for affinity to the cofactor and catalysis, interaction with 2'-phosphate group of NADP+
NADP+
-
binding of 1 mol NADP+ per enzyme subunit, His309 is highly important for cofactor binding, HIs315 is involved, while His319 is not
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mn2+
Mn2+
Mn2+
-
as Mn2+-isocitrate complex, Ser95, Asn97, and Thr78 are involved in binding
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Cd2+
-
binds to C379 of enzyme, resulting in loss of activity and structural alterations. Loss of glutaredoxin activity in cells treated with Cd2+ is more pronounced when cells are transfected with enzyme antisense cDNA
glutathione
-
oxidized glutathione leads to enzyme inactivation with simultaneous formation of a mixed disulfide between glutathione and the cysteine residues of enzyme. Enzymical reactivation by glutaredoxin2 in presence of reduced glutathione
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
acetic acid
mutant Y140T, 106fold activation compared to the wild-type enzyme
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
measurement methods, the maltose binding fusion protein of the recombinant enzymes alters the kinetic parameters, overview
-
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
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
5 - 8
additional information
additional information
pH-profile, recombinant wild-type and mutant enzymes
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
mainly localized to the principal piece of the porcine sperm flagellum
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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). IDHP_PIG
421
0
47526
Swiss-Prot
other Location (Reliability: 4)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
46600
-
2 * 46600, recombinant thrombin cleaved wild-type and mutant enzymes, SDS-PAGE
87000
90000
-
recombinant maltose binding fusion proteins, wild-type and mutant enzymes, gel filtration
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
dimer
dimer
-
2 * 46600, recombinant thrombin cleaved wild-type and mutant enzymes, SDS-PAGE
dimer
-
residues Arg314, Tyr316, Lys321, and Arg323 are not involved in subunit interaction
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
tyrosine phosphorylated enzyme shows a significantly lowered enzymatic activity
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
20 mg/ml purified recombinant wild-type and selenomethionine enzyme, complexed with Mn2+ and isocitrate, 4°C, hanging drop vapour diffusion method, for the wild-type enzyme: 0.002 ml of enzyme solution containing 0.1 M triethanolamine chloride, pH 7.7, 0.15 M Na2SO4, 8 mM DL-isocitrate, 4 mM MnSO4, plus equal volume of 20% PEG 6000, 3% glycerol, against 0.75 ml reservoir solution containing 0.1 M triethanolamine chloride, pH 7.7, 0.15 M Na2SO4, 8 mM DL-isocitrate, 4 mM MnSO4, and 40% w/v xylitol, for the selenomethionine enzyme: 0.002 ml of enzyme solution containing 0.1 M triethanolamine chloride, pH 7.7, 0.15 M Na2SO4, 8 mM DL-isocitrate, plus equal volume of 18% PEG 6000, 3% glycerol, against 0.75 ml reservoir solution containing 0.1 M triethanolamine chloride, pH 7.7, 0.15 M Na2SO4, and 18% PEG 6000, 7-10 days, X-ray diffraction structure determination and analysis at 2.7 A resolution, modeling
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
K212Q
site-directed mutagenesis, highly decreased activity in both reaction directions compared to the wild-type enzyme, altered pH-dependency of the activity
K212R
site-directed mutagenesis, highly decreased activity in both reaction directions compared to the wild-type enzyme, altered pH-dependency of the activity
K212Y
site-directed mutagenesis, highly decreased activity in both reaction directions compared to the wild-type enzyme, altered pH-dependency of the activity
Y140E
site-directed mutagenesis, highly decreased activity in both reaction directions compared to the wild-type enzyme, unaltered Km for isocitrate and NADP+
Y140F
site-directed mutagenesis, highly decreased activity in both reaction directions compared to the wild-type enzyme, unaltered Km for isocitrate and NADP+
Y140K
site-directed mutagenesis, highly decreased activity in both reaction directions compared to the wild-type enzyme, unaltered Km for isocitrate and NADP+
Y140T
site-directed mutagenesis, highly decreased activity in both reaction directions compared to the wild-type enzyme, unaltered Km for isocitrate and NADP+, highly increased activation by added exogenous acetic acid and phenol compared to the wild-type enzyme
H309F
-
site-directed mutagenesis, inactive mutant, poor cofactor binding, altered secondary structure
H309Q
-
site-directed mutagenesis, inactive mutant, poor cofactor binding, altered secondary structure
H315Q
-
site-directed mutagenesis, 40fold increased Km for NADP+ compared to the wild-type enzyme
H319Q
-
site-directed mutagenesis, cofactor binding and kinetics similar to the wild-type enzyme, slightly reduced activity
N97A
-
site-directed mutagenesis, decreased Vmax compared to the wild-type enzyme, slightly affected Km values, but increased pKa of the ionizable metal-liganded hydroxyl of enzyme-bound isocitrate compared to the wild-type enzyme
N97D
-
site-directed mutagenesis, highly decreased Vmax compared to the wild-type enzyme
R132X
-
mutation of an arginine residue in pig mitochondrial IDH2 equivalent to R132 in human IDH1 causes a dramatic increase in Km for isocitrate by a factor of 165, with minimal effect on Vmax
R314Q
-
site-directed mutagenesis, 10fold increased Km for NADP+ compared to the wild-type enzyme
S95A
-
site-directed mutagenesis, decreased Vmax, and increased Km for isocitrate and Mn2+ compared to the wild-type enzyme
S95D
-
site-directed mutagenesis, highly decreased Vmax compared to the wild-type enzyme
T78A
-
site-directed mutagenesis, decreased Vmax, and increased Km for isocitrate and Mn2+ compared to the wild-type enzyme
Y316L
-
site-directed mutagenesis, 4fold increased Km for NADP+ compared to the wild-type enzyme
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
instable in solutions of low ionic strength, stabilization by ammonium sulfate
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant enzyme variants fused to the maltose binding fusion protein, from Escherichia coli, to homogeneity by amylose affinity, and ion exchange chromatography
recombinant wild-type and mutant enzymes from Escherichia coli, to homogeneity
glutathione-Sepharose column chromatography and DEAE-Sepharose chromatography
recombinant wild-type and mutant enzymes from Escherichia coli, cleavage of the fusion proteins by thrombin, to homogeneity by amylose affinity chromatography
-
recombinant wild-type and mutant enzymes from Escherichia coli, to homogeneity by amylose affinity chromatography, thrombin digestion, and DEAE ion exchange chromatography
-
recombinant wild-type and mutant maltose binding fusion proteins from Escherichia coli by amylose affinity and size exclusion chromatography
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli as maltose binding fusion protein, wild-type and selenomethionine enzyme variants
expression of wild-type and mutant enzymes in Escherichia coli as maltose binding fusion proteins
-
expression of wild-type and mutant enzymes in Escherichia coli as maltose-binding fusion proteins
-
expression of wild-type and mutant enzymes in Escherichia coli TB1 as maltose binding fusion proteins
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
RENATURED/Commentary
ORGANISM
UNIPROT
LITERATURE
oxidized glutathione leads to enzyme inactivation with simultaneous formation of a mixed disulfide between glutathione and the cysteine residues of enzyme. Enzymical reactivation by glutaredoxin2 in presence of reduced glutathione
-
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Plaut, G.W.E.
Isocitrate dehydrogenase
The Enzymes, 2nd Ed. (Boyer, P. D. , Lardy, H. , Myrbck, K. , eds. )
7
105-126
1963
Aspergillus niger, Saccharomyces cerevisiae, Citrobacter freundii, Mycobacterium tuberculosis, Sus scrofa, Trypanosoma cruzi
-
Curry, R.A.; Ting, I.P.
Purification, properties, and kinetic observations on the isoenzymes of NADP isocitrate dehydrogenase of maize
Arch. Biochem. Biophys.
176
501-509
1976
Azotobacter sp., Geobacillus stearothermophilus, Cereibacter sphaeroides, Sus scrofa, Zea mays
Grissom, C.B.; Cleland, W.W.
Isotope effect studies of the chemical mechanism of pig heart NADP isocitrate dehydrogenase
Biochemistry
27
2934-2943
1988
Sus scrofa
Lee, P.; Colman, R.F.
Implication by site-directed mutagenesis of Arg314 and Tyr316 in the coenzyme site of pig mitochondrial NADP-dependent isocitrate dehydrogenase
Arch. Biochem. Biophys.
401
81-90
2002
Sus scrofa
Huang, Y.C.; Colman, R.F.
Evaluation by mutagenesis of the roles of His309, His315, and His319 in the coenzyme site of pig heart NADP-dependent isocitrate dehydrogenase
Biochemistry
41
5637-5643
2002
Sus scrofa
Ceccarelli, C.; Grodsky, N.B.; Ariyaratne, N.; Colman, R.F.; Bahnson, B.J.
Crystal structure of porcine mitochondrial NADP+-dependent isocitrate dehydrogenase complexed with Mn2+ and isocitrate. Insights into the enzyme mechanism
J. Biol. Chem.
277
43454-43462
2002
Sus scrofa (P33198), Sus scrofa
Kim, T.K.; Lee, P.; Colman, R.F.
Critical role of Lys212 and Tyr140 in porcine NADP-dependent isocitrate dehydrogenase
J. Biol. Chem.
278
49323-49331
2003
Sus scrofa (P33198), Sus scrofa
Kim, T.K.; Colman, R.F.
Ser95, Asn97, and Thr78 are important for the catalytic function of porcine NADP-dependent isocitrate dehydrogenase
Protein Sci.
14
140-147
2005
Sus scrofa
Lee, P.; Colman, R.F.
Thr373, Asp375, and Lys260 are in the coenzyme site of porcine NADP-dependent isocitrate dehydrogenase
Arch. Biochem. Biophys.
450
183-190
2006
Sus scrofa (P33198), Sus scrofa
Kil, I.S.; Park, J.W.
Regulation of mitochondrial NADP+-dependent isocitrate dehydrogenase activity by glutathionylation
J. Biol. Chem.
280
10846-10854
2005
Sus scrofa
Huang, Y.C.; Colman, R.F.
Location of the coenzyme binding site in the porcine mitochondrial NADP-dependent isocitrate dehydrogenase
J. Biol. Chem.
280
30349-30353
2005
Sus scrofa (P33198), Sus scrofa
Kil, I.S.; Shin, S.W.; Yeo, H.S.; Lee, Y.S.; Park, J.W.
Mitochondrial NADP+-dependent isocitrate dehydrogenase protects cadmium-induced apoptosis
Mol. Pharmacol.
70
1053-1061
2006
Mus musculus, Sus scrofa
Zhao, S.; Lin, Y.; Xu, W.; Jiang, W.; Zha, Z.; Wang, P.; Yu, W.; Li, Z.; Gong, L.; Peng, Y.; Ding, J.; Lei, Q.; Guan, K.L.; Xiong, Y.
Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha
Science
324
261-265
2009
Homo sapiens, Sus scrofa
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