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Information on EC 1.1.1.42 - isocitrate dehydrogenase (NADP+) and Organism(s) Mus musculus and UniProt Accession O88844
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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: Mus musculus
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+-dependent isocitrate 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
-
-
-
-
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+
-
-
-
?
isocitrate + NADP+
2-oxoglutarate + CO2 + NADPH + H+
-
cytosolic enzyme is critical in fat and cholesterol biosynthesis, enzyme content correlates with adipogenesis in wild-type adipocytes and in transgenic cells
-
-
?
additional information
?
-
-
enzyme plays an important regulatory role in cellular defense against oxidative stress and in senescence
-
-
?
additional information
?
-
-
NADP+-dependent isocitrate dehydrogenase plays an important protective role in apoptosis of HL-60 cells induced by singlet oxygen
-
-
?
additional information
?
-
-
IDPm expression in HepG2 cells regulates ethanol-induced toxicity
-
-
?
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
isocitrate + NADP+
2-oxoglutarate + CO2 + NADPH + H+
-
-
-
?
isocitrate + NADP+
2-oxoglutarate + CO2 + NADPH + H+
-
cytosolic enzyme is critical in fat and cholesterol biosynthesis, enzyme content correlates with adipogenesis in wild-type adipocytes and in transgenic cells
-
-
?
additional information
?
-
-
enzyme plays an important regulatory role in cellular defense against oxidative stress and in senescence
-
-
?
additional information
?
-
-
NADP+-dependent isocitrate dehydrogenase plays an important protective role in apoptosis of HL-60 cells induced by singlet oxygen
-
-
?
additional information
?
-
-
IDPm expression in HepG2 cells regulates ethanol-induced toxicity
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Cd2+
the enzyme activity is increased at a Cd2+ concentration below 0.1 mM
Mg2+
the maximum activity with Mg2+ is slightly lower than that with Cd2+
Mg2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Cd2+
above 0.1 mM, the enzyme loses activity, and at 2 mM Cd2+ most of the activity has disappeared. Chelation of Cd2+ by dithiothreitol cannot recover the lost enzyme activity. Inactivation of the enzyme by Cd2+ is less effective when the enzyme is activated with Cd2+ than Mg2+, More than 50% of the activity of the enzyme activated with 0.05 mM Cd2+ remains in the presence of 1 mM GSH
Mn2+
the specific activity of purified enzyme is increased by Mn2+ in the micromolar range
Cd2+
-
coadministration with oxalomalate results in inhibition of enzyme and glutaredoxin and enhanced susceptibility to apoptosis
Oxalomalate
-
competitive, coadministration with CD2+ results in inhibition of enzyme and glutaredoxin and enhanced susceptibility to apoptosis
additional information
-
ischemia-reperfusion significantly reduces IDPc expression and activity
-
additional information
ischemia-reperfusion reduces IDH2 expression and activity in both Idh2+/+ and Idh2-/- kidneys
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SIRT3
under calorie restriction, mitochondrial deacetylase Sirt3 deacetylates and activates isoform IDH2
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
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
6.5 - 9
pH 6.5: about 60% of maximal activity, pH 9.0: about 70% of maximal activity, isoenzyme IDP1
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
IDPc expression and activity is highest in the cortex, modest in the outer medulla and lowest in the inner medulla, IDPc is also highly expressed in the mitochondrion-rich intercalatal cells of the collecting duct
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
additional information
the mouse isoenzyme IDP2 colocalizes in cytosol and peroxisomes when expressed in yeast
-
additional information
the mouse isoenzyme IDP2 colocalizes in cytosol and peroxisomes when expressed in yeast
-
additional information
-
the mouse isoenzyme IDP2 colocalizes in cytosol and peroxisomes when expressed in yeast
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
malfunction
mitochondrial NADP+-dependent isocitrate dehydrogenase deficiency exacerbates mitochondrial and cell damage after kidney ischemia-reperfusion injury, Idh2 gene deletion exacerbates ROS production and oxidative stress after ischemia-reperfusion, and causes I/R-induced mitochondrial dysfunction and morphologic fragmentation, resulting in severe apoptosis in kidney tubule cells, it impairs reduction of NADP+ and GSSG within mitochondria
malfunction
enzyme deficiency increases cisplatin-induced oxidative damage in kidney tubule cells, inducing more severe nephrotoxicity
malfunction
enzyme knockout mice are more susceptible to high fat diet-induced obesity than wild type mice.Brown adipose tissue dysfunction in the enzyme knockout mice is due to mitochondrial dysfunction
physiological function
mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) catalyzes the oxidative decarboxylation of isocitrate to 2-oxooglutarate, synthesizing NADPH, which is essential for mitochondrial redox balance
physiological function
the enzyme is critical in the NADPH-associated mitochondrial antioxidant system and is involved in cisplatin nephrotoxicity. The mitochondrial enzyme-NADPH-glutathione antioxidant system is a target for the prevention of cisplatin-induced kidney cell death
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). IDHC_MOUSE
414
0
46674
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
hanging drop vapor diffusion method, using 0.1 M sodium citrate, pH 5.5, 16% (w/v) PEG 4000, 20% (v/v) isopropanol
wild type and mutant enzyme K256Q, sitting drop vapor diffusion method, using 0.1 M sodium citrate tribasic dehydrate (pH 5.6), 11.5% (v/v) 2-propanol and 10.8% (w/v) PEG 4000
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C245S
the activities of the mutant in the presence of Cd2+ are decreased as that of wild type enzyme
C379S
the activity of the mutant in the absence of Cd2+ is similar to that of the wild type enzyme, but the decrease of activity in the presence of Cd2+ is much reduced
additional information
additional information
-
construction of transgenic mice by infection of fertilized eggs, enzyme overexpressing transgenic mice show increased triglyceride and cholesterol levels and develop fatty liver, hyperlipidemia, and obesity
additional information
Idh2 gene deletion, generation of Idh2-/- mice, phenotype,overview
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of mouse isoenzyme IDP2 in Escherichia coli or Saccharomyces cerevisiae. Mouse enzyme can compensate for loss of yeast cytosolic IDP2 and of peroxisomal IDP3IDP3. Removal of the peroxisomal targeting signal of the mouse enzyme precludes both localization in peroxisomes and compensation for loss of yeast IDP3
expression of the cDNA in a construct of nucleotides 1-1714 with rat PEPCK promotor and the SV-40 polyadenylation signal, permanant expression in 3T3-L1 cells and in transgenic mice, the latter are constructed by infection of fertilized eggs
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
ischemia-reperfusion reduces IDH2 expression and activity in both Idh2+/+ and Idh2-/- kidneys. IDH1 expression decreases 1 day after ischemia and then returns to around normal level by 16 days after ischemia
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Koh, H.J.; Lee, S.M.; Son, B.G.; Lee, S.H.; Ryoo, Z.Y.; Chang, K.T.; Park, J.W.; Park, D.C.; Song, B.J.; Veech, R.L.; Song, H.; Huh, T.L.
Cytosolic NADP+-dependent isocitrate dehydrogenase plays a key role in lipid metabolism
J. Biol. Chem.
279
39968-39974
2004
Mus musculus
Kil, I.S.; Huh, T.L.; Lee, Y.S.; Lee, Y.M.; Park, J.W.
Regulation of replicative senescence by NADP+ -dependent isocitrate dehydrogenase
Free Radic. Biol. Med.
40
110-119
2006
Mus musculus
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
Lu, Q.; Minard, K.I.; McAlister-Henn, L.
Dual compartmental localization and function of mammalian NADP+-specific isocitrate dehydrogenase in yeast
Arch. Biochem. Biophys.
472
17-25
2008
Saccharomyces cerevisiae, Saccharomyces cerevisiae (P21954), Saccharomyces cerevisiae (P41939), Mus musculus (O88844), Mus musculus (P54071), Mus musculus
Park, S.Y.; Lee, S.M.; Shin, S.W.; Park, J.W.
Inactivation of mitochondrial NADP+-dependent isocitrate dehydrogenase by hypochlorous acid
Free Radic. Res.
42
467-473
2008
Mus musculus (O88844), Homo sapiens (P48735), Homo sapiens
Kim, S.Y.; Lee, S.M.; Tak, J.K.; Choi, K.S.; Kwon, T.K.; Park, J.W.
Regulation of singlet oxygen-induced apoptosis by cytosolic NADP+-dependent isocitrate dehydrogenase
Mol. Cell. Biochem.
302
27-34
2007
Mus musculus
Kim, J.; Kim, K.Y.; Jang, H.S.; Yoshida, T.; Tsuchiya, K.; Nitta, K.; Park, J.W.; Bonventre, J.V.; Park, K.M.
Role of cytosolic NADP+-dependent isocitrate dehydrogenase in ischemia-reperfusion injury in mouse kidney
Am. J. Physiol. Renal Physiol.
296
F622-F633
2009
Mus musculus
Yang, E.S.; Park, J.W.
Regulation of ethanol-induced toxicity by mitochondrial NADP+-dependent isocitrate dehydrogenase
Biochimie
91
1020-1028
2009
Mus musculus
Han, S.J.; Jang, H.S.; Noh, M.R.; Kim, J.; Kong, M.J.; Kim, J.I.; Park, J.W.; Park, K.M.
Mitochondrial NADP+-dependent isocitrate dehydrogenase deficiency exacerbates mitochondrial and cell damage after kidney ischemia-reperfusion injury
J. Am. Soc. Nephrol.
28
1200-1215
2017
Mus musculus (P54071), Mus musculus C57BL/6 (P54071)
Kong, M.J.; Han, S.J.; Kim, J.I.; Park, J.W.; Park, K.M.
Mitochondrial NADP+-dependent isocitrate dehydrogenase deficiency increases cisplatin-induced oxidative damage in the kidney tubule cells
Cell Death Dis.
9
488
2018
Mus musculus (P54071)
Lee, J.H.; Go, Y.; Kim, D.Y.; Lee, S.H.; Kim, O.H.; Jeon, Y.H.; Kwon, T.K.; Bae, J.H.; Song, D.K.; Rhyu, I.J.; Lee, I.K.; Shong, M.; Oh, B.C.; Petucci, C.; Park, J.W.; Osborne, T.F.; Im, S.S.
Isocitrate dehydrogenase 2 protects mice from high-fat diet-induced metabolic stress by limiting oxidative damage to the mitochondria from brown adipose tissue
Exp. Mol. Med.
52
238-252
2020
Mus musculus (P54071)
Cho, H.J.; Cho, H.Y.; Park, J.W.; Kwon, O.S.; Lee, H.S.; Huh, T.L.; Kang, B.S.
NADP+-dependent cytosolic isocitrate dehydrogenase provides NADPH in the presence of cadmium due to the moderate chelating effect of glutathione
J. Biol. Inorg. Chem.
23
849-860
2018
Mus musculus (O88844)
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