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Information on EC 1.1.1.41 - isocitrate dehydrogenase (NAD+) and Organism(s) Homo sapiens

for references in articles please use BRENDA:EC1.1.1.41
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IUBMB Comments
Requires Mn2+ or Mg2+ for activity. Unlike EC 1.1.1.42, isocitrate dehydrogenase (NADP+), oxalosuccinate cannot 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 NADP+ but much more slowly .
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Homo sapiens
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The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Archaea, Eukaryota
Reaction Schemes
hide
isocitrate
+
NAD+
=
2-oxoglutarate
+
CO2
+
NADH
+
H+
+
=
+
+
+
Synonyms
isocitrate dehydrogenase, isocitrate dehydrogenase 2, isocitric dehydrogenase, nad-dependent isocitrate dehydrogenase, idh3a, nad-idh, nad-isocitrate dehydrogenase, nad-icdh, nad+-dependent isocitrate dehydrogenase, nad-linked isocitrate dehydrogenase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
beta-ketoglutaric-isocitric carboxylase
-
-
-
-
hNAD-IDHalpha
-
isocitrate dehydrogenase
-
-
isocitrate dehydrogenase 3alpha subunit
-
isocitric acid dehydrogenase
-
-
-
-
isocitric dehydrogenase
-
-
-
-
NAD dependent isocitrate dehydrogenase
-
-
-
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NAD isocitrate dehydrogenase
-
-
-
-
NAD isocitric dehydrogenase
-
-
-
-
NAD+-dependent isocitrate dehydrogenase
-
-
NAD+-dependent isocitrate dehydrogenase 3
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NAD+-IDH
-
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NAD+-specific ICDH
-
-
-
-
NAD-dependent isocitrate dehydrogenase
NAD-IDH
NAD-linked isocitrate dehydrogenase
-
-
-
-
NAD-specific isocitrate dehydrogenase
threo-DS-isocitrate:NAD+ oxidoreductase (decarboxylating)
-
-
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
isocitrate + NAD+ = 2-oxoglutarate + CO2 + NADH + H+
show the reaction diagram
Arg97, and Arg99 contribute to activity, Arg88 is essential for catalysis
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
-
-
-
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oxidative decarboxylation
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-
-
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redox reaction
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-
-
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reduction
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-
-
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reductive carboxylation
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
isocitrate:NAD+ oxidoreductase (decarboxylating)
Requires Mn2+ or Mg2+ for activity. Unlike EC 1.1.1.42, isocitrate dehydrogenase (NADP+), oxalosuccinate cannot 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 [7]. The enzyme from some species can also use NADP+ but much more slowly [9].
CAS REGISTRY NUMBER
COMMENTARY hide
9001-58-5
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
D-isocitrate + NAD+
2-oxoglutarate + CO2 + NADH
show the reaction diagram
-
-
-
-
?
DL-isocitrate + NAD+
2-oxoglutarate + CO2 + NADH
show the reaction diagram
-
-
-
?
isocitrate + NAD+
2-oxoglutarate + CO2 + NADH + H+
show the reaction diagram
isocitrate + NAD+
2-oxoglutarate + NADH + H+ + CO2
show the reaction diagram
threo-Ds-isocitrate + NAD+
2-oxoglutarate + CO2 + NADH
show the reaction diagram
-
-
-
-
?
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
isocitrate + NAD+
2-oxoglutarate + CO2 + NADH + H+
show the reaction diagram
isocitrate + NAD+
2-oxoglutarate + NADH + H+ + CO2
show the reaction diagram
threo-Ds-isocitrate + NAD+
2-oxoglutarate + CO2 + NADH
show the reaction diagram
-
-
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
NADH
-
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Co2+
-
essential divalent metal ion
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
tributyltin
TBT, active in NT2/D1 carcinoma cells, overview. At nanomoler concentrations, tributyltin actions are mediated by genomic pathways via peroxisome proliferator-activated receptor gamma/retinoid X receptor, PPAR/RXR. Binding and in silico docking simulation analysis, overview
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
ATP
the enzyme can be activated by low concentrations of ATP. At high concentrations ATP is competitive with NAD+ for binding to the catalytic site
citrate
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.09 - 41
isocitrate
0.22 - 0.39
Mn2+
0.004 - 1.5
NAD+
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.27 - 36.8
D-isocitrate
0.27 - 36.8
isocitrate
0.27 - 36.8
NAD+
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0785 - 0.0949
NADH
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.2
-
D234C, alpha-subunit mutant, in 20 mM D-isocitrate and 1 mM MnSO4
1.4
-
D230C, alpha-subunit mutant, in 20 mM D-isocitrate and 1 mM MnSO4
13.5
-
purified recombinant mutant beta-R99Q
2.2
-
purified recombinant mutant gamma-R97Q
21.7
-
purified recombinant wild-type enzyme
22
-
wild type enzyme, in 20 mM D-isocitrate and 1 mM MnSO4
29
-
D206N, alpha-subunit mutant, in 20 mM D-isocitrate and 1 mM MnSO4
3.7
-
D215N, gamma-subunit mutant, in 20 mM D-isocitrate and 1 mM MnSO4
7.3
-
D217N, beta-subunit mutant, in 20 mM D-isocitrate and 1 mM MnSO4
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.2
-
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
25
-
assay at
37
-
assay at
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
malignant
Manually annotated by BRENDA team
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multiple
Manually annotated by BRENDA team
additional information
ubiquitous tissue specific expression of isocitrate dehydrogenase 3alpha subunit
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
metabolism
physiological function
IDH3alpha increases the phosphorylation level and activation of Akt (protein kinase B)
additional information
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
IDH3A_HUMAN
366
0
39592
Swiss-Prot
Mitochondrion (Reliability: 4)
IDH3B_HUMAN
385
0
42184
Swiss-Prot
-
IDH3G_HUMAN
393
0
42794
Swiss-Prot
-
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
238000
-
gel filtration
315000
-
about, recombinant wild-type and mutant enzymes, gel filtration
37000
-
2 * 37000, 1 * 39000, 1 * 39000
39000
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2 * 37000, 1 * 39000, 1 * 39000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
heterooctamer
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heterotetramer
tetramer
-
-
additional information
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
alphabeta heterodimer with the alpha subunit in apo form and in Ca2_-bound, NAD-bound, and NADH-bound forms, hanging drop vapor diffusion method, using either containing 8% (v/v) tacsimate (pH 6.0) and 20% (w/v) PEG 3350 or 0.2 M calcium acetate (pH 7.5) and 20% (w/v) PEG 3350
alphagamma heterodimer bound with an Mg2+ and an NADH at the active site and an NADH at the allosteric site, hanging drop vapor diffusion method, using 0.1 M HEPES (pH 7.5), 50 mM MgCl2, and 30% (w/v) PEGMME 550
alphagamma heterodimer with the active site bound with either Mg2+ alone or Mg2+ and ATP, and the allosteric site bound with Mg2+, citrate and ATP, hanging drop vapor diffusion method, using 0.2 M sodium citrate, pH 8.0, and 20% (w/v) PEG3350 or 0.2 M sodium citrate, pH 5.5, and 24% (v/v) PEG400
isoform IDH3 containing a beta mutant in apo form, hanging drop vapor diffusion method, using 0.05M NH4Cl, 0.05 Bis-Tris (pH 6.5), and 30% (w/v) pentaerythritol ethoxylate
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
alphaY126E
-
site-directed mutagenesis of subunit alpha, almost inactive mutant, shows low activity at pH 6.1 instead of pH 7.2, Km,Mn2+ is 30fold higher in the alphaY126E mutant as compared with the wild-type. Km,NAD+ for the alphaY126E mutant is 29fold higher than that of the wild-type. The Vmax of the wild-type at pH 6.1 is 0.0144 mmol/min/mg, whereas that for the alphaY126E mutant is only 0.00103 mmol/min/mg, suggesting a critical role for the residue in enzyme activity
alphaY126F
-
site-directed mutagenesis of subunit alpha, inactive mutant
alphaY126S
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site-directed mutagenesis of subunit alpha, inactive mutant
betaY137E
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site-directed mutagenesis of subunit beta, the mutant shows reduced activity compared to the wild-type enzyme
betaY137F
-
site-directed mutagenesis of subunit beta, the mutant shows reduced activity compared to the wild-type enzyme
betaY137S
-
site-directed mutagenesis of subunit beta, the mutant shows reduced activity compared to the wild-type enzyme
D181N
-
mutation in the alpha-subunit exhibits a 2000fold decrease in Vmax, with increases of 15fold in the Kms for Mn2+ and NAD+ and a much smaller change in the Km for isocitrate. Mutant enzyme fails to respond to ADP by lowering the Km for isocitrate, although it binds to ADP
D190N
-
mutation in the gamma-subunit results in 4-5fold decrease in Vmax as compared to wild-type enzyme. The Km-values for NAD+ and for Mn2+ of the mutant enzyme are 19 and 72 times, respectively, that of the wild-type enzyme with a much smaller effect on the Km for isocitrate. Mutant enzyme fails to respond to ADP by lowering the Km for isocitrate, although it binds to ADP
D192N
-
mutation in the beta-subunit results in 4-5fold decrease in Vmax as compared to wild-type enzyme. The Km-value for NAD+ of the mutant enzyme is 9times that of the normal enzyme with little or no effect on the affinity for Mn2+ or isocitrate. Mutant enzyme fails to respond to ADP by lowering the Km for isocitrate, although it binds to ADP
D206N
D215N
D217N
D230C
D230N
D234C
D234N
gammaY135F
-
site-directed mutagenesis of subunit gamma, inactive mutant
L98P
the mutation is associated with retinitis pigmentosa
R132C
-
naturally occuring IDH1 mutation
R132G
-
naturally occuring IDH1 mutation
R132H
-
naturally occuring IDH1 mutation
R132L
-
naturally occuring IDH1 mutation
R132S
-
naturally occuring IDH1 mutation
R132V
-
naturally occuring IDH1 mutation
R88Q
-
site-directed mutagenesis, residue of the alpha-subunit, inactive mutant
R97Q
-
site-directed mutagenesis, residue of the additional mutant gamma-subunit, highly reduced activity compared to the wild-type enzyme
R99Q
-
site-directed mutagenesis, residue of the beta-subunit, reduced activity compared to the wild-type enzyme
additional information
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
ammonium sulfate fractionation and gel filtration
-
Ni-NTA column chromatography and Superdex 200 gel filtration
recombinant wild-type and mutant enzymes from Escherichia coli
-
recombinant wild-type and mutant NAD-IDHs from Escherichia coli by ammonium sulfate fractionation, anion exchange chromatography, ultrafiltration, and gel filtration
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli
-
expressed in Escherichia coli BL21(DE3) Codon-Plus cells
expressed in Escherichia coli BL21(DE3) CodonPlus cells
expression in Escherichia coli
-
expression of wild-type and mutant NAD-IDHs in Escherichia coli
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gene IDH3A, real-time PCR expression analysis
genotyping in diverse cancer cell lines, overview
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IDH3alpha, DNA and amino acid sequence analysis and comparison
overexpression of the wild-type and a mutant enzyme, the latter containing the wild-type 2 subunits alpha and beta plus an additional third one, gamma, overexpression of the 3-subunit mutant and the same mutant with point mutations of Arg-residues in Escherichia coli
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
aflatoxin B1, AFB1, upregulates the enzyme in vivo and in vitro, in cells and in the process of AFB1-induced liver lesion
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
diagnostics
-
enzyme NAD+-dependent isocitrate dehydrogenase cann act as a mitochondrial marker in asthenozoospermia
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, Bos taurus, Saccharomyces cerevisiae, Cavia porcellus, Columba livia, Homo sapiens, Pisum sativum, Rattus norvegicus
-
Manually annotated by BRENDA team
Kim, Y.O.; Koh, H.J.; Kim, S.H.; Jo, S.H.; Huh, J.W.; Jeong, K.S.; Lee, I.J.; Song, B.J.; Huh, T.L.
Identification and functional characterization of a novel tissue-specific NAD+-dependent isocitrate dehydrogenase beta subunit isoform
J. Biol. Chem.
274
36866-36875
1999
Homo sapiens
Manually annotated by BRENDA team
Soundar, S.; Park, J.H.; Huh, T.L.; Colman, R.F.
Evaluation by mutagenesis of the importance of 3 arginines in alpha, beta, and gamma subunits of human NAD-dependent isocitrate dehydrogenase
J. Biol. Chem.
278
52146-52153
2003
Homo sapiens
Manually annotated by BRENDA team
Soundar, S.; Ohagan, M.; Fomulu, K.S.; Colman, R.F.
Identification of Mn2+-binding aspartates from alpha, beta, and gamma subunits of human NAD-dependent isocitrate dehydrogenase
J. Biol. Chem.
281
21073-21081
2006
Homo sapiens
Manually annotated by BRENDA team
Bzymek, K.P.; Colman, R.F.
Role of alpha-Asp181, beta-Asp192, and gamma-Asp190 in the distinctive subunits of human NAD-specific isocitrate dehydrogenase
Biochemistry
46
5391-5397
2007
Homo sapiens
Manually annotated by BRENDA team
Hartong, D.T.; Dange, M.; McGee, T.L.; Berson, E.L.; Dryja, T.P.; Colman, R.F.
Novel insights into the contributions of isocitrate dehydrogenases to the Krebs cycle from patients with retinitis pigmentosa
Nat. Genet.
40
1230-1234
2008
Homo sapiens (O43837)
Manually annotated by BRENDA team
Kang, M.R.; Kim, M.S.; Oh, J.E.; Kim, Y.R.; Song, S.Y.; Seo, S.I.; Lee, J.Y.; Yoo, N.J.; Lee, S.H.
Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers
Int. J. Cancer
125
353-355
2009
Homo sapiens
Manually annotated by BRENDA team
Dange, M.; Colman, R.F.
Each conserved active site tyr in the three subunits of human isocitrate dehydrogenase has a different function
J. Biol. Chem.
285
20520-20525
2010
Homo sapiens
Manually annotated by BRENDA team
Hagras, A.; Toraih, E.; Fawzy, M.
Mobile phones electromagnetic radiation and NAD
Biochim. Open
3
19-25
2016
Homo sapiens
Manually annotated by BRENDA team
Yamada, S.; Kotake, Y.; Demizu, Y.; Kurihara, M.; Sekino, Y.; Kanda, Y.
NAD-dependent isocitrate dehydrogenase as a novel target of tributyltin in human embryonic carcinoma cells
Sci. Rep.
4
5952
2014
Homo sapiens (P50213), Homo sapiens
Manually annotated by BRENDA team
Yang, C.; Fan, J.; Zhuang, Z.; Fang, Y.; Zhang, Y.; Wang, S.
The role of NAD+-dependent isocitrate dehydrogenase 3 subunit alpha in AFB1 induced liver lesion
Toxicol. Lett.
224
371-379
2014
Homo sapiens (P50213), Rattus norvegicus (Q99NA5), Mus musculus (Q9D6R2)
Manually annotated by BRENDA team
Sun, P.; Liu, Y.; Ma, T.; Ding, J.
Structure and allosteric regulation of human NAD-dependent isocitrate dehydrogenase
Cell Discov.
6
94
2020
Homo sapiens (P50213 and O43837 and P51553), Homo sapiens
Manually annotated by BRENDA team
Sun, P.; Ma, T.; Zhang, T.; Zhu, H.; Zhang, J.; Liu, Y.; Ding, J.
Molecular basis for the function of the alphabeta heterodimer of human NAD-dependent isocitrate dehydrogenase
J. Biol. Chem.
294
16214-16227
2019
Homo sapiens (P50213 and O43837), Homo sapiens
Manually annotated by BRENDA team
Sun, P.; Bai, T.; Ma, T.; Ding, J.
Molecular mechanism of the dual regulatory roles of ATP on the alphagamma heterodimer of human NAD-dependent isocitrate dehydrogenase
Sci. Rep.
10
6225
2020
Homo sapiens (P50213 and O43837 and P51553), Homo sapiens
Manually annotated by BRENDA team
Ma, T.; Peng, Y.; Huang, W.; Ding, J.
Molecular mechanism of the allosteric regulation of the alphagamma heterodimer of human NAD-dependent isocitrate dehydrogenase
Sci. Rep.
7
40921
2017
Homo sapiens (P50213 and O43837 and P51553), Homo sapiens
Manually annotated by BRENDA team
Liu, Y.; Hu, L.; Ma, T.; Yang, J.; Ding, J.
Insights into the inhibitory mechanisms of NADH on the alphagamma heterodimer of human NAD-dependent isocitrate dehydrogenase
Sci. Rep.
8
3146
2018
Homo sapiens (P50213 and O43837 and P51553), Homo sapiens
Manually annotated by BRENDA team