Molecule Information

General Information of the Molecule (ID: Mol04122)
Name
Isocitrate dehydrogenase [NADP] mitochondrial (IDH2) ,Homo sapiens
Synonyms
ICD-M; IDP; NADP(+)-specific ICDH; Oxalosuccinate decarboxylase
    Click to Show/Hide
Molecule Type
Protein
Gene Name
IDH2
Gene ID
3418
Location
chr15:90083045-90102477[-]
Sequence
MAGYLRVVRSLCRASGSRPAWAPAALTAPTSQEQPRRHYADKRIKVAKPVVEMDGDEMTR
IIWQFIKEKLILPHVDIQLKYFDLGLPNRDQTDDQVTIDSALATQKYSVAVKCATITPDE
ARVEEFKLKKMWKSPNGTIRNILGGTVFREPIICKNIPRLVPGWTKPITIGRHAHGDQYK
ATDFVADRAGTFKMVFTPKDGSGVKEWEVYNFPAGGVGMGMYNTDESISGFAHSCFQYAI
QKKWPLYMSTKNTILKAYDGRFKDIFQEIFDKHYKTDFDKNKIWYEHRLIDDMVAQVLKS
SGGFVWACKNYDGDVQSDILAQGFGSLGLMTSVLVCPDGKTIEAEAAHGTVTRHYREHQK
GRPTSTNPIASIFAWTRGLEHRGKLDGNQDLIRFAQMLEKVCVETVESGAMTKDLAGCIH
GLSNVKLNEHFLNTTDFLDTIKSNLDRALGRQ
    Click to Show/Hide
3D-structure
PDB ID
5GIS
Classification
Immune system
Method
X-ray diffraction
Resolution
1.93  Å
Function
Plays a role in intermediary metabolism and energy production (PubMed:19228619, PubMed:22416140). It may tightly associate or interact with the pyruvate dehydrogenase complex (PubMed:19228619, PubMed:22416140). .
    Click to Show/Hide
Uniprot ID
IDHP_HUMAN
Ensembl ID
ENSG00000182054
HGNC ID
HGNC:5383
        Click to Show/Hide the Complete Species Lineage
Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens
Type(s) of Resistant Mechanism of This Molecule
  ADTT: Aberration of the Drug's Therapeutic Target
  MRAP: Metabolic Reprogramming via Altered Pathways
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
4 drug(s) in total
Click to Show/Hide the Full List of Drugs
Rhodium trichloride hydrate
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Disease Class: Urothelial carcinoma [ICD-11: 2C94.2] [1]
Metabolic Type Glucose metabolism
Resistant Disease Urothelial carcinoma [ICD-11: 2C94.2]
 Disease Info 
Resistant Drug Rhodium trichloride hydrate
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Adrenergic signaling in cardiomyocytes Activation hsa04261
In Vivo Model BALB/c-nu/nu mice, with UMUC3GR cells Mice
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 Tumor volume assay
Mechanism Description Furthermore, we observed that gain-of-function of isocitrate dehydrogenase 2 (IDH2) induced reductive glutamine metabolism to stabilize Hif-1alpha expression and consequently stimulate aerobic glycolysis and PPP bypass in gemcitabine-resistant UC cells. Interestingly, IDH2-mediated metabolic reprogramming also caused cross resistance to CDDP, by elevating the antioxidant defense via increased NADPH and glutathione production. Downregulation or pharmacological suppression of IDH2 restored chemosensitivity.
Cytarabine
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [2]
Metabolic Type Glucose metabolism
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Resistant Drug Cytarabine
 Drug Info 
Molecule Alteration Mutation
.
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Longevity regulating pathway - multiple species Activation hsa04213
In Vitro Model AML cells N.A. Homo sapiens (Human) N.A.
HL-60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
IDH2 mutant AML cells Blood Homo sapiens (Human) CVCL_S481
KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
Experiment for
Drug Resistance		 IC50 assay
Mechanism Description The increase in glycolysis levels following IDH2 mutation may contribute to the reduced efficacy of Enasidenib in inhibiting the proliferation of IDH-mutant AML cells.
Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [2]
Metabolic Type Glucose metabolism
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Resistant Drug Cytarabine
 Drug Info 
Molecule Alteration Mutation
.
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Longevity regulating pathway - multiple species Activation hsa04213
In Vivo Model AML cell-transplanted tumor nude mice with IDH2 mutations Mice
Experiment for
Drug Resistance		 Tumor volume assay
Mechanism Description The increase in glycolysis levels following IDH2 mutation may contribute to the reduced efficacy of Enasidenib in inhibiting the proliferation of IDH-mutant AML cells.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [3]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Resistant Drug Cytarabine
 Drug Info 
Molecule Alteration Mutation
.
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation PI3K-Akt signaling pathway Activation hsa04151
In Vitro Model HL-60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description The IDH2 mutations are involved in Ara-C resistance by affecting the process of glycolysis in AML, and the PI3K-Akt signaling pathway plays an important role in this process. These pathways are expected to be important targets for targeted therapeutic intervention in the AML setting.
Gemcitabine
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Disease Class: Urothelial carcinoma [ICD-11: 2C94.2] [1]
Metabolic Type Glucose metabolism
Resistant Disease Urothelial carcinoma [ICD-11: 2C94.2]
 Disease Info 
Resistant Drug Gemcitabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Adrenergic signaling in cardiomyocytes Activation hsa04261
In Vivo Model BALB/c-nu/nu mice, with UMUC3GR cells Mice
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 Tumor volume assay
Mechanism Description Furthermore, we observed that gain-of-function of isocitrate dehydrogenase 2 (IDH2) induced reductive glutamine metabolism to stabilize Hif-1alpha expression and consequently stimulate aerobic glycolysis and PPP bypass in gemcitabine-resistant UC cells. Interestingly, IDH2-mediated metabolic reprogramming also caused cross resistance to CDDP, by elevating the antioxidant defense via increased NADPH and glutathione production. Downregulation or pharmacological suppression of IDH2 restored chemosensitivity.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Bladder cancer [ICD-11: 2C94.0] [4]
Resistant Disease Bladder cancer [ICD-11: 2C94.0]
 Disease Info 
Resistant Drug Gemcitabine
 Drug Info 
Molecule Alteration Expression
Activation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Aerobic glycolysis signaling pathway Regulation N.A.
HIF1alpha stabilization signaling pathway Regulation N.A.
In Vitro Model T24 cells Bladder Homo sapiens (Human) CVCL_0554
J82 cells Bladder Homo sapiens (Human) CVCL_0359
In Vivo Model BALB/c female nude mice model Mus musculus
Experiment for
Molecule Alteration		 MS analysis; Western blot assay; Immunohistochemistry
Experiment for
Drug Resistance		 IC50 assay; Cell proliferation assay; Migration ability assay; Invasion ability assay; Apoptosis assay
Mechanism Description Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1alpha (HIF1alpha) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized HIF1alpha expression. PHGDH downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion.
Disease Class: Bladder cancer [ICD-11: 2C94.0] [4]
Resistant Disease Bladder cancer [ICD-11: 2C94.0]
 Disease Info 
Resistant Drug Gemcitabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Aerobic glycolysis signaling pathway Regulation N.A.
In Vitro Model T24 cells Bladder Homo sapiens (Human) CVCL_0554
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 Trypan blue exclusion assay; XTT assay
Mechanism Description Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1alpha (HIF1alpha) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized?HIF1alpha?expression.?PHGDH?downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion. Cisplatin-resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (FASN) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl-CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1alpha expression.
Venetoclax
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Diffuse large B-cell lymphoma [ICD-11: 2A81.0] [5]
Resistant Disease Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
 Disease Info 
Resistant Drug Venetoclax
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Oxidative phosphorylation Activation hsa00190
Citrate cycle Regulation N.A.
Glutathione metabolism Activation hsa00480
Carbon metabolism Activation hsa01200
In Vitro Model SU-DHL-2 cells N.A. Homo sapiens (Human) CVCL_9950
SUDHL4 cells Blood Homo sapiens (Human) CVCL_0539
SUDHL5 cells Blood Homo sapiens (Human) CVCL_1735
SUDHL6 cells Blood Homo sapiens (Human) CVCL_2206
SUDHL8 cells Blood Homo sapiens (Human) CVCL_2207
SUDHL10 cells Blood Homo sapiens (Human) CVCL_1889
SUDHL16 cells Blood Homo sapiens (Human) CVCL_1890
Toledo cells Peripheral blood Homo sapiens (Human) CVCL_3611
Experiment for
Molecule Alteration		 Western blot assay; RNA Sequencing assay; Flow cytometry
Experiment for
Drug Resistance		 Cell survival and synergy assay; Caspase-3/7 apoptosis assay; Live/Dead assay
Mechanism Description Our findings demonstrate that multiple, complex mechanisms of venetoclax resistance can emerge in DLBCL. However, our elucidation of the increased vulnerability of venetoclax-resistant DLBCL to ETC complex I and IDH2 inhibition revealed potential new treatment approaches to overcome venetoclax resistance. Although there is still interest in adding venetoclax to decrease the threshold of apoptosis in the therapeutic armamentarium for DLBCL as a combination therapy, targeting other BCL2 family members, such as BCLW and BFL1, for which there are currently no specific targeted agents, could also be an option.
Preclinical Drug(s)
2 drug(s) in total
Click to Show/Hide the Full List of Drugs
AGI-6780
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Disease Class: Urothelial carcinoma [ICD-11: 2C94.2] [1]
Metabolic Type Glucose metabolism
Sensitive Disease Urothelial carcinoma [ICD-11: 2C94.2]
 Disease Info 
Sensitive Drug AGI-6780
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Adrenergic signaling in cardiomyocytes Activation hsa04261
In Vivo Model BALB/c-nu/nu mice, with UMUC3GR cells Mice
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 Tumor volume assay
Mechanism Description Furthermore, we observed that gain-of-function of isocitrate dehydrogenase 2 (IDH2) induced reductive glutamine metabolism to stabilize Hif-1alpha expression and consequently stimulate aerobic glycolysis and PPP bypass in gemcitabine-resistant UC cells. Interestingly, IDH2-mediated metabolic reprogramming also caused cross resistance to CDDP, by elevating the antioxidant defense via increased NADPH and glutathione production. Downregulation or pharmacological suppression of IDH2 restored chemosensitivity.
Enasidinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [3]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Resistant Drug Enasidinib
 Drug Info 
Molecule Alteration Mutation
.
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HL-60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description IDH2 mutations reduce AML sensitivity to Enasidinib
Investigative Drug(s)
1 drug(s) in total
Click to Show/Hide the Full List of Drugs
2-DG
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [3]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Sensitive Drug 2-DG
 Drug Info 
Molecule Alteration Mutation
.
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation PI3K-Akt signaling pathway Activation hsa04151
In Vitro Model HL-60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description The IDH2 mutations are involved in Ara-C resistance by affecting the process of glycolysis in AML, and the PI3K-Akt signaling pathway plays an important role in this process. These pathways are expected to be important targets for targeted therapeutic intervention in the AML setting. 2-DG significantly inhibited cell proliferation and glycolysis in IDH2 mutation cell lines.
References
Ref 1 IDH2 stabilizes HIF-1alpha-induced metabolic reprogramming and promotes chemoresistance in urothelial cancer. EMBO J. 2023 Feb 15;42(4):e110620.
Ref 2 Isocitrate dehydrogenase 2 mutation promotes cytarabine resistance in acute myeloid leukemia by Warburg effect. Hematol Oncol. 2024 Nov;42(6):e3316.
Ref 3 Isocitrate dehydrogenase 2 mutation promotes cytarabine resistance in acute myeloid leukemia by Warburg effect. Hematol Oncol. 2024 Nov;42(6):e3316.
Ref 4 Targeting metabolic reprogramming to overcome drug resistance in advanced bladder cancer: insights from gemcitabine- and cisplatin-resistant models. Mol Oncol. 2024 Sep;18(9):2196-2211.
Ref 5 Identifying Targetable Vulnerabilities to Circumvent or Overcome Venetoclax Resistance in Diffuse Large B-Cell Lymphoma. Cancers (Basel). 2024 Jun 3;16(11):2130.

If you find any error in data or bug in web service, please kindly report it to Dr. Sun and Dr. Yu.