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Protein

Isocitrate dehydrogenase [NADP] cytoplasmic

Gene

IDH1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Catalytic activityi

Isocitrate + NADP+ = 2-oxoglutarate + CO2 + NADPH.1 Publication

Cofactori

Mg2+1 Publication, Mn2+1 PublicationNote: Binds 1 Mg2+ or Mn2+ ion per subunit.1 Publication

Kineticsi

  1. KM=49 µM for NADP1 Publication
  2. KM=29 µM for magnesium chloride1 Publication
  3. KM=65 µM for isocitrate1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Binding sitei77Substrate1
    Binding sitei82NADP1 Publication1
    Binding sitei109Substrate1
    Binding sitei132Substrate1
    Sitei139Critical for catalysis1
    Sitei212Critical for catalysis1
    Metal bindingi252Magnesium or manganese1
    Binding sitei260NADP1 Publication1
    Metal bindingi275Magnesium or manganese1
    Binding sitei328NADP; via amide nitrogen and carbonyl oxygen1 Publication1

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi75 – 77NADP1 Publication3
    Nucleotide bindingi310 – 315NADP1 Publication6

    GO - Molecular functioni

    • (R)-2-hydroxyglutarate dehydrogenase activity Source: Reactome
    • cadherin binding Source: BHF-UCL
    • identical protein binding Source: IntAct
    • isocitrate dehydrogenase (NADP+) activity Source: UniProtKB
    • magnesium ion binding Source: UniProtKB
    • NAD binding Source: InterPro
    • NADP binding Source: Ensembl
    • protein homodimerization activity Source: UniProtKB
    • signaling receptor binding Source: UniProtKB

    GO - Biological processi

    Keywordsi

    Molecular functionOxidoreductase
    Biological processGlyoxylate bypass, Tricarboxylic acid cycle
    LigandMagnesium, Manganese, Metal-binding, NADP

    Enzyme and pathway databases

    BioCyciMetaCyc:HS06502-MONOMER
    BRENDAi1.1.1.42 2681
    ReactomeiR-HSA-2978092 Abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate
    R-HSA-389542 NADPH regeneration
    R-HSA-6798695 Neutrophil degranulation
    R-HSA-9033241 Peroxisomal protein import
    SABIO-RKO75874
    SIGNORiO75874

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Isocitrate dehydrogenase [NADP] cytoplasmic (EC:1.1.1.42)
    Short name:
    IDH
    Alternative name(s):
    Cytosolic NADP-isocitrate dehydrogenase
    IDP
    NADP(+)-specific ICDH
    Oxalosuccinate decarboxylase
    Gene namesi
    Name:IDH1
    Synonyms:PICD
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 2

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000138413.13
    HGNCiHGNC:5382 IDH1
    MIMi147700 gene
    neXtProtiNX_O75874

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Cytoplasm, Peroxisome

    Pathology & Biotechi

    Involvement in diseasei

    Glioma (GLM)2 Publications
    The gene represented in this entry is involved in disease pathogenesis. Mutations affecting Arg-132 are tissue-specific, and suggest that this residue plays a unique role in the development of high-grade gliomas. Mutations of Arg-132 to Cys, His, Leu or Ser abolish magnesium binding and abolish the conversion of isocitrate to alpha-ketoglutarate. Instead, alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. Elevated levels of R(-)-2-hydroxyglutarate are correlated with an elevated risk of malignant brain tumors.1 Publication
    Disease descriptionGliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes.
    See also OMIM:137800
    Genetic variations are associated with cartilaginous tumors such as enchondroma or chondrosarcoma. Mutations of Arg-132 to Cys, Gly or His abolish the conversion of isocitrate to alpha-ketoglutarate. Instead, alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate.1 Publication

    Organism-specific databases

    DisGeNETi3417
    MalaCardsiIDH1
    MIMi137800 phenotype
    OpenTargetsiENSG00000138413
    Orphaneti296 Enchondromatosis
    251579 Giant cell glioblastoma
    251576 Gliosarcoma
    163634 Maffucci syndrome
    99646 Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria
    PharmGKBiPA29630

    Chemistry databases

    ChEMBLiCHEMBL2007625
    DrugBankiDB03461 2'-Monophosphoadenosine 5'-Diphosphoribose
    DB09374 Indocyanine green
    DB01727 Isocitric Acid
    GuidetoPHARMACOLOGYi2884

    Polymorphism and mutation databases

    BioMutaiIDH1

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Initiator methionineiRemovedCombined sources
    ChainiPRO_00000835752 – 414Isocitrate dehydrogenase [NADP] cytoplasmicAdd BLAST413

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei2N-acetylserineCombined sources1
    Modified residuei42PhosphotyrosineCombined sources1
    Modified residuei81N6-acetyllysineBy similarity1
    Modified residuei126N6-succinyllysineBy similarity1
    Modified residuei224N6-acetyllysineBy similarity1
    Modified residuei233N6-acetyllysineBy similarity1
    Modified residuei243N6-acetyllysineBy similarity1
    Modified residuei321N6-acetyllysineCombined sources1
    Modified residuei389PhosphoserineBy similarity1
    Modified residuei400N6-succinyllysineBy similarity1

    Post-translational modificationi

    Acetylation at Lys-374 dramatically reduces catalytic activity.By similarity

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    EPDiO75874
    PaxDbiO75874
    PeptideAtlasiO75874
    PRIDEiO75874

    2D gel databases

    OGPiO75874
    REPRODUCTION-2DPAGEIPI00027223
    UCD-2DPAGEO75874

    PTM databases

    iPTMnetiO75874
    PhosphoSitePlusiO75874
    SwissPalmiO75874

    Expressioni

    Gene expression databases

    BgeeiENSG00000138413
    CleanExiHS_IDH1
    ExpressionAtlasiO75874 baseline and differential
    GenevisibleiO75874 HS

    Organism-specific databases

    HPAiCAB033218
    CAB062556
    HPA035248
    HPA057936

    Interactioni

    Subunit structurei

    Homodimer.2 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    itself4EBI-715695,EBI-715695

    GO - Molecular functioni

    • cadherin binding Source: BHF-UCL
    • identical protein binding Source: IntAct
    • protein homodimerization activity Source: UniProtKB
    • signaling receptor binding Source: UniProtKB

    Protein-protein interaction databases

    BioGridi109643, 62 interactors
    CORUMiO75874
    DIPiDIP-59311N
    IntActiO75874, 6 interactors
    MINTiO75874
    STRINGi9606.ENSP00000260985

    Chemistry databases

    BindingDBiO75874

    Structurei

    Secondary structure

    1414
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Beta strandi5 – 14Combined sources10
    Helixi17 – 29Combined sources13
    Turni30 – 34Combined sources5
    Beta strandi35 – 43Combined sources9
    Helixi46 – 51Combined sources6
    Turni52 – 54Combined sources3
    Helixi55 – 67Combined sources13
    Beta strandi68 – 72Combined sources5
    Helixi80 – 86Combined sources7
    Helixi95 – 103Combined sources9
    Beta strandi105 – 111Combined sources7
    Beta strandi126 – 134Combined sources9
    Helixi137 – 140Combined sources4
    Beta strandi142 – 146Combined sources5
    Beta strandi148 – 158Combined sources11
    Beta strandi165 – 172Combined sources8
    Beta strandi177 – 185Combined sources9
    Helixi186 – 203Combined sources18
    Beta strandi207 – 210Combined sources4
    Turni213 – 215Combined sources3
    Helixi219 – 234Combined sources16
    Helixi236 – 241Combined sources6
    Beta strandi246 – 248Combined sources3
    Helixi251 – 259Combined sources9
    Beta strandi263 – 269Combined sources7
    Beta strandi271 – 273Combined sources3
    Helixi276 – 278Combined sources3
    Helixi280 – 284Combined sources5
    Helixi288 – 290Combined sources3
    Beta strandi291 – 296Combined sources6
    Beta strandi303 – 309Combined sources7
    Helixi313 – 320Combined sources8
    Helixi330 – 347Combined sources18
    Helixi350 – 368Combined sources19
    Helixi374 – 381Combined sources8
    Helixi383 – 385Combined sources3
    Helixi388 – 390Combined sources3
    Helixi394 – 413Combined sources20

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    1T09X-ray2.70A/B1-414[»]
    1T0LX-ray2.41A/B/C/D1-414[»]
    3INMX-ray2.10A/B/C1-414[»]
    3MAPX-ray2.80A/B1-414[»]
    3MARX-ray3.41A/B1-414[»]
    3MASX-ray3.20A/B1-414[»]
    4I3KX-ray3.31A/B1-414[»]
    4I3LX-ray3.29A/B1-414[»]
    4KZOX-ray2.20A/B/C1-414[»]
    4L03X-ray2.10A/B/C1-414[»]
    4L04X-ray2.87A/B/C/D/E/F1-414[»]
    4L06X-ray2.28A/B/C/D/E/F1-414[»]
    4UMXX-ray1.88A/B1-414[»]
    4UMYX-ray2.07A/B1-414[»]
    4XRXX-ray3.20A/B1-414[»]
    4XS3X-ray3.29A/B1-414[»]
    5DE1X-ray2.25A/B2-414[»]
    5GIRX-ray1.93C/D126-137[»]
    5K10electron microscopy3.80A/B3-413[»]
    5K11electron microscopy3.80A/B3-413[»]
    5L57X-ray2.69A1-414[»]
    5L58X-ray3.04A1-414[»]
    5LGEX-ray2.70A/B/C/D1-414[»]
    5SUNX-ray2.48A/B1-414[»]
    5SVFX-ray2.34A/B/C/D1-414[»]
    5TQHX-ray2.20A/B/C/D1-414[»]
    5YFMX-ray2.40A/B/C1-414[»]
    5YFNX-ray2.50A/B1-414[»]
    6B0ZX-ray2.33A/B/C/D1-414[»]
    ProteinModelPortaliO75874
    SMRiO75874
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiO75874

    Family & Domainsi

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni94 – 100Substrate binding7

    Sequence similaritiesi

    Phylogenomic databases

    eggNOGiKOG1526 Eukaryota
    COG0538 LUCA
    GeneTreeiENSGT00390000012547
    HOGENOMiHOG000019858
    HOVERGENiHBG006119
    InParanoidiO75874
    KOiK00031
    OMAiAMGMYNQ
    OrthoDBiEOG091G06IY
    PhylomeDBiO75874
    TreeFamiTF300428

    Family and domain databases

    InterProiView protein in InterPro
    IPR019818 IsoCit/isopropylmalate_DH_CS
    IPR004790 Isocitrate_DH_NADP
    IPR024084 IsoPropMal-DH-like_dom
    PANTHERiPTHR11822 PTHR11822, 1 hit
    PfamiView protein in Pfam
    PF00180 Iso_dh, 1 hit
    PIRSFiPIRSF000108 IDH_NADP, 1 hit
    SMARTiView protein in SMART
    SM01329 Iso_dh, 1 hit
    TIGRFAMsiTIGR00127 nadp_idh_euk, 1 hit
    PROSITEiView protein in PROSITE
    PS00470 IDH_IMDH, 1 hit

    Sequencei

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    O75874-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MSKKISGGSV VEMQGDEMTR IIWELIKEKL IFPYVELDLH SYDLGIENRD
    60 70 80 90 100
    ATNDQVTKDA AEAIKKHNVG VKCATITPDE KRVEEFKLKQ MWKSPNGTIR
    110 120 130 140 150
    NILGGTVFRE AIICKNIPRL VSGWVKPIII GRHAYGDQYR ATDFVVPGPG
    160 170 180 190 200
    KVEITYTPSD GTQKVTYLVH NFEEGGGVAM GMYNQDKSIE DFAHSSFQMA
    210 220 230 240 250
    LSKGWPLYLS TKNTILKKYD GRFKDIFQEI YDKQYKSQFE AQKIWYEHRL
    260 270 280 290 300
    IDDMVAQAMK SEGGFIWACK NYDGDVQSDS VAQGYGSLGM MTSVLVCPDG
    310 320 330 340 350
    KTVEAEAAHG TVTRHYRMYQ KGQETSTNPI ASIFAWTRGL AHRAKLDNNK
    360 370 380 390 400
    ELAFFANALE EVSIETIEAG FMTKDLAACI KGLPNVQRSD YLNTFEFMDK
    410
    LGENLKIKLA QAKL
    Length:414
    Mass (Da):46,659
    Last modified:July 11, 2002 - v2
    Checksum:i60428B0B6E5851DC
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti32F → I in CAB66637 (PubMed:11230166).Curated1
    Sequence conflicti126K → E in CAB66637 (PubMed:11230166).Curated1
    Sequence conflicti172F → S in CAD97653 (PubMed:17974005).Curated1
    Sequence conflicti174E → G in CAD97653 (PubMed:17974005).Curated1
    Sequence conflicti218K → I in AAD02918 (PubMed:9866202).Curated1
    Sequence conflicti307A → S in AAH93020 (PubMed:15815621).Curated1
    Sequence conflicti329P → L in AAD02918 (PubMed:9866202).Curated1
    Sequence conflicti381K → R in AAD02918 (PubMed:9866202).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_036013132R → C in colorectal cancer and glioma samples; glioblastoma multiforme; somatic mutation; found in patients with cartilaginous tumors; abolishes magnesium binding and alters enzyme activity so that isocitrate is no longer converted to alpha-ketoglutarate but instead alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate; induces histone methylation; enhances expression of chondrocyte-related genes; disturbs the formation of cartilaginous matrix; inhibits osteogenic differentiation. 4 PublicationsCorresponds to variant dbSNP:rs121913499EnsemblClinVar.1
    Natural variantiVAR_055454132R → G in a glioma sample; glioblastoma multiforme; somatic mutation; found in patients with cartilaginous tumors. 2 Publications1
    Natural variantiVAR_055455132R → H in a glioma sample; glioblastoma multiforme; somatic mutation; found in patients with cartilaginous tumors; abolishes magnesium binding and alters enzyme activity so that isocitrate is no longer converted to alpha-ketoglutarate but instead alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. 3 PublicationsCorresponds to variant dbSNP:rs121913500EnsemblClinVar.1
    Natural variantiVAR_055456132R → L in a glioma sample; glioblastoma multiforme; somatic mutation; abolishes magnesium binding and alters enzyme activity so that isocitrate is no longer converted to alpha-ketoglutarate but instead alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. 2 Publications1
    Natural variantiVAR_055457132R → S in a glioma sample; glioblastoma multiforme; somatic mutation; abolishes magnesium binding and alters enzyme activity so that isocitrate is no longer converted to alpha-ketoglutarate but instead alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. 2 PublicationsCorresponds to variant dbSNP:rs121913499EnsemblClinVar.1
    Natural variantiVAR_049780178V → I. Corresponds to variant dbSNP:rs34218846EnsemblClinVar.1

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF020038 mRNA Translation: AAD02918.1
    AF113917 mRNA Translation: AAD29284.1
    AL136702 mRNA Translation: CAB66637.1
    CR541695 mRNA Translation: CAG46496.1
    BX537411 mRNA Translation: CAD97653.1
    AC016697 Genomic DNA Translation: AAX93221.1
    CH471063 Genomic DNA Translation: EAW70439.1
    BC012846 mRNA Translation: AAH12846.1
    BC093020 mRNA Translation: AAH93020.1
    U62389 mRNA Translation: AAB17375.1
    CCDSiCCDS2381.1
    PIRiT46280
    RefSeqiNP_001269315.1, NM_001282386.1
    NP_001269316.1, NM_001282387.1
    NP_005887.2, NM_005896.3
    UniGeneiHs.593422

    Genome annotation databases

    EnsembliENST00000345146; ENSP00000260985; ENSG00000138413
    ENST00000415913; ENSP00000390265; ENSG00000138413
    ENST00000446179; ENSP00000410513; ENSG00000138413
    GeneIDi3417
    KEGGihsa:3417

    Keywords - Coding sequence diversityi

    Polymorphism

    Similar proteinsi

    Entry informationi

    Entry nameiIDHC_HUMAN
    AccessioniPrimary (citable) accession number: O75874
    Secondary accession number(s): Q567U4
    , Q6FHQ6, Q7Z3V0, Q93090, Q9NTJ9, Q9UKW8
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 30, 2000
    Last sequence update: July 11, 2002
    Last modified: May 23, 2018
    This is version 193 of the entry and version 2 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

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