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Protein

Inosine-5'-monophosphate dehydrogenase 2

Gene

IMPDH2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth. Could also have a single-stranded nucleic acid-binding activity and could play a role in RNA and/or DNA metabolism. It may also have a role in the development of malignancy and the growth progression of some tumors.

Catalytic activityi

Inosine 5'-phosphate + NAD+ + H2O = xanthosine 5'-phosphate + NADH.UniRule annotation

Cofactori

Enzyme regulationi

Mycophenolic acid (MPA) is a non-competitive inhibitor that prevents formation of the closed enzyme conformation by binding to the same site as the amobile flap. In contrast, mizoribine monophosphate (MZP) is a competitive inhibitor that induces the closed conformation. MPA is a potent inhibitor of mammalian IMPDHs but a poor inhibitor of the bacterial enzymes. MZP is a more potent inhibitor of bacterial IMPDH. Subject to product inhibition by XMP and NADH. Also inhibited by ADP.UniRule annotation1 Publication

Kineticsi

  1. KM=9.3 µM for Inosine 5'-phosphate2 Publications
  2. KM=32 µM for NAD+2 Publications

    Pathwayi: XMP biosynthesis via de novo pathway

    This protein is involved in step 1 of the subpathway that synthesizes XMP from IMP.UniRule annotation
    Proteins known to be involved in this subpathway in this organism are:
    1. Inosine-5'-monophosphate dehydrogenase (IMPDH), Inosine-5'-monophosphate dehydrogenase (IMPDH1), Inosine-5'-monophosphate dehydrogenase (IMPDH), Inosine-5'-monophosphate dehydrogenase (IMPDH), Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1), Inosine-5'-monophosphate dehydrogenase 2 (IMPDH2), Inosine-5'-monophosphate dehydrogenase (IMPDH1), Inosine-5'-monophosphate dehydrogenase (DKFZp781N0678)
    This subpathway is part of the pathway XMP biosynthesis via de novo pathway, which is itself part of Purine metabolism.
    View all proteins of this organism that are known to be involved in the subpathway that synthesizes XMP from IMP, the pathway XMP biosynthesis via de novo pathway and in Purine metabolism.

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Metal bindingi326Potassium; via carbonyl oxygenUniRule annotation1 Publication1
    Metal bindingi328Potassium; via carbonyl oxygenUniRule annotation1 Publication1
    Binding sitei329IMPUniRule annotation1
    Active sitei331Thioimidate intermediateUniRule annotation1 Publication1
    Metal bindingi331Potassium; via carbonyl oxygenUniRule annotation1 Publication1
    Active sitei429Proton acceptorUniRule annotation1
    Binding sitei441IMPUniRule annotation1
    Metal bindingi500Potassium; via carbonyl oxygen; shared with tetrameric partnerUniRule annotation1
    Metal bindingi501Potassium; via carbonyl oxygen; shared with tetrameric partnerUniRule annotation1
    Metal bindingi502Potassium; via carbonyl oxygen; shared with tetrameric partnerUniRule annotation1

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi274 – 276NAD3
    Nucleotide bindingi324 – 326NADUniRule annotation3

    GO - Molecular functioni

    • DNA binding Source: UniProtKB-KW
    • IMP dehydrogenase activity Source: Reactome
    • metal ion binding Source: UniProtKB-HAMAP
    • nucleotide binding Source: UniProtKB
    • RNA binding Source: UniProtKB-KW

    GO - Biological processi

    Complete GO annotation...

    Keywords - Molecular functioni

    Oxidoreductase

    Keywords - Biological processi

    GMP biosynthesis, Purine biosynthesis

    Keywords - Ligandi

    DNA-binding, Metal-binding, NAD, Potassium, RNA-binding

    Enzyme and pathway databases

    BioCyciMetaCyc:HS11242-MONOMER.
    ZFISH:HS11242-MONOMER.
    BRENDAi1.1.1.205. 2681.
    ReactomeiR-HSA-6798695. Neutrophil degranulation.
    R-HSA-73817. Purine ribonucleoside monophosphate biosynthesis.
    SABIO-RKP12268.
    UniPathwayiUPA00601; UER00295.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Inosine-5'-monophosphate dehydrogenase 2UniRule annotation (EC:1.1.1.205UniRule annotation)
    Short name:
    IMP dehydrogenase 2UniRule annotation
    Short name:
    IMPD 2UniRule annotation
    Short name:
    IMPDH 2UniRule annotation
    Alternative name(s):
    IMPDH-II
    Gene namesi
    Name:IMPDH2UniRule annotation
    Synonyms:IMPD2
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 3

    Organism-specific databases

    HGNCiHGNC:6053. IMPDH2.

    Subcellular locationi

    GO - Cellular componenti

    • cytoplasm Source: UniProtKB
    • cytosol Source: Reactome
    • extracellular exosome Source: UniProtKB
    • membrane Source: UniProtKB
    • nucleus Source: UniProtKB
    • peroxisomal membrane Source: UniProtKB
    Complete GO annotation...

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    Pathology & Biotechi

    Organism-specific databases

    DisGeNETi3615.
    OpenTargetsiENSG00000178035.
    PharmGKBiPA29863.

    Chemistry databases

    ChEMBLiCHEMBL2002.
    DrugBankiDB01033. Mercaptopurine.
    DB00688. Mycophenolate mofetil.
    DB01024. Mycophenolic acid.
    GuidetoPHARMACOLOGYi2625.

    Polymorphism and mutation databases

    BioMutaiIMPDH2.
    DMDMi124419.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Initiator methionineiRemovedUniRule annotation1 Publication
    ChainiPRO_00000936732 – 514Inosine-5'-monophosphate dehydrogenase 2Add BLAST513

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei122PhosphoserineCombined sources1
    Modified residuei160PhosphoserineCombined sources1
    Modified residuei400PhosphotyrosineCombined sources1
    Modified residuei416PhosphoserineCombined sources1
    Modified residuei511N6-acetyllysineCombined sources1

    Post-translational modificationi

    The N-terminus is blocked.

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    EPDiP12268.
    MaxQBiP12268.
    PaxDbiP12268.
    PeptideAtlasiP12268.
    PRIDEiP12268.
    TopDownProteomicsiP12268.

    2D gel databases

    REPRODUCTION-2DPAGEIPI00291510.
    P12268.
    UCD-2DPAGEP12268.

    PTM databases

    iPTMnetiP12268.
    PhosphoSitePlusiP12268.
    SwissPalmiP12268.

    Expressioni

    Tissue specificityi

    IMP type I is the main species in normal leukocytes and type II predominates over type I in the tumor.

    Inductioni

    Selectively up-regulated in neoplastic and replicating cells.

    Gene expression databases

    BgeeiENSG00000178035.
    CleanExiHS_IMPDH2.
    ExpressionAtlasiP12268. baseline and differential.
    GenevisibleiP12268. HS.

    Organism-specific databases

    HPAiCAB020717.
    HPA001400.

    Interactioni

    Subunit structurei

    Homotetramer.UniRule annotation3 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    APIPQ96GX93EBI-353389,EBI-359248
    RSG1Q9BU203EBI-353389,EBI-750332

    Protein-protein interaction databases

    BioGridi109828. 88 interactors.
    IntActiP12268. 32 interactors.
    MINTiMINT-2860057.
    STRINGi9606.ENSP00000321584.

    Chemistry databases

    BindingDBiP12268.

    Structurei

    Secondary structure

    1514
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Beta strandi17 – 19Combined sources3
    Helixi20 – 24Combined sources5
    Beta strandi25 – 27Combined sources3
    Helixi32 – 34Combined sources3
    Beta strandi35 – 37Combined sources3
    Helixi46 – 48Combined sources3
    Beta strandi53 – 58Combined sources6
    Beta strandi60 – 67Combined sources8
    Turni71 – 73Combined sources3
    Helixi77 – 85Combined sources9
    Beta strandi89 – 91Combined sources3
    Helixi97 – 108Combined sources12
    Turni109 – 113Combined sources5
    Beta strandi123 – 125Combined sources3
    Beta strandi142 – 149Combined sources8
    Beta strandi152 – 158Combined sources7
    Helixi161 – 164Combined sources4
    Turni175 – 177Combined sources3
    Beta strandi183 – 185Combined sources3
    Helixi194 – 203Combined sources10
    Beta strandi209 – 212Combined sources4
    Beta strandi214 – 216Combined sources3
    Beta strandi220 – 222Combined sources3
    Beta strandi247 – 250Combined sources4
    Helixi256 – 265Combined sources10
    Beta strandi270 – 273Combined sources4
    Helixi281 – 293Combined sources13
    Beta strandi295 – 304Combined sources10
    Helixi307 – 316Combined sources10
    Beta strandi319 – 323Combined sources5
    Beta strandi328 – 331Combined sources4
    Helixi333 – 336Combined sources4
    Helixi343 – 354Combined sources12
    Helixi355 – 357Combined sources3
    Beta strandi361 – 365Combined sources5
    Helixi370 – 378Combined sources9
    Beta strandi382 – 387Combined sources6
    Helixi388 – 390Combined sources3
    Beta strandi396 – 398Combined sources3
    Beta strandi404 – 406Combined sources3
    Beta strandi409 – 412Combined sources4
    Turni417 – 419Combined sources3
    Beta strandi444 – 447Combined sources4
    Helixi453 – 471Combined sources19
    Helixi476 – 484Combined sources9
    Beta strandi490 – 492Combined sources3
    Helixi495 – 501Combined sources7

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    1B3OX-ray2.90A/B1-514[»]
    1NF7X-ray2.65A/B1-514[»]
    1NFBX-ray2.90A/B1-514[»]
    ProteinModelPortaliP12268.
    SMRiP12268.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP12268.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini114 – 173CBS 1UniRule annotationAdd BLAST60
    Domaini179 – 237CBS 2UniRule annotationAdd BLAST59

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni364 – 366IMP binding3
    Regioni387 – 388IMP binding2
    Regioni411 – 415IMP bindingUniRule annotation5

    Sequence similaritiesi

    Belongs to the IMPDH/GMPR family.UniRule annotation
    Contains 2 CBS domains.UniRule annotation

    Keywords - Domaini

    CBS domain, Repeat

    Phylogenomic databases

    eggNOGiKOG2550. Eukaryota.
    COG0516. LUCA.
    COG0517. LUCA.
    GeneTreeiENSGT00530000062923.
    HOGENOMiHOG000165752.
    HOVERGENiHBG052122.
    KOiK00088.
    OMAiIHKFIPY.
    OrthoDBiEOG091G0EAV.
    PhylomeDBiP12268.
    TreeFamiTF300378.

    Family and domain databases

    CDDicd00381. IMPDH. 1 hit.
    Gene3Di3.20.20.70. 1 hit.
    HAMAPiMF_01964. IMPDH. 1 hit.
    InterProiIPR013785. Aldolase_TIM.
    IPR000644. CBS_dom.
    IPR005990. IMP_DH.
    IPR015875. IMP_DH/GMP_Rdtase_CS.
    IPR001093. IMP_DH_GMPRt.
    [Graphical view]
    PfamiPF00571. CBS. 2 hits.
    PF00478. IMPDH. 1 hit.
    [Graphical view]
    PIRSFiPIRSF000130. IMPDH. 1 hit.
    SMARTiSM00116. CBS. 2 hits.
    [Graphical view]
    TIGRFAMsiTIGR01302. IMP_dehydrog. 1 hit.
    PROSITEiPS51371. CBS. 2 hits.
    PS00487. IMP_DH_GMP_RED. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

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

    P12268-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MADYLISGGT SYVPDDGLTA QQLFNCGDGL TYNDFLILPG YIDFTADQVD
    60 70 80 90 100
    LTSALTKKIT LKTPLVSSPM DTVTEAGMAI AMALTGGIGF IHHNCTPEFQ
    110 120 130 140 150
    ANEVRKVKKY EQGFITDPVV LSPKDRVRDV FEAKARHGFC GIPITDTGRM
    160 170 180 190 200
    GSRLVGIISS RDIDFLKEEE HDCFLEEIMT KREDLVVAPA GITLKEANEI
    210 220 230 240 250
    LQRSKKGKLP IVNEDDELVA IIARTDLKKN RDYPLASKDA KKQLLCGAAI
    260 270 280 290 300
    GTHEDDKYRL DLLAQAGVDV VVLDSSQGNS IFQINMIKYI KDKYPNLQVI
    310 320 330 340 350
    GGNVVTAAQA KNLIDAGVDA LRVGMGSGSI CITQEVLACG RPQATAVYKV
    360 370 380 390 400
    SEYARRFGVP VIADGGIQNV GHIAKALALG ASTVMMGSLL AATTEAPGEY
    410 420 430 440 450
    FFSDGIRLKK YRGMGSLDAM DKHLSSQNRY FSEADKIKVA QGVSGAVQDK
    460 470 480 490 500
    GSIHKFVPYL IAGIQHSCQD IGAKSLTQVR AMMYSGELKF EKRTSSAQVE
    510
    GGVHSLHSYE KRLF
    Length:514
    Mass (Da):55,805
    Last modified:May 1, 1991 - v2
    Checksum:i876BEA0EC1DDBEE9
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti190 – 191AG → RS in AAA36112 (PubMed:2902093).Curated2

    Polymorphismi

    Genetic variants in the IMPDH2 gene may account for the large inter-individual variability in enzyme activity, immunosuppressive efficacy and side effects in transplant recipients receiving mycophenolic acid.

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_070542263L → F Found in transplant patients; functional polymorphism; results in 10-fold decrease of enzymatic activity. 1 PublicationCorresponds to variant rs121434586dbSNPEnsembl.1

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    J04208 mRNA. Translation: AAA36112.1.
    L33842 Genomic DNA. Translation: AAA67054.1.
    L39210 Genomic DNA. Translation: AAB70699.1.
    BC006124 mRNA. Translation: AAH06124.1.
    BC012840 mRNA. Translation: AAH12840.1.
    BC015567 mRNA. Translation: AAH15567.1.
    L08114 Genomic DNA. Translation: AAA36113.1.
    CCDSiCCDS2786.1.
    PIRiI52303. A31997.
    RefSeqiNP_000875.2. NM_000884.2.
    UniGeneiHs.654400.

    Genome annotation databases

    EnsembliENST00000326739; ENSP00000321584; ENSG00000178035.
    GeneIDi3615.
    KEGGihsa:3615.
    UCSCiuc003cvt.4. human.

    Keywords - Coding sequence diversityi

    Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    J04208 mRNA. Translation: AAA36112.1.
    L33842 Genomic DNA. Translation: AAA67054.1.
    L39210 Genomic DNA. Translation: AAB70699.1.
    BC006124 mRNA. Translation: AAH06124.1.
    BC012840 mRNA. Translation: AAH12840.1.
    BC015567 mRNA. Translation: AAH15567.1.
    L08114 Genomic DNA. Translation: AAA36113.1.
    CCDSiCCDS2786.1.
    PIRiI52303. A31997.
    RefSeqiNP_000875.2. NM_000884.2.
    UniGeneiHs.654400.

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    1B3OX-ray2.90A/B1-514[»]
    1NF7X-ray2.65A/B1-514[»]
    1NFBX-ray2.90A/B1-514[»]
    ProteinModelPortaliP12268.
    SMRiP12268.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi109828. 88 interactors.
    IntActiP12268. 32 interactors.
    MINTiMINT-2860057.
    STRINGi9606.ENSP00000321584.

    Chemistry databases

    BindingDBiP12268.
    ChEMBLiCHEMBL2002.
    DrugBankiDB01033. Mercaptopurine.
    DB00688. Mycophenolate mofetil.
    DB01024. Mycophenolic acid.
    GuidetoPHARMACOLOGYi2625.

    PTM databases

    iPTMnetiP12268.
    PhosphoSitePlusiP12268.
    SwissPalmiP12268.

    Polymorphism and mutation databases

    BioMutaiIMPDH2.
    DMDMi124419.

    2D gel databases

    REPRODUCTION-2DPAGEIPI00291510.
    P12268.
    UCD-2DPAGEP12268.

    Proteomic databases

    EPDiP12268.
    MaxQBiP12268.
    PaxDbiP12268.
    PeptideAtlasiP12268.
    PRIDEiP12268.
    TopDownProteomicsiP12268.

    Protocols and materials databases

    DNASUi3615.
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000326739; ENSP00000321584; ENSG00000178035.
    GeneIDi3615.
    KEGGihsa:3615.
    UCSCiuc003cvt.4. human.

    Organism-specific databases

    CTDi3615.
    DisGeNETi3615.
    GeneCardsiIMPDH2.
    HGNCiHGNC:6053. IMPDH2.
    HPAiCAB020717.
    HPA001400.
    MIMi146691. gene.
    neXtProtiNX_P12268.
    OpenTargetsiENSG00000178035.
    PharmGKBiPA29863.
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiKOG2550. Eukaryota.
    COG0516. LUCA.
    COG0517. LUCA.
    GeneTreeiENSGT00530000062923.
    HOGENOMiHOG000165752.
    HOVERGENiHBG052122.
    KOiK00088.
    OMAiIHKFIPY.
    OrthoDBiEOG091G0EAV.
    PhylomeDBiP12268.
    TreeFamiTF300378.

    Enzyme and pathway databases

    UniPathwayiUPA00601; UER00295.
    BioCyciMetaCyc:HS11242-MONOMER.
    ZFISH:HS11242-MONOMER.
    BRENDAi1.1.1.205. 2681.
    ReactomeiR-HSA-6798695. Neutrophil degranulation.
    R-HSA-73817. Purine ribonucleoside monophosphate biosynthesis.
    SABIO-RKP12268.

    Miscellaneous databases

    ChiTaRSiIMPDH2. human.
    EvolutionaryTraceiP12268.
    GeneWikiiIMPDH2.
    GenomeRNAii3615.
    PROiP12268.
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000178035.
    CleanExiHS_IMPDH2.
    ExpressionAtlasiP12268. baseline and differential.
    GenevisibleiP12268. HS.

    Family and domain databases

    CDDicd00381. IMPDH. 1 hit.
    Gene3Di3.20.20.70. 1 hit.
    HAMAPiMF_01964. IMPDH. 1 hit.
    InterProiIPR013785. Aldolase_TIM.
    IPR000644. CBS_dom.
    IPR005990. IMP_DH.
    IPR015875. IMP_DH/GMP_Rdtase_CS.
    IPR001093. IMP_DH_GMPRt.
    [Graphical view]
    PfamiPF00571. CBS. 2 hits.
    PF00478. IMPDH. 1 hit.
    [Graphical view]
    PIRSFiPIRSF000130. IMPDH. 1 hit.
    SMARTiSM00116. CBS. 2 hits.
    [Graphical view]
    TIGRFAMsiTIGR01302. IMP_dehydrog. 1 hit.
    PROSITEiPS51371. CBS. 2 hits.
    PS00487. IMP_DH_GMP_RED. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Entry informationi

    Entry nameiIMDH2_HUMAN
    AccessioniPrimary (citable) accession number: P12268
    Secondary accession number(s): Q6LEF3
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: October 1, 1989
    Last sequence update: May 1, 1991
    Last modified: November 30, 2016
    This is version 200 of the entry and version 2 of the sequence. [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

    Miscellaneous

    Because IMPDH activity is tightly linked with cell proliferation, it has been recognized as a target for cancer and viral chemotherapy and as a target for immunosuppressive drugs. The activities of the antitumor drug tiazofurin, the antiviral drug ribavirin, and the immunosuppressive drugs mizoribine and mycophenolic acid (MPA) are attributed to the inhibition of IMPDH. In addition, bacterial and parasitic IMPDH's differ significantly from mammalian enzymes, which makes it a suitable target for anti-infective drugs.

    Keywords - Technical termi

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

    Documents

    1. Human chromosome 3
      Human chromosome 3: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    6. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    7. SIMILARITY comments
      Index of protein domains and families

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.