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Protein

Inosine-5'-monophosphate dehydrogenase 2

Gene

IMPDH2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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.

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.

Catalytic activityi

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

Cofactori

Activity 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 1 (IMPDH1), Inosine-5'-monophosphate dehydrogenase 2 (IMPDH2), Inosine-5'-monophosphate dehydrogenase (IMPDH), Inosine-5'-monophosphate dehydrogenase (IMPDH), Inosine-5'-monophosphate dehydrogenase (IMPDH1), Inosine-5'-monophosphate dehydrogenase (IMPDH1), Inosine-5'-monophosphate dehydrogenase (guaB), Inosine-5'-monophosphate dehydrogenase (DKFZp781N0678), Inosine-5'-monophosphate dehydrogenase (IMPDH)
    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-KW
    • nucleotide binding Source: UniProtKB
    • RNA binding Source: UniProtKB-KW

    GO - Biological processi

    Keywordsi

    Molecular functionDNA-binding, Oxidoreductase, RNA-binding
    Biological processGMP biosynthesis, Purine biosynthesis
    LigandMetal-binding, NAD, Potassium

    Enzyme and pathway databases

    BioCyciMetaCyc:HS11242-MONOMER
    BRENDAi1.1.1.205 2681
    ReactomeiR-HSA-6798695 Neutrophil degranulation
    R-HSA-73817 Purine ribonucleoside monophosphate biosynthesis
    SABIO-RKiP12268
    UniPathwayi
    UPA00601;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

    EuPathDBiHostDB:ENSG00000178035.11
    HGNCiHGNC:6053 IMPDH2
    MIMi146691 gene
    neXtProtiNX_P12268

    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, Nucleus

    Pathology & Biotechi

    Organism-specific databases

    DisGeNETi3615
    OpenTargetsiENSG00000178035
    PharmGKBiPA29863

    Chemistry databases

    ChEMBLiCHEMBL2002
    DrugBankiDB04566 Inosinic Acid
    DB01033 Mercaptopurine
    DB00688 Mycophenolate mofetil
    DB01024 Mycophenolic acid
    DB00157 NADH
    DB00811 Ribavirin
    DB03070 Selenazole-4-Carboxyamide-Adenine Dinucleotide
    DB06103 VX-148
    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
    Cross-linki195Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
    Cross-linki208Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
    Modified residuei400PhosphotyrosineCombined sources1
    Modified residuei416PhosphoserineCombined sources1
    Cross-linki438Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
    Modified residuei511N6-acetyllysineCombined sources1

    Post-translational modificationi

    The N-terminus is blocked.
    Acetylated by CLOCK in a circadian manner (PubMed:28985504).1 Publication

    Keywords - PTMi

    Acetylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

    Proteomic databases

    EPDiP12268
    MaxQBiP12268
    PaxDbiP12268
    PeptideAtlasiP12268
    PRIDEiP12268
    ProteomicsDBi52839
    TopDownProteomicsiP12268

    2D gel databases

    REPRODUCTION-2DPAGEiIPI00291510
    P12268
    UCD-2DPAGEiP12268

    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 Expressed in 234 organ(s), highest expression level in right ovary
    CleanExiHS_IMPDH2
    ExpressionAtlasiP12268 baseline and differential
    GenevisibleiP12268 HS

    Organism-specific databases

    HPAiCAB020717
    HPA001400

    Interactioni

    Subunit structurei

    Homotetramer (PubMed:7903306, Ref. 24, Ref. 25). Interacts with CLOCK; in a circadian manner (PubMed:28985504).UniRule annotation4 Publications

    Binary interactionsi

    Protein-protein interaction databases

    BioGridi109828, 100 interactors
    IntActiP12268, 40 interactors
    MINTiP12268
    STRINGi9606.ENSP00000321584

    Chemistry databases

    BindingDBiP12268

    Structurei

    Secondary structure

    1514
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details

    3D structure databases

    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

    Keywords - Domaini

    CBS domain, Repeat

    Phylogenomic databases

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

    Family and domain databases

    CDDicd00381 IMPDH, 1 hit
    Gene3Di3.20.20.70, 2 hits
    HAMAPiMF_01964 IMPDH, 1 hit
    InterProiView protein in InterPro
    IPR013785 Aldolase_TIM
    IPR000644 CBS_dom
    IPR005990 IMP_DH
    IPR015875 IMP_DH/GMP_Rdtase_CS
    IPR001093 IMP_DH_GMPRt
    PfamiView protein in Pfam
    PF00571 CBS, 2 hits
    PF00478 IMPDH, 1 hit
    PIRSFiPIRSF000130 IMPDH, 1 hit
    SMARTiView protein in SMART
    SM00116 CBS, 2 hits
    TIGRFAMsiTIGR01302 IMP_dehydrog, 1 hit
    PROSITEiView protein in PROSITE
    PS51371 CBS, 2 hits
    PS00487 IMP_DH_GMP_RED, 1 hit

    Sequence (1+)i

    Sequence statusi: Complete.

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

    This entry has 1 described isoform and 2 potential isoforms that are computationally mapped.iShow all

    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

    Computationally mapped potential isoform sequencesi

    There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
    EntryEntry nameProtein names
    Gene namesLengthAnnotation
    H0Y4R1H0Y4R1_HUMAN
    Inosine-5'-monophosphate dehydrogen...
    IMPDH2
    470Annotation score:
    E7ETK5E7ETK5_HUMAN
    Inosine-5'-monophosphate dehydrogen...
    IMPDH2
    279Annotation score:

    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 dbSNP:rs121434586EnsemblClinVar.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

    Similar proteinsi

    Entry informationi

    Entry nameiIMDH2_HUMAN
    AccessioniPrimary (citable) accession number: P12268
    Secondary accession number(s): Q6LEF3
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1989
    Last sequence update: May 1, 1991
    Last modified: September 12, 2018
    This is version 217 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
    UniProt is an ELIXIR core data resource
    Main funding by: National Institutes of Health

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