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Protein

Inosine-5'-monophosphate dehydrogenase

Gene

IMPDH

Organism
Tritrichomonas foetus (Trichomonas foetus) (Tritrichomonas suis)
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.UniRule annotation1 Publication

Catalytic activityi

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

Cofactori

K(+)UniRule annotation

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.UniRule annotation1 Publication

Kineticsi

  1. KM=1.7 µM for Inosine 5'-phosphate1 Publication
  2. KM=150 µM for NAD+1 Publication

    Pathway: 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)
    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)LengthDescriptionGraphical viewFeature identifierActions
    Metal bindingi20 – 201Potassium 2; via carbonyl oxygen1 Publication
    Metal bindingi22 – 221Potassium 21 Publication
    Metal bindingi264 – 2641Potassium 2; shared with tetrameric partner1 Publication
    Metal bindingi266 – 2661Potassium 2; via carbonyl oxygen; shared with tetrameric partner1 Publication
    Metal bindingi314 – 3141Potassium 1; via carbonyl oxygen1 Publication
    Metal bindingi316 – 3161Potassium 1; via carbonyl oxygen1 Publication
    Binding sitei317 – 3171IMP
    Active sitei319 – 3191Thioimidate intermediateUniRule annotation2 Publications
    Metal bindingi319 – 3191Potassium 1; via carbonyl oxygen1 Publication
    Binding sitei431 – 4311IMP
    Metal bindingi460 – 4601Potassium 2; via carbonyl oxygen1 Publication
    Metal bindingi485 – 4851Potassium 1; via carbonyl oxygen; shared with tetrameric partner1 Publication
    Metal bindingi486 – 4861Potassium 1; via carbonyl oxygen; shared with tetrameric partner1 Publication
    Metal bindingi487 – 4871Potassium 1; via carbonyl oxygen; shared with tetrameric partner1 Publication

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi261 – 2633NAD
    Nucleotide bindingi312 – 3143NAD

    GO - Molecular functioni

    • IMP dehydrogenase activity Source: UniProtKB-HAMAP
    • metal ion binding Source: UniProtKB-HAMAP
    • nucleotide binding Source: UniProtKB

    GO - Biological processi

    Complete GO annotation...

    Keywords - Molecular functioni

    Oxidoreductase

    Keywords - Biological processi

    GMP biosynthesis, Purine biosynthesis

    Keywords - Ligandi

    Metal-binding, NAD, Potassium

    Enzyme and pathway databases

    SABIO-RKP50097.
    UniPathwayiUPA00601; UER00295.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Inosine-5'-monophosphate dehydrogenaseUniRule annotation (EC:1.1.1.205UniRule annotation)
    Short name:
    IMP dehydrogenaseUniRule annotation
    Short name:
    IMPDUniRule annotation
    Short name:
    IMPDHUniRule annotation
    Gene namesi
    Name:IMPDHUniRule annotation
    OrganismiTritrichomonas foetus (Trichomonas foetus) (Tritrichomonas suis)
    Taxonomic identifieri56690 [NCBI]
    Taxonomic lineageiEukaryotaParabasaliaTritrichomonadidaTritrichomonadidaeTritrichomonas

    Subcellular locationi

    • Cytoplasm UniRule annotation

    GO - Cellular componenti

    Complete GO annotation...

    Keywords - Cellular componenti

    Cytoplasm

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi319 – 3191C → S: Has less than 0.06% of the wild-type activity. 1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 503503Inosine-5'-monophosphate dehydrogenasePRO_0000093676Add
    BLAST

    Interactioni

    Subunit structurei

    Homotetramer.UniRule annotation4 Publications

    Structurei

    Secondary structure

    1
    503
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi12 – 143Combined sources
    Beta strandi15 – 173Combined sources
    Helixi28 – 303Combined sources
    Beta strandi49 – 568Combined sources
    Turni60 – 623Combined sources
    Helixi65 – 739Combined sources
    Beta strandi77 – 804Combined sources
    Beta strandi82 – 843Combined sources
    Helixi86 – 9712Combined sources
    Turni98 – 1003Combined sources
    Beta strandi235 – 2384Combined sources
    Beta strandi240 – 2423Combined sources
    Helixi243 – 25311Combined sources
    Beta strandi256 – 2605Combined sources
    Helixi268 – 28114Combined sources
    Helixi282 – 2843Combined sources
    Beta strandi287 – 2926Combined sources
    Helixi295 – 30410Combined sources
    Beta strandi307 – 3115Combined sources
    Helixi317 – 3215Combined sources
    Turni322 – 3254Combined sources
    Helixi331 – 34919Combined sources
    Beta strandi350 – 3523Combined sources
    Beta strandi355 – 3595Combined sources
    Helixi364 – 3729Combined sources
    Beta strandi376 – 3816Combined sources
    Helixi382 – 3854Combined sources
    Beta strandi390 – 3923Combined sources
    Beta strandi394 – 3974Combined sources
    Beta strandi400 – 4067Combined sources
    Helixi411 – 4144Combined sources
    Helixi416 – 4194Combined sources
    Beta strandi421 – 4233Combined sources
    Beta strandi434 – 4385Combined sources
    Helixi443 – 46018Combined sources
    Helixi466 – 4727Combined sources
    Beta strandi475 – 4773Combined sources
    Turni480 – 4823Combined sources
    Turni484 – 4863Combined sources
    Beta strandi490 – 4934Combined sources

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1AK5X-ray2.30A1-503[»]
    1LRTX-ray2.20A/B/C/D2-503[»]
    1ME7X-ray2.15A1-503[»]
    1ME8X-ray1.90A1-503[»]
    1ME9X-ray2.20A1-503[»]
    1MEHX-ray1.95A1-503[»]
    1MEIX-ray2.20A1-503[»]
    1MEWX-ray2.15A1-503[»]
    1PVNX-ray2.00A/B/C/D2-503[»]
    DisProtiDP00399.
    ProteinModelPortaliP50097.
    SMRiP50097. Positions 2-494.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP50097.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini103 – 16361CBS 1UniRule annotationAdd
    BLAST
    Domaini167 – 22862CBS 2UniRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni358 – 3603IMP binding
    Regioni381 – 3822IMP binding
    Regioni405 – 4095IMP binding

    Sequence similaritiesi

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

    Keywords - Domaini

    CBS domain, Repeat

    Family and domain databases

    Gene3Di3.20.20.70. 1 hit.
    HAMAPiMF_01964. IMPDH.
    InterProiIPR013785. Aldolase_TIM.
    IPR000644. CBS_dom.
    IPR005990. IMP_DH.
    IPR015875. IMP_DH/GMP_Rdtase_CS.
    IPR001093. IMP_DH_GMPRt.
    [Graphical view]
    PANTHERiPTHR11911:SF6. PTHR11911:SF6. 1 hit.
    PfamiPF00571. CBS. 2 hits.
    PF00478. IMPDH. 1 hit.
    [Graphical view]
    PIRSFiPIRSF000130. IMPDH. 1 hit.
    SMARTiSM00116. CBS. 2 hits.
    [Graphical view]
    PROSITEiPS51371. CBS. 2 hits.
    PS00487. IMP_DH_GMP_RED. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    P50097-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MAKYYNEPCH TFNEYLLIPG LSTVDCIPSN VNLSTPLVKF QKGQQSEINL
    60 70 80 90 100
    KIPLVSAIMQ SVSGEKMAIA LAREGGISFI FGSQSIESQA AMVHAVKNFK
    110 120 130 140 150
    AGFVVSDSNV KPDQTFADVL AISQRTTHNT VAVTDDGTPH GVLLGLVTQR
    160 170 180 190 200
    DYPIDLTQTE TKVSDMMTPF SKLVTAHQDT KLSEANKIIW EKKLNALPII
    210 220 230 240 250
    DDDQHLRYIV FRKDYDRSQV CHNELVDSQK RYLVGAGINT RDFRERVPAL
    260 270 280 290 300
    VEAGADVLCI DSSDGFSEWQ KITIGWIREK YGDKVKVGAG NIVDGEGFRY
    310 320 330 340 350
    LADAGADFIK IGIGGGSICI TREQKGIGRG QATAVIDVVA ERNKYFEETG
    360 370 380 390 400
    IYIPVCSDGG IVYDYHMTLA LAMGADFIML GRYFARFEES PTRKVTINGS
    410 420 430 440 450
    VMKEYWGEGS SRARNWQRYD LGGKQKLSFE EGVDSYVPYA GKLKDNVEAS
    460 470 480 490 500
    LNKVKSTMCN CGALTIPQLQ SKAKITLVSS VSIVEGGAHD VIVKDRINDY

    HPK
    Length:503
    Mass (Da):55,473
    Last modified:October 1, 1996 - v1
    Checksum:iE204EADE7ECC4134
    GO

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    L18917 Genomic DNA. Translation: AAB01581.1.
    PIRiA58910.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    L18917 Genomic DNA. Translation: AAB01581.1.
    PIRiA58910.

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1AK5X-ray2.30A1-503[»]
    1LRTX-ray2.20A/B/C/D2-503[»]
    1ME7X-ray2.15A1-503[»]
    1ME8X-ray1.90A1-503[»]
    1ME9X-ray2.20A1-503[»]
    1MEHX-ray1.95A1-503[»]
    1MEIX-ray2.20A1-503[»]
    1MEWX-ray2.15A1-503[»]
    1PVNX-ray2.00A/B/C/D2-503[»]
    DisProtiDP00399.
    ProteinModelPortaliP50097.
    SMRiP50097. Positions 2-494.
    ModBaseiSearch...
    MobiDBiSearch...

    Protocols and materials databases

    Structural Biology KnowledgebaseSearch...

    Enzyme and pathway databases

    UniPathwayiUPA00601; UER00295.
    SABIO-RKP50097.

    Miscellaneous databases

    EvolutionaryTraceiP50097.

    Family and domain databases

    Gene3Di3.20.20.70. 1 hit.
    HAMAPiMF_01964. IMPDH.
    InterProiIPR013785. Aldolase_TIM.
    IPR000644. CBS_dom.
    IPR005990. IMP_DH.
    IPR015875. IMP_DH/GMP_Rdtase_CS.
    IPR001093. IMP_DH_GMPRt.
    [Graphical view]
    PANTHERiPTHR11911:SF6. PTHR11911:SF6. 1 hit.
    PfamiPF00571. CBS. 2 hits.
    PF00478. IMPDH. 1 hit.
    [Graphical view]
    PIRSFiPIRSF000130. IMPDH. 1 hit.
    SMARTiSM00116. CBS. 2 hits.
    [Graphical view]
    PROSITEiPS51371. CBS. 2 hits.
    PS00487. IMP_DH_GMP_RED. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Publicationsi

    1. "Cloning, sequencing, and structural analysis of the DNA encoding inosine monophosphate dehydrogenase (EC 1.1.1.205) from Tritrichomonas foetus."
      Beck J.T., Zhao S., Wang C.C.
      Exp. Parasitol. 78:101-112(1994) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
      Strain: UNK.
    2. Wang C.C.
      Submitted (FEB-1996) to the EMBL/GenBank/DDBJ databases
      Cited for: SEQUENCE REVISION.
    3. "A novel mechanism of mycophenolic acid resistance in the protozoan parasite Tritrichomonas foetus."
      Hedstrom L., Cheung K.S., Wang C.C.
      Biochem. Pharmacol. 39:151-160(1990) [PubMed] [Europe PMC] [Abstract]
      Cited for: ENZYME REGULATION.
    4. "Identification of the IMP binding site in the IMP dehydrogenase from Tritrichomonas foetus."
      Huete-Perez J.A., Wu J.C., Whitby F.G., Wang C.C.
      Biochemistry 34:13889-13894(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: CHARACTERIZATION.
    5. "Kinetic mechanism of Tritrichomonas foetus inosine 5'-monophosphate dehydrogenase."
      Digits J.A., Hedstrom L.
      Biochemistry 38:2295-2306(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF CYS-319.
    6. "Inosine 5'-monophosphate dehydrogenase binds nucleic acids in vitro and in vivo."
      McLean J.E., Hamaguchi N., Belenky P., Mortimer S.E., Stanton M., Hedstrom L.
      Biochem. J. 379:243-251(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEIC ACID-BINDING.
    7. "Crystal structure of Tritrichomonas foetus inosine-5'-monophosphate dehydrogenase and the enzyme-product complex."
      Whitby F.G., Luecke H., Kuhn P., Somoza J.R., Huete-Perez J.A., Phillips J.D., Hill C.P., Fletterick R.J., Wang C.C.
      Biochemistry 36:10666-10674(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
    8. "Crystal structure of a ternary complex of Tritrichomonas foetus inosine 5'-monophosphate dehydrogenase: NAD+ orients the active site loop for catalysis."
      Gan L., Petsko G.A., Hedstrom L.
      Biochemistry 41:13309-13317(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 4-377 IN COMPLEX WITH SUBSTRATE AND INHIBITOR, POTASSIUM-BINDING.
    9. "Crystal structure of Tritrichomonas foetus inosine monophosphate dehydrogenase in complex with the inhibitor ribavirin monophosphate reveals a catalysis-dependent ion-binding site."
      Prosise G.L., Wu J.Z., Luecke H.
      J. Biol. Chem. 277:50654-50659(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) IN COMPLEX WITH INHIBITOR, ACTIVE SITE.
    10. "The immunosuppressive agent mizoribine monophosphate forms a transition state analogue complex with inosine monophosphate dehydrogenase."
      Gan L., Seyedsayamdost M.R., Shuto S., Matsuda A., Petsko G.A., Hedstrom L.
      Biochemistry 42:857-863(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 4-377 IN COMPLEX WITH INHIBITOR (MIZORIBINE MONOPHOSPHATE; MZP) AND POTASSIUM, ACTIVE SITE.
    11. "Crystal structures of Tritrichomonas foetus inosine monophosphate dehydrogenase in complex with substrate, cofactor and analogs: a structural basis for the random-in ordered-out kinetic mechanism."
      Prosise G.L., Luecke H.
      J. Mol. Biol. 326:517-527(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1-483 IN COMPLEX WITH SUBSTRATE; PRODUCT; INHIBITOR (MYCOPHENOLIC ACID; MPA) AND NAD(+).

    Entry informationi

    Entry nameiIMDH_TRIFO
    AccessioniPrimary (citable) accession number: P50097
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: October 1, 1996
    Last sequence update: October 1, 1996
    Last modified: March 4, 2015
    This is version 111 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)

    Miscellaneousi

    Miscellaneous

    Contains 2 potassium ions bound at each subunit interface. The second potassium binding site is not conserved and not observed in crystal structures of IMPDHs from other organisms (PubMed:12403633).1 Publication

    Keywords - Technical termi

    3D-structure

    Documents

    1. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    2. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    3. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3

    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 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.