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P12268 (IMDH2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 173. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Inosine-5'-monophosphate dehydrogenase 2

Short name=IMP dehydrogenase 2
Short name=IMPD 2
Short name=IMPDH 2
EC=1.1.1.205
Alternative name(s):
IMPDH-II
Gene names
Name:IMPDH2
Synonyms:IMPD2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length514 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. HAMAP-Rule MF_03156

Catalytic activity

Inosine 5'-phosphate + NAD+ + H2O = xanthosine 5'-phosphate + NADH. HAMAP-Rule MF_03156

Cofactor

Potassium.

Enzyme regulation

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. Ref.7

Pathway

Purine metabolism; XMP biosynthesis via de novo pathway; XMP from IMP: step 1/1. HAMAP-Rule MF_03156

Subunit structure

Homotetramer. Ref.7

Subcellular location

Cytoplasm. Nucleus Ref.9.

Tissue specificity

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

Induction

Selectively up-regulated in neoplastic and replicating cells. Ref.7

Post-translational modification

The N-terminus is blocked. HAMAP-Rule MF_03156

Polymorphism

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. HAMAP-Rule MF_03156

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.

Sequence similarities

Belongs to the IMPDH/GMPR family.

Contains 2 CBS domains.

Biophysicochemical properties

Kinetic parameters:

KM=9.3 µM for Inosine 5'-phosphate Ref.7 Ref.8

KM=32 µM for NAD+

Ontologies

Keywords
   Biological processGMP biosynthesis
Purine biosynthesis
   Cellular componentCytoplasm
Nucleus
   Coding sequence diversityPolymorphism
   DomainCBS domain
Repeat
   LigandDNA-binding
Metal-binding
NAD
Potassium
RNA-binding
   Molecular functionOxidoreductase
   PTMAcetylation
Phosphoprotein
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processGMP biosynthetic process

Inferred from electronic annotation. Source: UniProtKB-HAMAP

nucleobase-containing small molecule metabolic process

Traceable author statement. Source: Reactome

purine nucleobase metabolic process

Traceable author statement. Source: Reactome

purine ribonucleoside monophosphate biosynthetic process

Traceable author statement. Source: Reactome

small molecule metabolic process

Traceable author statement. Source: Reactome

   Cellular_componentcytoplasm

Inferred from direct assay Ref.9. Source: UniProtKB

cytosol

Traceable author statement. Source: Reactome

extracellular vesicular exosome

Inferred from direct assay PubMed 20458337. Source: UniProt

nucleus

Inferred from direct assay Ref.9. Source: UniProtKB

peroxisomal membrane

Inferred from direct assay PubMed 21525035. Source: UniProtKB

   Molecular_functionDNA binding

Inferred from electronic annotation. Source: UniProtKB-KW

IMP dehydrogenase activity

Traceable author statement Ref.2. Source: ProtInc

RNA binding

Inferred from electronic annotation. Source: UniProtKB-KW

adenyl nucleotide binding

Inferred from electronic annotation. Source: InterPro

metal ion binding

Inferred from electronic annotation. Source: UniProtKB-HAMAP

nucleotide binding

Inferred from direct assay Ref.9. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed Ref.7
Chain2 – 514513Inosine-5'-monophosphate dehydrogenase 2 HAMAP-Rule MF_03156
PRO_0000093673

Regions

Domain114 – 17360CBS 1
Domain179 – 23759CBS 2
Nucleotide binding274 – 2763NAD HAMAP-Rule MF_03156
Nucleotide binding324 – 3263NAD By similarity
Region364 – 3663IMP binding HAMAP-Rule MF_03156
Region387 – 3882IMP binding HAMAP-Rule MF_03156
Region411 – 4155IMP binding By similarity

Sites

Active site3311Thioimidate intermediate Ref.18
Metal binding3261Potassium; via carbonyl oxygen
Metal binding3281Potassium; via carbonyl oxygen
Metal binding3311Potassium; via carbonyl oxygen
Metal binding5001Potassium; via carbonyl oxygen; shared with tetrameric partner By similarity
Metal binding5011Potassium; via carbonyl oxygen; shared with tetrameric partner By similarity
Metal binding5021Potassium; via carbonyl oxygen; shared with tetrameric partner By similarity
Binding site3291IMP By similarity
Binding site4411IMP By similarity

Amino acid modifications

Modified residue1221Phosphoserine Ref.13 Ref.16
Modified residue4001Phosphotyrosine Ref.10
Modified residue4161Phosphoserine Ref.16
Modified residue5111N6-acetyllysine Ref.15

Natural variations

Natural variant2631L → F Found in transplant patients; functional polymorphism that results in 10-fold decrease of enzymatic activity. Ref.12
Corresponds to variant rs121434586 [ dbSNP | Ensembl ].
VAR_070542

Experimental info

Sequence conflict190 – 1912AG → RS in AAA36112. Ref.1

Secondary structure

.................................................................................... 514
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P12268 [UniParc].

Last modified May 1, 1991. Version 2.
Checksum: 876BEA0EC1DDBEE9

FASTA51455,805
        10         20         30         40         50         60 
MADYLISGGT SYVPDDGLTA QQLFNCGDGL TYNDFLILPG YIDFTADQVD LTSALTKKIT 

        70         80         90        100        110        120 
LKTPLVSSPM DTVTEAGMAI AMALTGGIGF IHHNCTPEFQ ANEVRKVKKY EQGFITDPVV 

       130        140        150        160        170        180 
LSPKDRVRDV FEAKARHGFC GIPITDTGRM GSRLVGIISS RDIDFLKEEE HDCFLEEIMT 

       190        200        210        220        230        240 
KREDLVVAPA GITLKEANEI LQRSKKGKLP IVNEDDELVA IIARTDLKKN RDYPLASKDA 

       250        260        270        280        290        300 
KKQLLCGAAI GTHEDDKYRL DLLAQAGVDV VVLDSSQGNS IFQINMIKYI KDKYPNLQVI 

       310        320        330        340        350        360 
GGNVVTAAQA KNLIDAGVDA LRVGMGSGSI CITQEVLACG RPQATAVYKV SEYARRFGVP 

       370        380        390        400        410        420 
VIADGGIQNV GHIAKALALG ASTVMMGSLL AATTEAPGEY FFSDGIRLKK YRGMGSLDAM 

       430        440        450        460        470        480 
DKHLSSQNRY FSEADKIKVA QGVSGAVQDK GSIHKFVPYL IAGIQHSCQD IGAKSLTQVR 

       490        500        510 
AMMYSGELKF EKRTSSAQVE GGVHSLHSYE KRLF 

« Hide

References

« Hide 'large scale' references
[1]"Cloning and sequence analysis of the human and Chinese hamster inosine-5'-monophosphate dehydrogenase cDNAs."
Collart F.R., Huberman E.
J. Biol. Chem. 263:15769-15772(1988) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE.
[2]"Two distinct cDNAs for human IMP dehydrogenase."
Natsumeda Y., Ohno S., Kawasaki H., Konno Y., Weber G., Suzuki K.
J. Biol. Chem. 265:5292-5295(1990) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Spleen.
[3]"Cloning and sequence of the human type II IMP dehydrogenase gene."
Glesne D.A., Huberman E.
Biochem. Biophys. Res. Commun. 205:537-544(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
Tissue: Blood.
[4]"Characterization of the human inosine-5'-monophosphate dehydrogenase type II gene."
Zimmermann A.G., Spychala J., Mitchell B.S.
J. Biol. Chem. 270:6808-6814(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: B-cell, Colon and Placenta.
[6]"Chromosomal localization and structure of the human type II IMP dehydrogenase gene."
Glesne D.A., Collart F.R., Varkony T., Drabkin H., Huberman E.
Genomics 16:274-277(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 461-514.
[7]"Characterization of human type I and type II IMP dehydrogenases."
Carr S.F., Papp E., Wu J.C., Natsumeda Y.
J. Biol. Chem. 268:27286-27290(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 2-11, BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, ENZYME REGULATION.
[8]"Recombinant human inosine monophosphate dehydrogenase type I and type II proteins. Purification and characterization of inhibitor binding."
Hager P.W., Collart F.R., Huberman E., Mitchell B.S.
Biochem. Pharmacol. 49:1323-1329(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF N-TERMINUS, BIOPHYSICOCHEMICAL PROPERTIES.
[9]"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: SUBCELLULAR LOCATION, NUCLEIC ACID-BINDING.
[10]"Immunoaffinity profiling of tyrosine phosphorylation in cancer cells."
Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., Zha X.-M., Polakiewicz R.D., Comb M.J.
Nat. Biotechnol. 23:94-101(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-400, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[11]"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks."
Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.
Cell 127:635-648(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[12]"A novel variant L263F in human inosine 5'-monophosphate dehydrogenase 2 is associated with diminished enzyme activity."
Wang J., Zeevi A., Webber S., Girnita D.M., Addonizio L., Selby R., Hutchinson I.V., Burckart G.J.
Pharmacogenet. Genomics 17:283-290(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: POLYMORPHISM, VARIANT PHE-263.
[13]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-122, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[14]"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."
Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.
Anal. Chem. 81:4493-4501(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[15]"Lysine acetylation targets protein complexes and co-regulates major cellular functions."
Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M.
Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-511, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[16]"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-122 AND SER-416, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[17]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[18]"Crystal structure of human type II inosine monophosphate dehydrogenase: implications for ligand binding and drug design."
Colby T.D., Vanderveen K., Strickler M.D., Markham G.D., Goldstein B.M.
Proc. Natl. Acad. Sci. U.S.A. 96:3531-3536(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS), ACTIVE SITE.
[19]"Crystal structure of human inosine monophosphate dehydrogenase type II complexed with the MPA/NAD analog C2-MAD."
Risal D., Strickler M.D., Goldstein B.M.
Submitted (DEC-2002) to the PDB data bank
Cited for: X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) IN COMPLEX WITH INHIBITOR AND POTASSIUM.
[20]"The conformation of NAD bound to human inosine monophosphate Dehydrogenase Type II."
Risal D., Strickler M.D., Goldstein B.M.
Submitted (DEC-2002) to the PDB data bank
Cited for: X-RAY CRYSTALLOGRAPHY (2.90 ANGSTROMS) IN COMPLEX WITH NAD(+).
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
CCDSCCDS2786.1.
PIRA31997. I52303.
RefSeqNP_000875.2. NM_000884.2.
UniGeneHs.654400.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1B3OX-ray2.90A/B1-514[»]
1NF7X-ray2.65A/B1-514[»]
1NFBX-ray2.90A/B1-514[»]
ProteinModelPortalP12268.
SMRP12268. Positions 10-514.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid109828. 35 interactions.
IntActP12268. 12 interactions.
MINTMINT-2860057.
STRING9606.ENSP00000321584.

Chemistry

BindingDBP12268.
ChEMBLCHEMBL2111369.
DrugBankDB00688. Mycophenolate mofetil.
DB01024. Mycophenolic acid.
DB00157. NADH.
GuidetoPHARMACOLOGY2625.

PTM databases

PhosphoSiteP12268.

Polymorphism databases

DMDM124419.

2D gel databases

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

Proteomic databases

MaxQBP12268.
PaxDbP12268.
PeptideAtlasP12268.
PRIDEP12268.

Protocols and materials databases

DNASU3615.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000326739; ENSP00000321584; ENSG00000178035.
GeneID3615.
KEGGhsa:3615.
UCSCuc003cvt.3. human.

Organism-specific databases

CTD3615.
GeneCardsGC03M049061.
HGNCHGNC:6053. IMPDH2.
HPACAB020717.
HPA001400.
MIM146691. gene.
neXtProtNX_P12268.
PharmGKBPA29863.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0517.
HOGENOMHOG000165752.
HOVERGENHBG052122.
InParanoidP12268.
KOK00088.
OMAFQAKARH.
PhylomeDBP12268.
TreeFamTF300378.

Enzyme and pathway databases

BioCycMetaCyc:HS11242-MONOMER.
ReactomeREACT_111217. Metabolism.
SABIO-RKP12268.
UniPathwayUPA00601; UER00295.

Gene expression databases

ArrayExpressP12268.
BgeeP12268.
CleanExHS_IMPDH2.
GenevestigatorP12268.

Family and domain databases

Gene3D3.20.20.70. 1 hit.
HAMAPMF_01964. IMPDH.
InterProIPR013785. Aldolase_TIM.
IPR000644. CBS_dom.
IPR005990. IMP_DH.
IPR015875. IMP_DH/GMP_Rdtase_CS.
IPR001093. IMP_DH_GMPRt.
[Graphical view]
PfamPF00571. CBS. 2 hits.
PF00478. IMPDH. 1 hit.
[Graphical view]
PIRSFPIRSF000130. IMPDH. 1 hit.
SMARTSM00116. CBS. 2 hits.
[Graphical view]
TIGRFAMsTIGR01302. IMP_dehydrog. 1 hit.
PROSITEPS51371. CBS. 2 hits.
PS00487. IMP_DH_GMP_RED. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSIMPDH2. human.
EvolutionaryTraceP12268.
GeneWikiIMPDH2.
GenomeRNAi3615.
NextBio14143.
PROP12268.
SOURCESearch...

Entry information

Entry nameIMDH2_HUMAN
AccessionPrimary (citable) accession number: P12268
Secondary accession number(s): Q6LEF3
Entry history
Integrated into UniProtKB/Swiss-Prot: October 1, 1989
Last sequence update: May 1, 1991
Last modified: July 9, 2014
This is version 173 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

PATHWAY comments

Index of metabolic and biosynthesis pathways

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 3

Human chromosome 3: entries, gene names and cross-references to MIM