Full text data of IMPDH2
IMPDH2
(IMPD2)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Inosine-5'-monophosphate dehydrogenase 2; IMP dehydrogenase 2; IMPD 2; IMPDH 2; 1.1.1.205 (IMPDH-II)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Inosine-5'-monophosphate dehydrogenase 2; IMP dehydrogenase 2; IMPD 2; IMPDH 2; 1.1.1.205 (IMPDH-II)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00291510
IPI00291510 Inosine-5-monophosphate dehydrogenase 2 Rate limiting enzyme in the de novo synthesis of guanine nucleotides and therefore is involved in the regulation of cell growth, lecukocytes, IMP dehydrogenase activity soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
IPI00291510 Inosine-5-monophosphate dehydrogenase 2 Rate limiting enzyme in the de novo synthesis of guanine nucleotides and therefore is involved in the regulation of cell growth, lecukocytes, IMP dehydrogenase activity soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
UniProt
P12268
ID IMDH2_HUMAN Reviewed; 514 AA.
AC P12268; Q6LEF3;
DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAY-1991, sequence version 2.
DT 22-JAN-2014, entry version 167.
DE RecName: Full=Inosine-5'-monophosphate dehydrogenase 2;
DE Short=IMP dehydrogenase 2;
DE Short=IMPD 2;
DE Short=IMPDH 2;
DE EC=1.1.1.205;
DE AltName: Full=IMPDH-II;
GN Name=IMPDH2; Synonyms=IMPD2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=2902093;
RA Collart F.R., Huberman E.;
RT "Cloning and sequence analysis of the human and Chinese hamster
RT inosine-5'-monophosphate dehydrogenase cDNAs.";
RL J. Biol. Chem. 263:15769-15772(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Spleen;
RX PubMed=1969416;
RA Natsumeda Y., Ohno S., Kawasaki H., Konno Y., Weber G., Suzuki K.;
RT "Two distinct cDNAs for human IMP dehydrogenase.";
RL J. Biol. Chem. 265:5292-5295(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Blood;
RX PubMed=7999076; DOI=10.1006/bbrc.1994.2698;
RA Glesne D.A., Huberman E.;
RT "Cloning and sequence of the human type II IMP dehydrogenase gene.";
RL Biochem. Biophys. Res. Commun. 205:537-544(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=7896827; DOI=10.1074/jbc.270.12.6808;
RA Zimmermann A.G., Spychala J., Mitchell B.S.;
RT "Characterization of the human inosine-5'-monophosphate dehydrogenase
RT type II gene.";
RL J. Biol. Chem. 270:6808-6814(1995).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=B-cell, Colon, and Placenta;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 461-514.
RX PubMed=8098009; DOI=10.1006/geno.1993.1177;
RA Glesne D.A., Collart F.R., Varkony T., Drabkin H., Huberman E.;
RT "Chromosomal localization and structure of the human type II IMP
RT dehydrogenase gene.";
RL Genomics 16:274-277(1993).
RN [7]
RP PROTEIN SEQUENCE OF 2-11, BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, AND
RP ENZYME REGULATION.
RX PubMed=7903306;
RA Carr S.F., Papp E., Wu J.C., Natsumeda Y.;
RT "Characterization of human type I and type II IMP dehydrogenases.";
RL J. Biol. Chem. 268:27286-27290(1993).
RN [8]
RP PROTEIN SEQUENCE OF N-TERMINUS, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=7763314; DOI=10.1016/0006-2952(95)00026-V;
RA Hager P.W., Collart F.R., Huberman E., Mitchell B.S.;
RT "Recombinant human inosine monophosphate dehydrogenase type I and type
RT II proteins. Purification and characterization of inhibitor binding.";
RL Biochem. Pharmacol. 49:1323-1329(1995).
RN [9]
RP SUBCELLULAR LOCATION, AND NUCLEIC ACID-BINDING.
RX PubMed=14766016; DOI=10.1042/BJ20031585;
RA McLean J.E., Hamaguchi N., Belenky P., Mortimer S.E., Stanton M.,
RA Hedstrom L.;
RT "Inosine 5'-monophosphate dehydrogenase binds nucleic acids in vitro
RT and in vivo.";
RL Biochem. J. 379:243-251(2004).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-400, AND MASS
RP SPECTROMETRY.
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-122, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [14]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-511, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-122 AND SER-416, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS), AND ACTIVE SITE.
RX PubMed=10097070; DOI=10.1073/pnas.96.7.3531;
RA Colby T.D., Vanderveen K., Strickler M.D., Markham G.D.,
RA Goldstein B.M.;
RT "Crystal structure of human type II inosine monophosphate
RT dehydrogenase: implications for ligand binding and drug design.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:3531-3536(1999).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) IN COMPLEX WITH INHIBITOR AND
RP POTASSIUM.
RA Risal D., Strickler M.D., Goldstein B.M.;
RT "Crystal structure of human inosine monophosphate dehydrogenase type
RT II complexed with the MPA/NAD analog C2-MAD.";
RL Submitted (DEC-2002) to the PDB data bank.
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.90 ANGSTROMS) IN COMPLEX WITH NAD(+).
RA Risal D., Strickler M.D., Goldstein B.M.;
RT "The conformation of NAD bound to human inosine monophosphate
RT Dehydrogenase Type II.";
RL Submitted (DEC-2002) to the PDB data bank.
CC -!- FUNCTION: Catalyzes the conversion of inosine 5'-phosphate (IMP)
CC to xanthosine 5'-phosphate (XMP), the first committed and rate-
CC limiting step in the de novo synthesis of guanine nucleotides, and
CC therefore plays an important role in the regulation of cell
CC growth. Could also have a single-stranded nucleic acid-binding
CC activity and could play a role in RNA and/or DNA metabolism. It
CC may also have a role in the development of malignancy and the
CC growth progression of some tumors.
CC -!- CATALYTIC ACTIVITY: Inosine 5'-phosphate + NAD(+) + H(2)O =
CC xanthosine 5'-phosphate + NADH.
CC -!- COFACTOR: Potassium.
CC -!- ENZYME REGULATION: Mycophenolic acid (MPA) is a non-competitive
CC inhibitor that prevents formation of the closed enzyme
CC conformation by binding to the same site as the amobile flap. In
CC contrast, mizoribine monophosphate (MZP) is a competitive
CC inhibitor that induces the closed conformation. MPA is a potent
CC inhibitor of mammalian IMPDHs but a poor inhibitor of the
CC bacterial enzymes. MZP is a more potent inhibitor of bacterial
CC IMPDH. Subject to product inhibition by XMP and NADH. Also
CC inhibited by ADP.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=9.3 uM for Inosine 5'-phosphate;
CC KM=32 uM for NAD(+);
CC -!- PATHWAY: Purine metabolism; XMP biosynthesis via de novo pathway;
CC XMP from IMP: step 1/1.
CC -!- SUBUNIT: Homotetramer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus.
CC -!- TISSUE SPECIFICITY: IMP type I is the main species in normal
CC leukocytes and type II predominates over type I in the tumor.
CC -!- INDUCTION: Selectively up-regulated in neoplastic and replicating
CC cells.
CC -!- PTM: The N-terminus is blocked.
CC -!- MISCELLANEOUS: Because IMPDH activity is tightly linked with cell
CC proliferation, it has been recognized as a target for cancer and
CC viral chemotherapy and as a target for immunosuppressive drugs.
CC The activities of the antitumor drug tiazofurin, the antiviral
CC drug ribavirin, and the immunosuppressive drugs mizoribine and
CC mycophenolic acid (MPA) are attributed to the inhibition of IMPDH.
CC In addition, bacterial and parasitic IMPDH's differ significantly
CC from mammalian enzymes, which makes it a suitable target for anti-
CC infective drugs.
CC -!- SIMILARITY: Belongs to the IMPDH/GMPR family.
CC -!- SIMILARITY: Contains 2 CBS domains.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; J04208; AAA36112.1; -; mRNA.
DR EMBL; L33842; AAA67054.1; -; Genomic_DNA.
DR EMBL; L39210; AAB70699.1; -; Genomic_DNA.
DR EMBL; BC006124; AAH06124.1; -; mRNA.
DR EMBL; BC012840; AAH12840.1; -; mRNA.
DR EMBL; BC015567; AAH15567.1; -; mRNA.
DR EMBL; L08114; AAA36113.1; -; Genomic_DNA.
DR PIR; I52303; A31997.
DR RefSeq; NP_000875.2; NM_000884.2.
DR UniGene; Hs.654400; -.
DR PDB; 1B3O; X-ray; 2.90 A; A/B=1-514.
DR PDB; 1NF7; X-ray; 2.65 A; A/B=1-514.
DR PDB; 1NFB; X-ray; 2.90 A; A/B=1-514.
DR PDBsum; 1B3O; -.
DR PDBsum; 1NF7; -.
DR PDBsum; 1NFB; -.
DR ProteinModelPortal; P12268; -.
DR SMR; P12268; 10-514.
DR IntAct; P12268; 12.
DR MINT; MINT-2860057; -.
DR STRING; 9606.ENSP00000321584; -.
DR BindingDB; P12268; -.
DR ChEMBL; CHEMBL2002; -.
DR DrugBank; DB00688; Mycophenolate mofetil.
DR DrugBank; DB01024; Mycophenolic acid.
DR DrugBank; DB00157; NADH.
DR PhosphoSite; P12268; -.
DR DMDM; 124419; -.
DR REPRODUCTION-2DPAGE; IPI00291510; -.
DR REPRODUCTION-2DPAGE; P12268; -.
DR UCD-2DPAGE; P12268; -.
DR PaxDb; P12268; -.
DR PeptideAtlas; P12268; -.
DR PRIDE; P12268; -.
DR DNASU; 3615; -.
DR Ensembl; ENST00000326739; ENSP00000321584; ENSG00000178035.
DR GeneID; 3615; -.
DR KEGG; hsa:3615; -.
DR UCSC; uc003cvt.3; human.
DR CTD; 3615; -.
DR GeneCards; GC03M049061; -.
DR HGNC; HGNC:6053; IMPDH2.
DR HPA; CAB020717; -.
DR HPA; HPA001400; -.
DR MIM; 146691; gene.
DR neXtProt; NX_P12268; -.
DR PharmGKB; PA29863; -.
DR eggNOG; COG0517; -.
DR HOGENOM; HOG000165752; -.
DR HOVERGEN; HBG052122; -.
DR InParanoid; P12268; -.
DR KO; K00088; -.
DR OMA; FQAKARH; -.
DR PhylomeDB; P12268; -.
DR BioCyc; MetaCyc:HS11242-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P12268; -.
DR UniPathway; UPA00601; UER00295.
DR ChiTaRS; IMPDH2; human.
DR EvolutionaryTrace; P12268; -.
DR GeneWiki; IMPDH2; -.
DR GenomeRNAi; 3615; -.
DR NextBio; 14143; -.
DR PRO; PR:P12268; -.
DR ArrayExpress; P12268; -.
DR Bgee; P12268; -.
DR CleanEx; HS_IMPDH2; -.
DR Genevestigator; P12268; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005778; C:peroxisomal membrane; IDA:UniProtKB.
DR GO; GO:0030554; F:adenyl nucleotide binding; IEA:InterPro.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0003938; F:IMP dehydrogenase activity; TAS:ProtInc.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0000166; F:nucleotide binding; IDA:UniProtKB.
DR GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR GO; GO:0071353; P:cellular response to interleukin-4; IEA:Ensembl.
DR GO; GO:0006177; P:GMP biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0046651; P:lymphocyte proliferation; IEA:Ensembl.
DR GO; GO:0051289; P:protein homotetramerization; IEA:Ensembl.
DR GO; GO:0006144; P:purine nucleobase metabolic process; TAS:Reactome.
DR GO; GO:0009168; P:purine ribonucleoside monophosphate biosynthetic process; TAS:Reactome.
DR GO; GO:0060041; P:retina development in camera-type eye; IEA:Ensembl.
DR Gene3D; 3.20.20.70; -; 1.
DR HAMAP; MF_01964; IMPDH; 1; -.
DR InterPro; IPR013785; Aldolase_TIM.
DR InterPro; IPR000644; CBS_dom.
DR InterPro; IPR005990; IMP_DH.
DR InterPro; IPR015875; IMP_DH/GMP_Rdtase_CS.
DR InterPro; IPR001093; IMP_DH_GMPRt.
DR PANTHER; PTHR11911:SF6; PTHR11911:SF6; 1.
DR Pfam; PF00571; CBS; 2.
DR Pfam; PF00478; IMPDH; 1.
DR PIRSF; PIRSF000130; IMPDH; 1.
DR SMART; SM00116; CBS; 2.
DR TIGRFAMs; TIGR01302; IMP_dehydrog; 1.
DR PROSITE; PS51371; CBS; 2.
DR PROSITE; PS00487; IMP_DH_GMP_RED; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; CBS domain; Complete proteome; Cytoplasm;
KW Direct protein sequencing; DNA-binding; GMP biosynthesis;
KW Metal-binding; NAD; Nucleus; Oxidoreductase; Phosphoprotein;
KW Potassium; Purine biosynthesis; Reference proteome; Repeat;
KW RNA-binding.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 514 Inosine-5'-monophosphate dehydrogenase 2.
FT /FTId=PRO_0000093673.
FT DOMAIN 114 173 CBS 1.
FT DOMAIN 179 237 CBS 2.
FT NP_BIND 274 276 NAD.
FT NP_BIND 324 326 NAD (By similarity).
FT REGION 364 366 IMP binding.
FT REGION 387 388 IMP binding.
FT REGION 411 415 IMP binding (By similarity).
FT ACT_SITE 331 331 Thioimidate intermediate.
FT METAL 326 326 Potassium; via carbonyl oxygen.
FT METAL 328 328 Potassium; via carbonyl oxygen.
FT METAL 331 331 Potassium; via carbonyl oxygen.
FT METAL 500 500 Potassium; via carbonyl oxygen; shared
FT with tetrameric partner (By similarity).
FT METAL 501 501 Potassium; via carbonyl oxygen; shared
FT with tetrameric partner (By similarity).
FT METAL 502 502 Potassium; via carbonyl oxygen; shared
FT with tetrameric partner (By similarity).
FT BINDING 329 329 IMP (By similarity).
FT BINDING 441 441 IMP (By similarity).
FT MOD_RES 122 122 Phosphoserine.
FT MOD_RES 400 400 Phosphotyrosine.
FT MOD_RES 416 416 Phosphoserine.
FT MOD_RES 511 511 N6-acetyllysine.
FT CONFLICT 190 191 AG -> RS (in Ref. 1; AAA36112).
FT STRAND 17 19
FT HELIX 20 24
FT STRAND 25 27
FT HELIX 32 34
FT STRAND 35 37
FT HELIX 46 48
FT STRAND 53 58
FT STRAND 60 67
FT TURN 71 73
FT HELIX 77 85
FT STRAND 89 91
FT HELIX 97 108
FT STRAND 112 115
FT STRAND 147 149
FT HELIX 161 164
FT TURN 175 177
FT STRAND 183 185
FT HELIX 194 203
FT STRAND 214 216
FT STRAND 220 222
FT STRAND 247 250
FT HELIX 256 265
FT STRAND 270 273
FT HELIX 281 293
FT STRAND 295 304
FT HELIX 307 316
FT STRAND 319 323
FT STRAND 328 331
FT HELIX 333 336
FT HELIX 343 354
FT HELIX 355 357
FT STRAND 361 365
FT HELIX 370 378
FT STRAND 382 387
FT HELIX 388 390
FT STRAND 396 398
FT STRAND 404 406
FT STRAND 409 412
FT TURN 417 419
FT STRAND 444 447
FT HELIX 453 471
FT HELIX 476 484
FT STRAND 490 492
FT HELIX 495 501
SQ SEQUENCE 514 AA; 55805 MW; 876BEA0EC1DDBEE9 CRC64;
MADYLISGGT SYVPDDGLTA QQLFNCGDGL TYNDFLILPG YIDFTADQVD LTSALTKKIT
LKTPLVSSPM DTVTEAGMAI AMALTGGIGF IHHNCTPEFQ ANEVRKVKKY EQGFITDPVV
LSPKDRVRDV FEAKARHGFC GIPITDTGRM GSRLVGIISS RDIDFLKEEE HDCFLEEIMT
KREDLVVAPA GITLKEANEI LQRSKKGKLP IVNEDDELVA IIARTDLKKN RDYPLASKDA
KKQLLCGAAI GTHEDDKYRL DLLAQAGVDV VVLDSSQGNS IFQINMIKYI KDKYPNLQVI
GGNVVTAAQA KNLIDAGVDA LRVGMGSGSI CITQEVLACG RPQATAVYKV SEYARRFGVP
VIADGGIQNV GHIAKALALG ASTVMMGSLL AATTEAPGEY FFSDGIRLKK YRGMGSLDAM
DKHLSSQNRY FSEADKIKVA QGVSGAVQDK GSIHKFVPYL IAGIQHSCQD IGAKSLTQVR
AMMYSGELKF EKRTSSAQVE GGVHSLHSYE KRLF
//
ID IMDH2_HUMAN Reviewed; 514 AA.
AC P12268; Q6LEF3;
DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAY-1991, sequence version 2.
DT 22-JAN-2014, entry version 167.
DE RecName: Full=Inosine-5'-monophosphate dehydrogenase 2;
DE Short=IMP dehydrogenase 2;
DE Short=IMPD 2;
DE Short=IMPDH 2;
DE EC=1.1.1.205;
DE AltName: Full=IMPDH-II;
GN Name=IMPDH2; Synonyms=IMPD2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=2902093;
RA Collart F.R., Huberman E.;
RT "Cloning and sequence analysis of the human and Chinese hamster
RT inosine-5'-monophosphate dehydrogenase cDNAs.";
RL J. Biol. Chem. 263:15769-15772(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Spleen;
RX PubMed=1969416;
RA Natsumeda Y., Ohno S., Kawasaki H., Konno Y., Weber G., Suzuki K.;
RT "Two distinct cDNAs for human IMP dehydrogenase.";
RL J. Biol. Chem. 265:5292-5295(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Blood;
RX PubMed=7999076; DOI=10.1006/bbrc.1994.2698;
RA Glesne D.A., Huberman E.;
RT "Cloning and sequence of the human type II IMP dehydrogenase gene.";
RL Biochem. Biophys. Res. Commun. 205:537-544(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=7896827; DOI=10.1074/jbc.270.12.6808;
RA Zimmermann A.G., Spychala J., Mitchell B.S.;
RT "Characterization of the human inosine-5'-monophosphate dehydrogenase
RT type II gene.";
RL J. Biol. Chem. 270:6808-6814(1995).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=B-cell, Colon, and Placenta;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 461-514.
RX PubMed=8098009; DOI=10.1006/geno.1993.1177;
RA Glesne D.A., Collart F.R., Varkony T., Drabkin H., Huberman E.;
RT "Chromosomal localization and structure of the human type II IMP
RT dehydrogenase gene.";
RL Genomics 16:274-277(1993).
RN [7]
RP PROTEIN SEQUENCE OF 2-11, BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, AND
RP ENZYME REGULATION.
RX PubMed=7903306;
RA Carr S.F., Papp E., Wu J.C., Natsumeda Y.;
RT "Characterization of human type I and type II IMP dehydrogenases.";
RL J. Biol. Chem. 268:27286-27290(1993).
RN [8]
RP PROTEIN SEQUENCE OF N-TERMINUS, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=7763314; DOI=10.1016/0006-2952(95)00026-V;
RA Hager P.W., Collart F.R., Huberman E., Mitchell B.S.;
RT "Recombinant human inosine monophosphate dehydrogenase type I and type
RT II proteins. Purification and characterization of inhibitor binding.";
RL Biochem. Pharmacol. 49:1323-1329(1995).
RN [9]
RP SUBCELLULAR LOCATION, AND NUCLEIC ACID-BINDING.
RX PubMed=14766016; DOI=10.1042/BJ20031585;
RA McLean J.E., Hamaguchi N., Belenky P., Mortimer S.E., Stanton M.,
RA Hedstrom L.;
RT "Inosine 5'-monophosphate dehydrogenase binds nucleic acids in vitro
RT and in vivo.";
RL Biochem. J. 379:243-251(2004).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-400, AND MASS
RP SPECTROMETRY.
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-122, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [14]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-511, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-122 AND SER-416, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS), AND ACTIVE SITE.
RX PubMed=10097070; DOI=10.1073/pnas.96.7.3531;
RA Colby T.D., Vanderveen K., Strickler M.D., Markham G.D.,
RA Goldstein B.M.;
RT "Crystal structure of human type II inosine monophosphate
RT dehydrogenase: implications for ligand binding and drug design.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:3531-3536(1999).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) IN COMPLEX WITH INHIBITOR AND
RP POTASSIUM.
RA Risal D., Strickler M.D., Goldstein B.M.;
RT "Crystal structure of human inosine monophosphate dehydrogenase type
RT II complexed with the MPA/NAD analog C2-MAD.";
RL Submitted (DEC-2002) to the PDB data bank.
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.90 ANGSTROMS) IN COMPLEX WITH NAD(+).
RA Risal D., Strickler M.D., Goldstein B.M.;
RT "The conformation of NAD bound to human inosine monophosphate
RT Dehydrogenase Type II.";
RL Submitted (DEC-2002) to the PDB data bank.
CC -!- FUNCTION: Catalyzes the conversion of inosine 5'-phosphate (IMP)
CC to xanthosine 5'-phosphate (XMP), the first committed and rate-
CC limiting step in the de novo synthesis of guanine nucleotides, and
CC therefore plays an important role in the regulation of cell
CC growth. Could also have a single-stranded nucleic acid-binding
CC activity and could play a role in RNA and/or DNA metabolism. It
CC may also have a role in the development of malignancy and the
CC growth progression of some tumors.
CC -!- CATALYTIC ACTIVITY: Inosine 5'-phosphate + NAD(+) + H(2)O =
CC xanthosine 5'-phosphate + NADH.
CC -!- COFACTOR: Potassium.
CC -!- ENZYME REGULATION: Mycophenolic acid (MPA) is a non-competitive
CC inhibitor that prevents formation of the closed enzyme
CC conformation by binding to the same site as the amobile flap. In
CC contrast, mizoribine monophosphate (MZP) is a competitive
CC inhibitor that induces the closed conformation. MPA is a potent
CC inhibitor of mammalian IMPDHs but a poor inhibitor of the
CC bacterial enzymes. MZP is a more potent inhibitor of bacterial
CC IMPDH. Subject to product inhibition by XMP and NADH. Also
CC inhibited by ADP.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=9.3 uM for Inosine 5'-phosphate;
CC KM=32 uM for NAD(+);
CC -!- PATHWAY: Purine metabolism; XMP biosynthesis via de novo pathway;
CC XMP from IMP: step 1/1.
CC -!- SUBUNIT: Homotetramer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus.
CC -!- TISSUE SPECIFICITY: IMP type I is the main species in normal
CC leukocytes and type II predominates over type I in the tumor.
CC -!- INDUCTION: Selectively up-regulated in neoplastic and replicating
CC cells.
CC -!- PTM: The N-terminus is blocked.
CC -!- MISCELLANEOUS: Because IMPDH activity is tightly linked with cell
CC proliferation, it has been recognized as a target for cancer and
CC viral chemotherapy and as a target for immunosuppressive drugs.
CC The activities of the antitumor drug tiazofurin, the antiviral
CC drug ribavirin, and the immunosuppressive drugs mizoribine and
CC mycophenolic acid (MPA) are attributed to the inhibition of IMPDH.
CC In addition, bacterial and parasitic IMPDH's differ significantly
CC from mammalian enzymes, which makes it a suitable target for anti-
CC infective drugs.
CC -!- SIMILARITY: Belongs to the IMPDH/GMPR family.
CC -!- SIMILARITY: Contains 2 CBS domains.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; J04208; AAA36112.1; -; mRNA.
DR EMBL; L33842; AAA67054.1; -; Genomic_DNA.
DR EMBL; L39210; AAB70699.1; -; Genomic_DNA.
DR EMBL; BC006124; AAH06124.1; -; mRNA.
DR EMBL; BC012840; AAH12840.1; -; mRNA.
DR EMBL; BC015567; AAH15567.1; -; mRNA.
DR EMBL; L08114; AAA36113.1; -; Genomic_DNA.
DR PIR; I52303; A31997.
DR RefSeq; NP_000875.2; NM_000884.2.
DR UniGene; Hs.654400; -.
DR PDB; 1B3O; X-ray; 2.90 A; A/B=1-514.
DR PDB; 1NF7; X-ray; 2.65 A; A/B=1-514.
DR PDB; 1NFB; X-ray; 2.90 A; A/B=1-514.
DR PDBsum; 1B3O; -.
DR PDBsum; 1NF7; -.
DR PDBsum; 1NFB; -.
DR ProteinModelPortal; P12268; -.
DR SMR; P12268; 10-514.
DR IntAct; P12268; 12.
DR MINT; MINT-2860057; -.
DR STRING; 9606.ENSP00000321584; -.
DR BindingDB; P12268; -.
DR ChEMBL; CHEMBL2002; -.
DR DrugBank; DB00688; Mycophenolate mofetil.
DR DrugBank; DB01024; Mycophenolic acid.
DR DrugBank; DB00157; NADH.
DR PhosphoSite; P12268; -.
DR DMDM; 124419; -.
DR REPRODUCTION-2DPAGE; IPI00291510; -.
DR REPRODUCTION-2DPAGE; P12268; -.
DR UCD-2DPAGE; P12268; -.
DR PaxDb; P12268; -.
DR PeptideAtlas; P12268; -.
DR PRIDE; P12268; -.
DR DNASU; 3615; -.
DR Ensembl; ENST00000326739; ENSP00000321584; ENSG00000178035.
DR GeneID; 3615; -.
DR KEGG; hsa:3615; -.
DR UCSC; uc003cvt.3; human.
DR CTD; 3615; -.
DR GeneCards; GC03M049061; -.
DR HGNC; HGNC:6053; IMPDH2.
DR HPA; CAB020717; -.
DR HPA; HPA001400; -.
DR MIM; 146691; gene.
DR neXtProt; NX_P12268; -.
DR PharmGKB; PA29863; -.
DR eggNOG; COG0517; -.
DR HOGENOM; HOG000165752; -.
DR HOVERGEN; HBG052122; -.
DR InParanoid; P12268; -.
DR KO; K00088; -.
DR OMA; FQAKARH; -.
DR PhylomeDB; P12268; -.
DR BioCyc; MetaCyc:HS11242-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P12268; -.
DR UniPathway; UPA00601; UER00295.
DR ChiTaRS; IMPDH2; human.
DR EvolutionaryTrace; P12268; -.
DR GeneWiki; IMPDH2; -.
DR GenomeRNAi; 3615; -.
DR NextBio; 14143; -.
DR PRO; PR:P12268; -.
DR ArrayExpress; P12268; -.
DR Bgee; P12268; -.
DR CleanEx; HS_IMPDH2; -.
DR Genevestigator; P12268; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005778; C:peroxisomal membrane; IDA:UniProtKB.
DR GO; GO:0030554; F:adenyl nucleotide binding; IEA:InterPro.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0003938; F:IMP dehydrogenase activity; TAS:ProtInc.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0000166; F:nucleotide binding; IDA:UniProtKB.
DR GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR GO; GO:0071353; P:cellular response to interleukin-4; IEA:Ensembl.
DR GO; GO:0006177; P:GMP biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0046651; P:lymphocyte proliferation; IEA:Ensembl.
DR GO; GO:0051289; P:protein homotetramerization; IEA:Ensembl.
DR GO; GO:0006144; P:purine nucleobase metabolic process; TAS:Reactome.
DR GO; GO:0009168; P:purine ribonucleoside monophosphate biosynthetic process; TAS:Reactome.
DR GO; GO:0060041; P:retina development in camera-type eye; IEA:Ensembl.
DR Gene3D; 3.20.20.70; -; 1.
DR HAMAP; MF_01964; IMPDH; 1; -.
DR InterPro; IPR013785; Aldolase_TIM.
DR InterPro; IPR000644; CBS_dom.
DR InterPro; IPR005990; IMP_DH.
DR InterPro; IPR015875; IMP_DH/GMP_Rdtase_CS.
DR InterPro; IPR001093; IMP_DH_GMPRt.
DR PANTHER; PTHR11911:SF6; PTHR11911:SF6; 1.
DR Pfam; PF00571; CBS; 2.
DR Pfam; PF00478; IMPDH; 1.
DR PIRSF; PIRSF000130; IMPDH; 1.
DR SMART; SM00116; CBS; 2.
DR TIGRFAMs; TIGR01302; IMP_dehydrog; 1.
DR PROSITE; PS51371; CBS; 2.
DR PROSITE; PS00487; IMP_DH_GMP_RED; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; CBS domain; Complete proteome; Cytoplasm;
KW Direct protein sequencing; DNA-binding; GMP biosynthesis;
KW Metal-binding; NAD; Nucleus; Oxidoreductase; Phosphoprotein;
KW Potassium; Purine biosynthesis; Reference proteome; Repeat;
KW RNA-binding.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 514 Inosine-5'-monophosphate dehydrogenase 2.
FT /FTId=PRO_0000093673.
FT DOMAIN 114 173 CBS 1.
FT DOMAIN 179 237 CBS 2.
FT NP_BIND 274 276 NAD.
FT NP_BIND 324 326 NAD (By similarity).
FT REGION 364 366 IMP binding.
FT REGION 387 388 IMP binding.
FT REGION 411 415 IMP binding (By similarity).
FT ACT_SITE 331 331 Thioimidate intermediate.
FT METAL 326 326 Potassium; via carbonyl oxygen.
FT METAL 328 328 Potassium; via carbonyl oxygen.
FT METAL 331 331 Potassium; via carbonyl oxygen.
FT METAL 500 500 Potassium; via carbonyl oxygen; shared
FT with tetrameric partner (By similarity).
FT METAL 501 501 Potassium; via carbonyl oxygen; shared
FT with tetrameric partner (By similarity).
FT METAL 502 502 Potassium; via carbonyl oxygen; shared
FT with tetrameric partner (By similarity).
FT BINDING 329 329 IMP (By similarity).
FT BINDING 441 441 IMP (By similarity).
FT MOD_RES 122 122 Phosphoserine.
FT MOD_RES 400 400 Phosphotyrosine.
FT MOD_RES 416 416 Phosphoserine.
FT MOD_RES 511 511 N6-acetyllysine.
FT CONFLICT 190 191 AG -> RS (in Ref. 1; AAA36112).
FT STRAND 17 19
FT HELIX 20 24
FT STRAND 25 27
FT HELIX 32 34
FT STRAND 35 37
FT HELIX 46 48
FT STRAND 53 58
FT STRAND 60 67
FT TURN 71 73
FT HELIX 77 85
FT STRAND 89 91
FT HELIX 97 108
FT STRAND 112 115
FT STRAND 147 149
FT HELIX 161 164
FT TURN 175 177
FT STRAND 183 185
FT HELIX 194 203
FT STRAND 214 216
FT STRAND 220 222
FT STRAND 247 250
FT HELIX 256 265
FT STRAND 270 273
FT HELIX 281 293
FT STRAND 295 304
FT HELIX 307 316
FT STRAND 319 323
FT STRAND 328 331
FT HELIX 333 336
FT HELIX 343 354
FT HELIX 355 357
FT STRAND 361 365
FT HELIX 370 378
FT STRAND 382 387
FT HELIX 388 390
FT STRAND 396 398
FT STRAND 404 406
FT STRAND 409 412
FT TURN 417 419
FT STRAND 444 447
FT HELIX 453 471
FT HELIX 476 484
FT STRAND 490 492
FT HELIX 495 501
SQ SEQUENCE 514 AA; 55805 MW; 876BEA0EC1DDBEE9 CRC64;
MADYLISGGT SYVPDDGLTA QQLFNCGDGL TYNDFLILPG YIDFTADQVD LTSALTKKIT
LKTPLVSSPM DTVTEAGMAI AMALTGGIGF IHHNCTPEFQ ANEVRKVKKY EQGFITDPVV
LSPKDRVRDV FEAKARHGFC GIPITDTGRM GSRLVGIISS RDIDFLKEEE HDCFLEEIMT
KREDLVVAPA GITLKEANEI LQRSKKGKLP IVNEDDELVA IIARTDLKKN RDYPLASKDA
KKQLLCGAAI GTHEDDKYRL DLLAQAGVDV VVLDSSQGNS IFQINMIKYI KDKYPNLQVI
GGNVVTAAQA KNLIDAGVDA LRVGMGSGSI CITQEVLACG RPQATAVYKV SEYARRFGVP
VIADGGIQNV GHIAKALALG ASTVMMGSLL AATTEAPGEY FFSDGIRLKK YRGMGSLDAM
DKHLSSQNRY FSEADKIKVA QGVSGAVQDK GSIHKFVPYL IAGIQHSCQD IGAKSLTQVR
AMMYSGELKF EKRTSSAQVE GGVHSLHSYE KRLF
//
MIM
146691
*RECORD*
*FIELD* NO
146691
*FIELD* TI
+146691 IMP DEHYDROGENASE 2; IMPDH2
;;INOSINE-5-PRIME-MONOPHOSPHATE DEHYDROGENASE, TYPE II; IMPD2; IMPDHII
read moreIMPDH2 ENZYME ACTIVITY, VARIATION IN, INCLUDED
*FIELD* TX
DESCRIPTION
Human type II inosine 5-prime-monophosphate dehydrogenase (EC 1.1.1.205)
is the rate-limiting enzyme in de novo guanine nucleotide biosynthesis.
Regulated inosine 5-prime-monophosphate dehydrogenase activity is
associated with cellular proliferation, transformation, and
differentiation (Glesne and Huberman, 1994).
See also IMP dehydrogenase-1 (IMPDH1; 146690).
CLONING
Glesne and Huberman (1994) isolated YAC clones containing the IMPDH2
gene and cloned the full-length human cDNA from a human peripheral blood
genomic library. IMPDH2 shares 84% amino acid identity with IMPDH1. They
identified 4 Sp1-binding sites but did not identify a TATA box. The
transcriptional start sites were determined by S1 nuclease mapping to be
somewhat heterogeneous, but the predominant mRNA species showed a
5-prime end at 102 and 85 nucleotides from the translational initiation
codon. Zimmermann et al. (1995) also cloned the IMPDH2 gene and
characterized regulatory elements, including a TATA box and SP1, AP2,
ATF, and CREB transcription factor-binding sites in the 5-prime flanking
region of the gene.
GENE STRUCTURE
Glesne and Huberman (1994) determined that the IMPDH2 gene contains 13
exons and spans approximately 5 kb. Zimmermann et al. (1995) determined
that the IMPDH2 gene contains 14 exons spanning approximately 5.8 kb.
They also characterized regulatory elements in the 5-prime flanking
region of the gene.
MAPPING
Using PCR primers specific for type II IMPDH, Glesne et al. (1993)
screened a panel of human/Chinese hamster cell somatic hybrids and a
separate deletion panel of chromosome 3 hybrids and localized the gene
to chromosome 3p24.2-p21.2.
By FISH, Kost-Alimova et al. (1998) refined the localization of the
IMPDH2 gene to 3p21.2.
GENE FUNCTION
Using proteomic analysis, Toubiana et al. (2011) found that stimulation
of a human monocyte cell line with TLR2 (603028) agonists resulted in
rapidly increased expression of posttranslationally modified IMPDHII in
lipid rafts. Mass spectrometric and immunoprecipitation analyses
determined that the IMPDHII modification involved tyrosine
phosphorylation. Luciferase analysis showed that IMPDHII inhibited NFKB
(see 164011) activity and reduced TNF (191160) production, but IMPDHII
did not modify MAP kinase activation or prevent degradation of IKB (see
164008). IMPDHII inhibited phosphorylation of p65 (NFKB3; 164014) and
modulated PI3K (see 601232) activation upstream of AKT (164730). IMPDHII
inhibition of NFKB activation involved dephosphorylation of the
p85-alpha subunit (PIK3R1; 171833) of PI3K through increased SHP1
(PTPN6; 176883) activity.
MOLECULAR GENETICS
Wang et al. (2007) identified a missense mutation in the IMPDH2 gene
(146691.0001) that reduces activity of IMPDH2 to 10% of that of
wildtype. The authors suggested that this functional variant may
contribute to interindividual differences in transplant patient response
to treatment with mycophenolate mofetil (MMF), the active metabolite of
which targets IMPDH2.
*FIELD* AV
.0001
IMPDH2 ENZYME ACTIVITY, VARIATION IN
IMPDH2, LEU263PHE
Wang et al. (2007) analyzed the IMPDH2 gene in DNA samples from 152
solid organ transplant patients and identified a 787C-T transition in
exon 7 of the IMPDH2 gene, resulting in a leu263-to-phe (L263F)
substitution at a highly conserved residue within the alpha helix of the
alpha/beta barrel core domain of the protein, which contains the entire
machinery for enzyme catalytic activity. Kinetic assay demonstrated that
the enzyme activity of the L263F variant was reduced 10-fold compared to
wildtype. The authors suggested that this functional variant may
contribute to interindividual differences in transplant patient response
to treatment with mycophenolate mofetil (MMF), the active metabolite of
which (mycophenolic acid) targets IMPDH2.
*FIELD* RF
1. Glesne, D.; Collart, F.; Varkony, T.; Drabkin, H.; Huberman, E.
: Chromosomal localization and structure of the human type II IMP
dehydrogenase gene (IMPDH2). Genomics 16: 274-277, 1993.
2. Glesne, D. A.; Huberman, E.: Cloning and sequencing of the human
type II IMP dehydrogenase gene. Biochem. Biophys. Res. Commun. 205:
537-544, 1994.
3. Kost-Alimova, M. V.; Glesne, D. A.; Huberman, E.; Zelenin, A. V.
: Assignment of inosine 5-prime-monophosphate dehydrogenase type 2
(IMPDH2) to human chromosome band 3p21.2 by in situ hybridization. Cytogenet.
Cell Genet. 82: 145-146, 1998.
4. Toubiana, J.; Rossi, A.-L.; Grimaldi, D.; Belaidouni, N.; Chafey,
P.; Clary, G.; Courtine, E.; Pene, F.; Mira, J.-P.; Claessens, Y.-E.;
Chiche, J.-D.: IMPDHII protein inhibits Toll-like receptor 2-mediated
activation of NF-kappa-B. J. Biol. Chem. 286: 23319-23333, 2011.
5. Wang, J.; Zeevi, A.; Webber, S.; Girnita, D. M.; Addonizio, L.;
Selby, R.; Hutchinson, I. V.; Burckart, G. J.: A novel variant L263F
in human inosine 5-prime-monophosphate dehydrogenase 2 is associated
with diminished enzyme activity. Pharmacogenet. Genomics 17: 283-290,
2007.
6. Zimmermann, A. G.; Spychala, J.; Mitchell, B. S.: Characterization
of the human inosine-5-prime-monophosphate dehydrogenase type II gene. J.
Biol. Chem. 270: 6808-6814, 1995.
*FIELD* CN
Paul J. Converse - updated: 12/02/2013
Marla J. F. O'Neill - updated: 2/5/2009
Carol A. Bocchini - updated: 3/9/1999
Alan F. Scott - updated: 6/21/1995
*FIELD* CD
Victor A. McKusick: 6/8/1990
*FIELD* ED
mgross: 12/02/2013
mcolton: 11/8/2013
wwang: 2/18/2009
terry: 2/5/2009
carol: 9/22/1999
terry: 3/9/1999
carol: 3/9/1999
joanna: 5/7/1998
mark: 6/21/1995
carol: 2/17/1995
carol: 5/27/1993
carol: 5/7/1993
supermim: 3/16/1992
carol: 6/8/1990
*RECORD*
*FIELD* NO
146691
*FIELD* TI
+146691 IMP DEHYDROGENASE 2; IMPDH2
;;INOSINE-5-PRIME-MONOPHOSPHATE DEHYDROGENASE, TYPE II; IMPD2; IMPDHII
read moreIMPDH2 ENZYME ACTIVITY, VARIATION IN, INCLUDED
*FIELD* TX
DESCRIPTION
Human type II inosine 5-prime-monophosphate dehydrogenase (EC 1.1.1.205)
is the rate-limiting enzyme in de novo guanine nucleotide biosynthesis.
Regulated inosine 5-prime-monophosphate dehydrogenase activity is
associated with cellular proliferation, transformation, and
differentiation (Glesne and Huberman, 1994).
See also IMP dehydrogenase-1 (IMPDH1; 146690).
CLONING
Glesne and Huberman (1994) isolated YAC clones containing the IMPDH2
gene and cloned the full-length human cDNA from a human peripheral blood
genomic library. IMPDH2 shares 84% amino acid identity with IMPDH1. They
identified 4 Sp1-binding sites but did not identify a TATA box. The
transcriptional start sites were determined by S1 nuclease mapping to be
somewhat heterogeneous, but the predominant mRNA species showed a
5-prime end at 102 and 85 nucleotides from the translational initiation
codon. Zimmermann et al. (1995) also cloned the IMPDH2 gene and
characterized regulatory elements, including a TATA box and SP1, AP2,
ATF, and CREB transcription factor-binding sites in the 5-prime flanking
region of the gene.
GENE STRUCTURE
Glesne and Huberman (1994) determined that the IMPDH2 gene contains 13
exons and spans approximately 5 kb. Zimmermann et al. (1995) determined
that the IMPDH2 gene contains 14 exons spanning approximately 5.8 kb.
They also characterized regulatory elements in the 5-prime flanking
region of the gene.
MAPPING
Using PCR primers specific for type II IMPDH, Glesne et al. (1993)
screened a panel of human/Chinese hamster cell somatic hybrids and a
separate deletion panel of chromosome 3 hybrids and localized the gene
to chromosome 3p24.2-p21.2.
By FISH, Kost-Alimova et al. (1998) refined the localization of the
IMPDH2 gene to 3p21.2.
GENE FUNCTION
Using proteomic analysis, Toubiana et al. (2011) found that stimulation
of a human monocyte cell line with TLR2 (603028) agonists resulted in
rapidly increased expression of posttranslationally modified IMPDHII in
lipid rafts. Mass spectrometric and immunoprecipitation analyses
determined that the IMPDHII modification involved tyrosine
phosphorylation. Luciferase analysis showed that IMPDHII inhibited NFKB
(see 164011) activity and reduced TNF (191160) production, but IMPDHII
did not modify MAP kinase activation or prevent degradation of IKB (see
164008). IMPDHII inhibited phosphorylation of p65 (NFKB3; 164014) and
modulated PI3K (see 601232) activation upstream of AKT (164730). IMPDHII
inhibition of NFKB activation involved dephosphorylation of the
p85-alpha subunit (PIK3R1; 171833) of PI3K through increased SHP1
(PTPN6; 176883) activity.
MOLECULAR GENETICS
Wang et al. (2007) identified a missense mutation in the IMPDH2 gene
(146691.0001) that reduces activity of IMPDH2 to 10% of that of
wildtype. The authors suggested that this functional variant may
contribute to interindividual differences in transplant patient response
to treatment with mycophenolate mofetil (MMF), the active metabolite of
which targets IMPDH2.
*FIELD* AV
.0001
IMPDH2 ENZYME ACTIVITY, VARIATION IN
IMPDH2, LEU263PHE
Wang et al. (2007) analyzed the IMPDH2 gene in DNA samples from 152
solid organ transplant patients and identified a 787C-T transition in
exon 7 of the IMPDH2 gene, resulting in a leu263-to-phe (L263F)
substitution at a highly conserved residue within the alpha helix of the
alpha/beta barrel core domain of the protein, which contains the entire
machinery for enzyme catalytic activity. Kinetic assay demonstrated that
the enzyme activity of the L263F variant was reduced 10-fold compared to
wildtype. The authors suggested that this functional variant may
contribute to interindividual differences in transplant patient response
to treatment with mycophenolate mofetil (MMF), the active metabolite of
which (mycophenolic acid) targets IMPDH2.
*FIELD* RF
1. Glesne, D.; Collart, F.; Varkony, T.; Drabkin, H.; Huberman, E.
: Chromosomal localization and structure of the human type II IMP
dehydrogenase gene (IMPDH2). Genomics 16: 274-277, 1993.
2. Glesne, D. A.; Huberman, E.: Cloning and sequencing of the human
type II IMP dehydrogenase gene. Biochem. Biophys. Res. Commun. 205:
537-544, 1994.
3. Kost-Alimova, M. V.; Glesne, D. A.; Huberman, E.; Zelenin, A. V.
: Assignment of inosine 5-prime-monophosphate dehydrogenase type 2
(IMPDH2) to human chromosome band 3p21.2 by in situ hybridization. Cytogenet.
Cell Genet. 82: 145-146, 1998.
4. Toubiana, J.; Rossi, A.-L.; Grimaldi, D.; Belaidouni, N.; Chafey,
P.; Clary, G.; Courtine, E.; Pene, F.; Mira, J.-P.; Claessens, Y.-E.;
Chiche, J.-D.: IMPDHII protein inhibits Toll-like receptor 2-mediated
activation of NF-kappa-B. J. Biol. Chem. 286: 23319-23333, 2011.
5. Wang, J.; Zeevi, A.; Webber, S.; Girnita, D. M.; Addonizio, L.;
Selby, R.; Hutchinson, I. V.; Burckart, G. J.: A novel variant L263F
in human inosine 5-prime-monophosphate dehydrogenase 2 is associated
with diminished enzyme activity. Pharmacogenet. Genomics 17: 283-290,
2007.
6. Zimmermann, A. G.; Spychala, J.; Mitchell, B. S.: Characterization
of the human inosine-5-prime-monophosphate dehydrogenase type II gene. J.
Biol. Chem. 270: 6808-6814, 1995.
*FIELD* CN
Paul J. Converse - updated: 12/02/2013
Marla J. F. O'Neill - updated: 2/5/2009
Carol A. Bocchini - updated: 3/9/1999
Alan F. Scott - updated: 6/21/1995
*FIELD* CD
Victor A. McKusick: 6/8/1990
*FIELD* ED
mgross: 12/02/2013
mcolton: 11/8/2013
wwang: 2/18/2009
terry: 2/5/2009
carol: 9/22/1999
terry: 3/9/1999
carol: 3/9/1999
joanna: 5/7/1998
mark: 6/21/1995
carol: 2/17/1995
carol: 5/27/1993
carol: 5/7/1993
supermim: 3/16/1992
carol: 6/8/1990