P12268 (IMDH2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	514 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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
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. HAMAP-Rule MF_03156
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 process	GMP biosynthesis Purine biosynthesis
Cellular component	Cytoplasm Nucleus
Domain	CBS domain Repeat
Ligand	DNA-binding Metal-binding NAD Potassium RNA-binding
Molecular function	Oxidoreductase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	GMP biosynthetic process Inferred from electronic annotation. Source: HAMAP lymphocyte proliferation Inferred from electronic annotation. Source: Compara protein homotetramerization Inferred from electronic annotation. Source: Compara purine nucleobase metabolic process Traceable author statement. Source: Reactome purine ribonucleoside monophosphate biosynthetic process Traceable author statement. Source: Reactome retina development in camera-type eye Inferred from electronic annotation. Source: Compara
Cellular_component	cytosol Traceable author statement. Source: Reactome nucleus Inferred from direct assay Ref.9. Source: UniProtKB peroxisomal membrane Inferred from direct assay PubMed 21525035. Source: UniProtKB
Molecular_function	DNA 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 metal ion binding Inferred from electronic annotation. Source: HAMAP nucleotide binding Inferred from direct assay Ref.9. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.7

Chain

2 – 514

513

Inosine-5'-monophosphate dehydrogenase 2 HAMAP-Rule MF_03156

PRO_0000093673

Regions

Domain

114 – 173

60

CBS 1

Domain

179 – 237

59

CBS 2

Nucleotide binding

274 – 276

3

NAD HAMAP-Rule MF_03156

Nucleotide binding

324 – 326

3

NAD By similarity

Region

364 – 366

3

IMP binding HAMAP-Rule MF_03156

Region

387 – 388

2

IMP binding HAMAP-Rule MF_03156

Region

411 – 415

5

IMP binding By similarity

Sites

Active site

331

1

Thioimidate intermediate Ref.16

Metal binding

326

1

Potassium; via carbonyl oxygen

Metal binding

328

1

Potassium; via carbonyl oxygen

Metal binding

331

1

Potassium; via carbonyl oxygen

Metal binding

500

1

Potassium; via carbonyl oxygen; shared with tetrameric partner By similarity

Metal binding

501

1

Potassium; via carbonyl oxygen; shared with tetrameric partner By similarity

Metal binding

502

1

Potassium; via carbonyl oxygen; shared with tetrameric partner By similarity

Binding site

329

1

IMP By similarity

Binding site

441

1

IMP By similarity

Amino acid modifications

Modified residue

122

1

Phosphoserine Ref.12 Ref.14

Modified residue

400

1

Phosphotyrosine Ref.10

Modified residue

416

1

Phosphoserine Ref.14

Modified residue

511

1

N6-acetyllysine Ref.13

Experimental info

Sequence conflict

190 – 191

2

AG → RS in AAA36112. Ref.1

Secondary structure

1

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514

Helix Strand Turn

Details...

Beta strand

17 – 19

3

Helix

20 – 24

5

Beta strand

25 – 27

3

Helix

32 – 34

3

Beta strand

35 – 37

3

Helix

46 – 48

3

Beta strand

53 – 58

6

Beta strand

60 – 67

8

Turn

71 – 73

3

Helix

77 – 85

9

Beta strand

89 – 91

3

Helix

97 – 108

12

Beta strand

112 – 115

4

Beta strand

147 – 149

3

Helix

161 – 164

4

Turn

175 – 177

3

Beta strand

183 – 185

3

Helix

194 – 203

10

Beta strand

214 – 216

3

Beta strand

220 – 222

3

Beta strand

247 – 250

4

Helix

256 – 265

10

Beta strand

270 – 273

4

Helix

281 – 293

13

Beta strand

295 – 304

10

Helix

307 – 316

10

Beta strand

319 – 323

5

Beta strand

328 – 331

4

Helix

333 – 336

4

Helix

343 – 354

12

Helix

355 – 357

3

Beta strand

361 – 365

5

Helix

370 – 378

9

Beta strand

382 – 387

6

Helix

388 – 390

3

Beta strand

396 – 398

3

Beta strand

404 – 406

3

Beta strand

409 – 412

4

Turn

417 – 419

3

Beta strand

444 – 447

4

Helix

453 – 471

19

Helix

476 – 484

9

Beta strand

490 – 492

3

Helix

495 – 501

7

Sequences

	Sequence		Length	Mass (Da)
	P12268 [UniParc]. Last modified May 1, 1991. Version 2. Checksum: 876BEA0EC1DDBEE9	FASTA	514	55,805
	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

References

	« Hide 'large scale' referencesShow '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, MASS SPECTROMETRY.
[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 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, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[13]	"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, MASS SPECTROMETRY.
[14]	"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, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[15]	"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].
[16]	"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.
[17]	"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.
[18]	"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.

IPI

IPI00291510.

PIR

A31997. I52303.

RefSeq

NP_000875.2. NM_000884.2.

UniGene

Hs.654400.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1B3O	X-ray	2.90	A/B	1-514	[»]
1NF7	X-ray	2.65	A/B	1-514	[»]
1NFB	X-ray	2.90	A/B	1-514	[»]

ProteinModelPortal

P12268.

SMR

P12268. Positions 10-514.

ModBase

Search...

Protein-protein interaction databases

IntAct

P12268. 9 interactions.

MINT

MINT-2860057.

STRING

9606.ENSP00000321584.

PTM databases

PhosphoSite

P12268.

Polymorphism databases

DMDM

124419.

2D gel databases

REPRODUCTION-2DPAGE

IPI00291510.
P12268.

UCD-2DPAGE

P12268.

Proteomic databases

PaxDb

P12268.

PeptideAtlas

P12268.

PRIDE

P12268.

Protocols and materials databases

DNASU

3615.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000326739; ENSP00000321584; ENSG00000178035.

GeneID

3615.

KEGG

hsa:3615.

UCSC

uc003cvt.3. human.

Organism-specific databases

CTD

3615.

GeneCards

GC03M049061.

HGNC

HGNC:6053. IMPDH2.

HPA

CAB020717.
HPA001400.

MIM

146691. gene.

neXtProt

NX_P12268.

PharmGKB

PA29863.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0517.

HOGENOM

HOG000165752.

HOVERGEN

HBG052122.

InParanoid

P12268.

KO

K00088.

OMA

KRYEQGF.

OrthoDB

EOG40VVP8.

PhylomeDB

P12268.

Enzyme and pathway databases

BioCyc

MetaCyc:HS11242-MONOMER.

Reactome

REACT_111217. Metabolism.

SABIO-RK

P12268.

UniPathway

UPA00601; UER00295.

Gene expression databases

ArrayExpress

P12268.

Bgee

P12268.

CleanEx

HS_IMPDH2.

Genevestigator

P12268.

GermOnline

ENSG00000178035. Homo sapiens.

Family and domain databases

Gene3D

3.20.20.70. 1 hit.

HAMAP

MF_01964. IMPDH.

InterPro

IPR013785. Aldolase_TIM.
IPR000644. Cysta_beta_synth_core.
IPR005990. IMP_DH.
IPR015875. IMP_DH/GMP_Rdtase_CS.
IPR001093. IMP_DH_GMPRt.
[Graphical view]

PANTHER

PTHR11911:SF6. PTHR11911:SF6. 1 hit.

Pfam

PF00571. CBS. 2 hits.
PF00478. IMPDH. 1 hit.
[Graphical view]

PIRSF

PIRSF000130. IMPDH. 1 hit.

SMART

SM00116. CBS. 2 hits.
[Graphical view]

TIGRFAMs

TIGR01302. IMP_dehydrog. 1 hit.

PROSITE

PS51371. CBS. 2 hits.
PS00487. IMP_DH_GMP_RED. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P12268.

ChEMBL

CHEMBL2002.

ChiTaRS

IMPDH2. human.

DrugBank

DB00688. Mycophenolate mofetil.
DB01024. Mycophenolic acid.
DB00157. NADH.

EvolutionaryTrace

P12268.

GenomeRNAi

3615.

NextBio

14143.

SOURCE

Search...

Entry information

Entry name

IMDH2_HUMAN

Accession

Primary (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:	April 3, 2013
This is version 160 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.