P12268 · IMDH2_HUMAN
- ProteinInosine-5'-monophosphate dehydrogenase 2
- GeneIMPDH2
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids514 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
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 (PubMed:7763314, PubMed:7903306).
Could also have a single-stranded nucleic acid-binding activity and could play a role in RNA and/or DNA metabolism (PubMed:14766016).
It may also have a role in the development of malignancy and the growth progression of some tumors
Could also have a single-stranded nucleic acid-binding activity and could play a role in RNA and/or DNA metabolism (PubMed:14766016).
It may also have a role in the development of malignancy and the growth progression of some tumors
Miscellaneous
Because IMPDH activity is tightly linked with cell proliferation, it has been recognized as a target for cancer and viral chemotherapy and as a target for immunosuppressive drugs. The activities of the antitumor drug tiazofurin, the antiviral drug ribavirin, and the immunosuppressive drugs mizoribine and mycophenolic acid (MPA) are attributed to the inhibition of IMPDH. In addition, bacterial and parasitic IMPDH's differ significantly from mammalian enzymes, which makes it a suitable target for anti-infective drugs.
Catalytic activity
- H2O + IMP + NAD+ = H+ + NADH + XMP
Cofactor
Activity 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 (PubMed:7903306).
Also inhibited by ADP
Also inhibited by ADP
Kinetics
KM | SUBSTRATE | pH | TEMPERATURE[C] | NOTES | EVIDENCE | |
---|---|---|---|---|---|---|
9.3 μM | Inosine 5'-phosphate | |||||
32 μM | NAD+ |
Pathway
Purine metabolism; XMP biosynthesis via de novo pathway; XMP from IMP: step 1/1.
Features
Showing features for binding site, active site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 274-276 | NAD+ (UniProtKB | ChEBI) | ||||
Sequence: DSS | ||||||
Binding site | 324-326 | NAD+ (UniProtKB | ChEBI) | ||||
Sequence: GMG | ||||||
Binding site | 326 | K+ (UniProtKB | ChEBI); ligand shared between two tetrameric partners; in other chain | ||||
Sequence: G | ||||||
Binding site | 328 | K+ (UniProtKB | ChEBI); ligand shared between two tetrameric partners; in other chain | ||||
Sequence: G | ||||||
Binding site | 329 | IMP (UniProtKB | ChEBI) | ||||
Sequence: S | ||||||
Active site | 331 | Thioimidate intermediate | ||||
Sequence: C | ||||||
Binding site | 331 | K+ (UniProtKB | ChEBI); ligand shared between two tetrameric partners; in other chain | ||||
Sequence: C | ||||||
Binding site | 364-366 | IMP (UniProtKB | ChEBI) | ||||
Sequence: DGG | ||||||
Binding site | 387-388 | IMP (UniProtKB | ChEBI) | ||||
Sequence: GS | ||||||
Binding site | 411-415 | IMP (UniProtKB | ChEBI) | ||||
Sequence: YRGMG | ||||||
Active site | 429 | Proton acceptor | ||||
Sequence: R | ||||||
Binding site | 441 | IMP (UniProtKB | ChEBI) | ||||
Sequence: Q | ||||||
Binding site | 500 | K+ (UniProtKB | ChEBI); ligand shared between two tetrameric partners | ||||
Sequence: E | ||||||
Binding site | 501 | K+ (UniProtKB | ChEBI); ligand shared between two tetrameric partners | ||||
Sequence: G | ||||||
Binding site | 502 | K+ (UniProtKB | ChEBI); ligand shared between two tetrameric partners | ||||
Sequence: G |
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | cytoplasm | |
Cellular Component | cytosol | |
Cellular Component | extracellular exosome | |
Cellular Component | extracellular region | |
Cellular Component | ficolin-1-rich granule lumen | |
Cellular Component | membrane | |
Cellular Component | nucleus | |
Cellular Component | peroxisomal membrane | |
Cellular Component | secretory granule lumen | |
Molecular Function | DNA binding | |
Molecular Function | IMP dehydrogenase activity | |
Molecular Function | metal ion binding | |
Molecular Function | nucleotide binding | |
Molecular Function | RNA binding | |
Biological Process | 'de novo' XMP biosynthetic process | |
Biological Process | cellular response to interleukin-4 | |
Biological Process | circadian rhythm | |
Biological Process | GMP biosynthetic process | |
Biological Process | GTP biosynthetic process | |
Biological Process | lymphocyte proliferation |
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameInosine-5'-monophosphate dehydrogenase 2
- EC number
- Short namesIMP dehydrogenase 2; IMPD 2; IMPDH 2
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP12268
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Note: Can form fiber-like subcellular structures termed 'cytoophidia' in response to intracellular guanine-nucleotide depletion.
Keywords
- Cellular component
Disease & Variants
Features
Showing features for natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_070542 | 263 | results in 10-fold decrease of enzymatic activity; dbSNP:rs121434586 | |||
Sequence: L → F |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 419 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for initiator methionine, chain, modified residue, modified residue (large scale data), cross-link.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Initiator methionine | 1 | UniProt | Removed | ||||
Sequence: M | |||||||
Chain | PRO_0000093673 | 2-514 | UniProt | Inosine-5'-monophosphate dehydrogenase 2 | |||
Sequence: ADYLISGGTSYVPDDGLTAQQLFNCGDGLTYNDFLILPGYIDFTADQVDLTSALTKKITLKTPLVSSPMDTVTEAGMAIAMALTGGIGFIHHNCTPEFQANEVRKVKKYEQGFITDPVVLSPKDRVRDVFEAKARHGFCGIPITDTGRMGSRLVGIISSRDIDFLKEEEHDCFLEEIMTKREDLVVAPAGITLKEANEILQRSKKGKLPIVNEDDELVAIIARTDLKKNRDYPLASKDAKKQLLCGAAIGTHEDDKYRLDLLAQAGVDVVVLDSSQGNSIFQINMIKYIKDKYPNLQVIGGNVVTAAQAKNLIDAGVDALRVGMGSGSICITQEVLACGRPQATAVYKVSEYARRFGVPVIADGGIQNVGHIAKALALGASTVMMGSLLAATTEAPGEYFFSDGIRLKKYRGMGSLDAMDKHLSSQNRYFSEADKIKVAQGVSGAVQDKGSIHKFVPYLIAGIQHSCQDIGAKSLTQVRAMMYSGELKFEKRTSSAQVEGGVHSLHSYEKRLF | |||||||
Modified residue | 122 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 122 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 159 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 160 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 160 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Cross-link | 195 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2) | ||||
Sequence: K | |||||||
Cross-link | 208 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2) | ||||
Sequence: K | |||||||
Modified residue | 400 | UniProt | Phosphotyrosine | ||||
Sequence: Y | |||||||
Modified residue | 416 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 416 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 426 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Cross-link | 438 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2) | ||||
Sequence: K | |||||||
Modified residue (large scale data) | 444 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 495 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 496 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 505 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 508 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 511 | UniProt | N6-acetyllysine | ||||
Sequence: K |
Post-translational modification
Ubiquitinated leading to its degradation by the proteasome.
The N-terminus is blocked.
Acetylated by CLOCK in a circadian manner (PubMed:28985504).
Keywords
- PTM
Proteomic databases
2D gel databases
PTM databases
Expression
Tissue specificity
IMPDH1 is the main species in normal leukocytes and IMPDH2 predominates over IMPDH1 in the tumor.
Induction
Selectively up-regulated in neoplastic and replicating cells.
Gene expression databases
Organism-specific databases
Interaction
Subunit
Homotetramer (PubMed:7903306, Ref.28, Ref.29). Interacts with CLOCK; in a circadian manner (PubMed:28985504).
Interacts with ANKRD9; leading to its ubiquitination and degradation by the proteasome (PubMed:30293565).
Interacts with ANKRD9; leading to its ubiquitination and degradation by the proteasome (PubMed:30293565).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | P12268 | AGR2 O95994 | 3 | EBI-353389, EBI-712648 | |
BINARY | P12268 | APIP Q96GX9 | 3 | EBI-353389, EBI-359248 | |
BINARY | P12268 | CPLANE2 Q9BU20 | 6 | EBI-353389, EBI-750332 | |
BINARY | P12268 | IL1F10 Q8WWZ1 | 3 | EBI-353389, EBI-13318821 | |
BINARY | P12268 | IMPDH1 P20839-3 | 3 | EBI-353389, EBI-12188657 | |
BINARY | P12268 | POU6F2 P78424 | 3 | EBI-353389, EBI-12029004 | |
BINARY | P12268 | STAT3 P40763 | 3 | EBI-353389, EBI-518675 | |
BINARY | P12268 | TRAF2 Q12933 | 3 | EBI-353389, EBI-355744 |
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 114-173 | CBS 1 | ||||
Sequence: FITDPVVLSPKDRVRDVFEAKARHGFCGIPITDTGRMGSRLVGIISSRDIDFLKEEEHDC | ||||||
Domain | 179-237 | CBS 2 | ||||
Sequence: MTKREDLVVAPAGITLKEANEILQRSKKGKLPIVNEDDELVAIIARTDLKKNRDYPLAS |
Sequence similarities
Belongs to the IMPDH/GMPR family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length514
- Mass (Da)55,805
- Last updated1991-05-01 v2
- Checksum876BEA0EC1DDBEE9
Computationally mapped potential isoform sequences
There are 6 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
E7ETK5 | E7ETK5_HUMAN | IMPDH2 | 489 | ||
H0Y4R1 | H0Y4R1_HUMAN | IMPDH2 | 538 | ||
A0A7I2YQK5 | A0A7I2YQK5_HUMAN | IMPDH2 | 513 | ||
A0A7I2V337 | A0A7I2V337_HUMAN | IMPDH2 | 47 | ||
A0A7I2V2T3 | A0A7I2V2T3_HUMAN | IMPDH2 | 522 | ||
A0A7I2V5N6 | A0A7I2V5N6_HUMAN | IMPDH2 | 123 |
Features
Showing features for sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 190-191 | in Ref. 1; AAA36112 | ||||
Sequence: AG → RS |
Polymorphism
Genetic variants in the IMPDH2 gene are responsible for the large inter-individual variability in enzyme activity and may influence immunosuppressive efficacy and side effects in transplant recipients receiving mycophenolic acid [MIM:617995].
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
J04208 EMBL· GenBank· DDBJ | AAA36112.1 EMBL· GenBank· DDBJ | mRNA | ||
L33842 EMBL· GenBank· DDBJ | AAA67054.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
L39210 EMBL· GenBank· DDBJ | AAB70699.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC006124 EMBL· GenBank· DDBJ | AAH06124.1 EMBL· GenBank· DDBJ | mRNA | ||
BC012840 EMBL· GenBank· DDBJ | AAH12840.1 EMBL· GenBank· DDBJ | mRNA | ||
BC015567 EMBL· GenBank· DDBJ | AAH15567.1 EMBL· GenBank· DDBJ | mRNA | ||
L08114 EMBL· GenBank· DDBJ | AAA36113.1 EMBL· GenBank· DDBJ | Genomic DNA |