UniProt functional annotation for P12268



	UniProt functional annotation for P12268

UniProt code: P12268.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

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:7903306, PubMed:7763314). 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. {ECO:0000269|PubMed:14766016, ECO:0000269|PubMed:7763314, ECO:0000269|PubMed:7903306}.

Catalytic activity: Reaction=H2O + IMP + NAD(+) = H(+) + NADH + XMP; Xref=Rhea:RHEA:11708, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:57464, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:58053; EC=1.1.1.205; Evidence={ECO:0000269|PubMed:7763314, ECO:0000269|PubMed:7903306};

Cofactor: Name=K(+); Xref=ChEBI:CHEBI:29103;

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. {ECO:0000255|HAMAP- Rule:MF_03156, ECO:0000269|PubMed:7903306}.

Biophysicochemical properties: Kinetic parameters: KM=9.3 uM for Inosine 5'-phosphate {ECO:0000269|PubMed:7763314, ECO:0000269|PubMed:7903306}; KM=32 uM for NAD(+) {ECO:0000269|PubMed:7763314, ECO:0000269|PubMed:7903306};

Pathway: Purine metabolism; XMP biosynthesis via de novo pathway; XMP from IMP: step 1/1. {ECO:0000269|PubMed:7763314, ECO:0000269|PubMed:7903306}.

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). {ECO:0000269|PubMed:28985504, ECO:0000269|PubMed:30293565, ECO:0000269|PubMed:7903306, ECO:0000269|Ref.28, ECO:0000269|Ref.29}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:14766016}. Nucleus {ECO:0000269|PubMed:14766016}. Cytoplasm, cytosol {ECO:0000269|PubMed:31337707}. Note=Can form fiber-like subcellular structures termed 'cytoophidia' in response to intracellular guanine- nucleotide depletion. {ECO:0000269|PubMed:24477477, ECO:0000269|PubMed:31337707}.

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.

Ptm: Ubiquitinated leading to its degradation by the proteasome. {ECO:0000269|PubMed:30293565}.

Ptm: The N-terminus is blocked.

Ptm: Acetylated by CLOCK in a circadian manner (PubMed:28985504). {ECO:0000269|PubMed:28985504}.

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]. {ECO:0000269|PubMed:17496727}.

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.

Similarity: Belongs to the IMPDH/GMPR family. {ECO:0000255|HAMAP- Rule:MF_03156}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



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:7903306, PubMed:7763314). 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. {ECO:0000269\|PubMed:14766016, ECO:0000269\|PubMed:7763314, ECO:0000269\|PubMed:7903306}.


Catalytic activity:		Reaction=H2O + IMP + NAD(+) = H(+) + NADH + XMP; Xref=Rhea:RHEA:11708, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:57464, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:58053; EC=1.1.1.205; Evidence={ECO:0000269\|PubMed:7763314, ECO:0000269\|PubMed:7903306};
Cofactor:		Name=K(+); Xref=ChEBI:CHEBI:29103;
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. {ECO:0000255\|HAMAP- Rule:MF_03156, ECO:0000269\|PubMed:7903306}.
Biophysicochemical properties:		Kinetic parameters: KM=9.3 uM for Inosine 5'-phosphate {ECO:0000269\|PubMed:7763314, ECO:0000269\|PubMed:7903306}; KM=32 uM for NAD(+) {ECO:0000269\|PubMed:7763314, ECO:0000269\|PubMed:7903306};
Pathway:		Purine metabolism; XMP biosynthesis via de novo pathway; XMP from IMP: step 1/1. {ECO:0000269\|PubMed:7763314, ECO:0000269\|PubMed:7903306}.
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). {ECO:0000269\|PubMed:28985504, ECO:0000269\|PubMed:30293565, ECO:0000269\|PubMed:7903306, ECO:0000269\|Ref.28, ECO:0000269\|Ref.29}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:14766016}. Nucleus {ECO:0000269\|PubMed:14766016}. Cytoplasm, cytosol {ECO:0000269\|PubMed:31337707}. Note=Can form fiber-like subcellular structures termed 'cytoophidia' in response to intracellular guanine- nucleotide depletion. {ECO:0000269\|PubMed:24477477, ECO:0000269\|PubMed:31337707}.
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.
Ptm:		Ubiquitinated leading to its degradation by the proteasome. {ECO:0000269\|PubMed:30293565}.
Ptm:		The N-terminus is blocked.
Ptm:		Acetylated by CLOCK in a circadian manner (PubMed:28985504). {ECO:0000269\|PubMed:28985504}.
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]. {ECO:0000269\|PubMed:17496727}.
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.
Similarity:		Belongs to the IMPDH/GMPR family. {ECO:0000255\|HAMAP- Rule:MF_03156}.