Alternative titles; symbols
HGNC Approved Gene Symbol: IMPDH2
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:49,024,325-49,029,398 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | [IMPDH2 enzyme activity, variation in] | 617995 | 3 |
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).
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.
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.
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.
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.
Wang et al. (2007) identified a missense mutation in the IMPDH2 gene (L263F; 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.
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 (IMPDH2V; 617995). 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.
Glesne, D. A., Huberman, E. Cloning and sequencing of the human type II IMP dehydrogenase gene. Biochem. Biophys. Res. Commun. 205: 537-544, 1994. [PubMed: 7999076] [Full Text: https://doi.org/10.1006/bbrc.1994.2698]
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. [PubMed: 8098009] [Full Text: https://doi.org/10.1006/geno.1993.1177]
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. [PubMed: 9858805] [Full Text: https://doi.org/10.1159/000015088]
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. [PubMed: 21460227] [Full Text: https://doi.org/10.1074/jbc.M110.201210]
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. [PubMed: 17496727] [Full Text: https://doi.org/10.1097/FPC.0b013e328012b8cf]
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. [PubMed: 7896827] [Full Text: https://doi.org/10.1074/jbc.270.12.6808]