HGNC Approved Gene Symbol: ITPKA
Cytogenetic location: 15q15.1 Genomic coordinates (GRCh38): 15:41,493,874-41,503,551 (from NCBI)
Inositol 1,4,5-trisphosphate 3-kinase (ITPK) catalyzes the phosphorylation of Ins(1,4,5)P3 to Ins(1,3,4,5)P4, both of which are modulators of calcium homeostasis. ITPK isoforms include ITPKA, ITPKB (147522), and ITPKC (606476), all of which contain a conserved catalytic unit in their C termini, but have unique N-terminal sequences and tissue distributions.
Takazawa et al. (1991) used a rat brain ITPK cDNA to screen a human hippocampus cDNA library. By sequencing 3 overlapping clones, they identified a 1,383-bp open reading frame encoding a 461-amino acid protein with a calculated molecular weight of 50,988. The coding amino acid sequence showed an overall 93% similarity with the sequence of the rat brain enzyme; see Takazawa et al. (1990).
Gonzalez et al. (2004) reported the structure of ITPKA both free and in complex with the substrate Mn(2+)/ATP/Ins(1,4,5)P3 and the product Mn(2+)/ADP/Ins(1,3,4,5)P4. The catalytic domain consists of N- and C-terminal lobes and an alpha-only subdomain. The N-terminal and C-terminal lobes bind ATP and resemble other protein and lipid kinases. In the apo form, the N-terminal helix of the N-terminal lobe occupies much of the volume of the positively charged ATP binding pocket. The alpha-only subdomain binds all of the phosphates of Ins(1,4,5)P3 in a positively charged pocket, explaining the enzyme's substrate specificity and its inability to phosphorylate PtdIns(4,5)P2 due to stearic hindrance. The proximity of the gamma-phosphate position in the ATP to its final position in the product supports a direct in-line mechanism of phosphoryl transfer that involves the critical lys264.
Erneux et al. (1992) used in situ hybridization to map the ITPKA gene to 15q14-q21.
Erneux, C., Roeckel, N., Takazawa, K., Mailleux, P., Vassart, G., Mattei, M. G. Localization of the genes for human inositol 1,4,5-trisphosphate 3-kinase A (ITPKA) and B (ITPKB) to chromosome regions 15q14-q21 and 1q41-q43, respectively, by in situ hybridization. Genomics 14: 546-547, 1992. [PubMed: 1330886] [Full Text: https://doi.org/10.1016/s0888-7543(05)80265-4]
Gonzalez, B., Schell, M. J., Letcher, A. J., Veprintsev, D. B., Irvine, R. F., Williams, R. L. Structure of a human inositol 1,4,5-trisphosphate 3-kinase: substrate binding reveals why it is not a phosphoinositide 3-kinase. Molec. Cell 15: 689-701, 2004. [PubMed: 15350214] [Full Text: https://doi.org/10.1016/j.molcel.2004.08.004]
Takazawa, K., Perret, J., Dumont, J. E., Erneux, C. Human brain inositol 1,4,5-trisphosphate 3-kinase cDNA sequence. Nucleic Acids Res. 18: 7141 only, 1990. [PubMed: 2175886] [Full Text: https://doi.org/10.1093/nar/18.23.7141]
Takazawa, K., Perret, J., Dumont, J. E., Erneux, C. Molecular cloning and expression of a human brain inositol 1,4,5-trisphosphate 3-kinase. Biochem. Biophys. Res. Commun. 174: 529-535, 1991. [PubMed: 1847047] [Full Text: https://doi.org/10.1016/0006-291x(91)91449-m]