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2 ATP + 1D-myo-inositol 1,4,5-trisphosphate
2 ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
-
-
-
?
ATP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
-
-
-
?
ATP + 1D-myo-inositol 1,4,5,6-tetrakisphosphate
ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
-
-
-
?
ATP + 1D-myo-inositol 1,4,5-trisphosphate
ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
ATP + 1D-myo-inositol 1,4,5-trisphosphate
ADP + 1D-myo-inositol 1,4,5,6-tetrakisphosphate
ATP + 1D-myo-inositol 4,5-bisphosphate
ADP + 1D-myo-inositol 3,4,5-trisphosphate
-
-
-
?
2 ATP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate + 1D-myo-inositol 1,4,5,6-tetrakisphosphate
2 ADP + 2 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
-
in rats and humans
-
-
?
2 ATP + 1D-myo-inositol 1,4,5-trisphosphate
2 ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
-
-
-
-
r
3 ATP + 2 1D-myo-inositol 1,4,5-trisphosphate
3 ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
-
in rats and humans
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
-
-
-
-
?
ATP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
ATP + 1D-myo-inositol 1,3,4,6-tetrakisphosphate
ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
ATP + 1D-myo-inositol 1,4,5,6-tetrakisphosphate
ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
ATP + 1D-myo-inositol 1,4,5-trisphosphate
ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
ATP + 1D-myo-inositol 1,4,5-trisphosphate
ADP + 1D-myo-inositol 1,3,4,6-tetrakisphosphate
-
2fold less active compared to 1D-myo-inositol 1,3,4,6-tetrakisphosphate
-
-
?
ATP + 1D-myo-inositol 1,4,5-trisphosphate
ADP + 1D-myo-inositol 1,4,5,6-tetrakisphosphate
ATP + inositol 1,3,4,5-tetrakisphosphate
ADP + inositol (1,3,4,5,6)-pentakisphosphate
-
substrate preference for inositol 1,3,4,6-tetrakisphosphate over inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate
-
-
?
ATP + inositol 1,4,5,6-tetrakisphosphate
ADP + inositol (1,3,4,5,6)-pentakisphosphate
ATP + inositol 1,4,5-trisphosphate
ADP + inositol (1,3,4,5)-tetrakisphosphate
-
substrate preference for inositol 1,3,4,6-tetrakisphosphate over inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate
-
-
?
inositol (1,3,4,6)-tetrakisphosphate + ATP
ADP + inositol (1,3,4,5,6)-pentakisphosphate
-
substrate preference for inositol 1,3,4,6-tetrakisphosphate over inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate
-
-
?
inositol (1,4,5,6)-tetrakisphosphate + ATP
inositol (1,3,4,5,6)-pentakisphosphate + ADP
-
hITPK1 has more than 13000fold preference for inositol (3,4,5,6)-tetrakisphosphate over its enantiomer inositol (1,4,5,6)-tetrakisphosphate
-
-
?
inositol (3,4,5,6)-tetrakisphosphate + ATP
inositol (1,3,4,5,6)-pentakisphosphate + ADP
-
hITPK1 has more than 13000fold preference for inositol (3,4,5,6)-tetrakisphosphate over its enantiomer inositol (1,4,5,6)-tetrakisphosphate
-
-
?
additional information
?
-
ATP + 1D-myo-inositol 1,4,5-trisphosphate
ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
-
-
-
?
ATP + 1D-myo-inositol 1,4,5-trisphosphate
ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
-
-
-
ir
ATP + 1D-myo-inositol 1,4,5-trisphosphate
ADP + 1D-myo-inositol 1,4,5,6-tetrakisphosphate
-
-
-
?
ATP + 1D-myo-inositol 1,4,5-trisphosphate
ADP + 1D-myo-inositol 1,4,5,6-tetrakisphosphate
-
-
-
ir
ATP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
-
low activity
-
-
?
ATP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
-
43fold less active compared to 1D-myo-inositol 1,3,4,6-tetrakisphosphate
-
-
?
ATP + 1D-myo-inositol 1,3,4,6-tetrakisphosphate
ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
-
-
-
-
?
ATP + 1D-myo-inositol 1,3,4,6-tetrakisphosphate
ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
-
preferred substrate
-
-
?
ATP + 1D-myo-inositol 1,4,5,6-tetrakisphosphate
ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
-
-
-
-
?
ATP + 1D-myo-inositol 1,4,5,6-tetrakisphosphate
ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
-
recombinant enzyme in yeast mutant cells
-
-
?
ATP + 1D-myo-inositol 1,4,5-trisphosphate
ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
-
-
-
-
?
ATP + 1D-myo-inositol 1,4,5-trisphosphate
ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
-
2fold less active compared to 1D-myo-inositol 1,3,4,6-tetrakisphosphate
-
-
?
ATP + 1D-myo-inositol 1,4,5-trisphosphate
ADP + 1D-myo-inositol 1,4,5,6-tetrakisphosphate
-
-
-
-
?
ATP + 1D-myo-inositol 1,4,5-trisphosphate
ADP + 1D-myo-inositol 1,4,5,6-tetrakisphosphate
-
-
-
-
ir
ATP + inositol 1,4,5,6-tetrakisphosphate
ADP + inositol (1,3,4,5,6)-pentakisphosphate
-
-
-
-
?
ATP + inositol 1,4,5,6-tetrakisphosphate
ADP + inositol (1,3,4,5,6)-pentakisphosphate
-
stable over-expression of the human protein in HEK-293 cells abrogates the in vivo elevation of inositol 1,4,5,6-tetrakisphosphate from the Salmonella dublin SopB protein. The enzyme may play a role in regulation of the level of inositol 1,4,5,6-tetrakisphosphate in human cells
-
-
?
additional information
?
-
inositol polyphosphate multikinase is an enzyme that displays soluble inositol phosphate kinase activity, lipid kinase activity, and various noncatalytic interactions
-
-
?
additional information
?
-
-
inositol polyphosphate multikinase is an enzyme that displays soluble inositol phosphate kinase activity, lipid kinase activity, and various noncatalytic interactions
-
-
?
additional information
?
-
IPMK is a broad-specificity enzyme that converts inositol 1,4,5-trisphosphate into inositol 1,4,5,6-tetrakisphosphate (IP4) and subsequently inositol 1,3,4,5,6-pentakisphosphate
-
-
?
additional information
?
-
recombinant HsIMPK uses 3-kinase activity to phosphorylate Ins(1,4,5)P3 to Ins(1,3,4,5)P4, and then phosphorylates the latter with a 6-kinase activity that yields Ins(1,3,4,5,6)P5. It also shows PtdIns(4,5)P2 3-kinase activity. Substrate binding structures, overview
-
-
-
additional information
?
-
-
recombinant HsIMPK uses 3-kinase activity to phosphorylate Ins(1,4,5)P3 to Ins(1,3,4,5)P4, and then phosphorylates the latter with a 6-kinase activity that yields Ins(1,3,4,5,6)P5. It also shows PtdIns(4,5)P2 3-kinase activity. Substrate binding structures, overview
-
-
-
additional information
?
-
-
the enzyme is involved in the inositol phosphate metabolism which is important for several cellular functions and signaling, metabolism overview
-
-
?
additional information
?
-
-
the enzyme might be involved in regulation of cell growth
-
-
?
additional information
?
-
-
the enzyme regulates inositol 1,4,5,6-tetrakisphosphate
-
-
?
additional information
?
-
-
substrate specificity model, the enzyme shows inositol phosphate 5-kinase activity, overview
-
-
?
additional information
?
-
-
substrate specificity, product identification
-
-
?
additional information
?
-
-
inositol (1,4,5,6)-tetrakisphosphate is not a physiological substrate
-
-
?
additional information
?
-
-
enzyme has a preferred 5-kinase activity over 3-kinase and 6-kinase activities
-
-
?
additional information
?
-
-
role in chromatin remodelling
-
-
?
additional information
?
-
-
Studies in the rat cells and mice suggest that Ins(1,4,5)P3 3-kinases likely contribute little to the synthesis of inositol pentakisphosphate and inositol hexakisphosphate
-
-
?
additional information
?
-
-
The 3-step pathway to InsP6 mediated by phospholipase C, IPMK and inositol kinase (Ipk1) in yeast contrasts with an alternative description of a 5-step pathway in human cells.
-
-
?
additional information
?
-
-
inositol polyphosphate multikinase is a multifunctional enzyme with PI3-kinase, IP3-kinase and catalytically independent activities. IPMK is a PI3-kinase which phosphorylates PIP2 into PIP3, serving as a physiologic activator of Akt/PKB. It also possesses IP3-kinase activity, converting IP3 into IP4 (1,3,4,5) or IP4 (1,4,5,6). Whether the phosphorylation of IP3 at the 3-position or the 6-position is physiologically regulated
-
-
?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
-
-
-
?
ATP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
-
-
-
?
ATP + 1D-myo-inositol 1,4,5,6-tetrakisphosphate
ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
-
-
-
?
ATP + 1D-myo-inositol 1,4,5-trisphosphate
ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
-
-
-
?
ATP + 1D-myo-inositol 1,4,5-trisphosphate
ADP + 1D-myo-inositol 1,4,5,6-tetrakisphosphate
-
-
-
?
ATP + 1D-myo-inositol 4,5-bisphosphate
ADP + 1D-myo-inositol 3,4,5-trisphosphate
-
-
-
?
2 ATP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate + 1D-myo-inositol 1,4,5,6-tetrakisphosphate
2 ADP + 2 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
-
in rats and humans
-
-
?
2 ATP + 1D-myo-inositol 1,4,5-trisphosphate
2 ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
-
-
-
-
r
3 ATP + 2 1D-myo-inositol 1,4,5-trisphosphate
3 ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
-
in rats and humans
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
-
-
-
-
?
ATP + 1D-myo-inositol 1,3,4,6-tetrakisphosphate
ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
-
-
-
-
?
ATP + 1D-myo-inositol 1,4,5,6-tetrakisphosphate
ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
ATP + 1D-myo-inositol 1,4,5-trisphosphate
ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
-
-
-
-
?
ATP + 1D-myo-inositol 1,4,5-trisphosphate
ADP + 1D-myo-inositol 1,4,5,6-tetrakisphosphate
ATP + inositol 1,4,5,6-tetrakisphosphate
ADP + inositol (1,3,4,5,6)-pentakisphosphate
-
stable over-expression of the human protein in HEK-293 cells abrogates the in vivo elevation of inositol 1,4,5,6-tetrakisphosphate from the Salmonella dublin SopB protein. The enzyme may play a role in regulation of the level of inositol 1,4,5,6-tetrakisphosphate in human cells
-
-
?
additional information
?
-
ATP + 1D-myo-inositol 1,4,5,6-tetrakisphosphate
ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
-
-
-
-
?
ATP + 1D-myo-inositol 1,4,5,6-tetrakisphosphate
ADP + 1D-myo-inositol 1,3,4,5,6-pentakisphosphate
-
recombinant enzyme in yeast mutant cells
-
-
?
ATP + 1D-myo-inositol 1,4,5-trisphosphate
ADP + 1D-myo-inositol 1,4,5,6-tetrakisphosphate
-
-
-
-
?
ATP + 1D-myo-inositol 1,4,5-trisphosphate
ADP + 1D-myo-inositol 1,4,5,6-tetrakisphosphate
-
-
-
-
ir
additional information
?
-
inositol polyphosphate multikinase is an enzyme that displays soluble inositol phosphate kinase activity, lipid kinase activity, and various noncatalytic interactions
-
-
?
additional information
?
-
-
inositol polyphosphate multikinase is an enzyme that displays soluble inositol phosphate kinase activity, lipid kinase activity, and various noncatalytic interactions
-
-
?
additional information
?
-
IPMK is a broad-specificity enzyme that converts inositol 1,4,5-trisphosphate into inositol 1,4,5,6-tetrakisphosphate (IP4) and subsequently inositol 1,3,4,5,6-pentakisphosphate
-
-
?
additional information
?
-
-
the enzyme is involved in the inositol phosphate metabolism which is important for several cellular functions and signaling, metabolism overview
-
-
?
additional information
?
-
-
the enzyme might be involved in regulation of cell growth
-
-
?
additional information
?
-
-
the enzyme regulates inositol 1,4,5,6-tetrakisphosphate
-
-
?
additional information
?
-
-
inositol (1,4,5,6)-tetrakisphosphate is not a physiological substrate
-
-
?
additional information
?
-
-
role in chromatin remodelling
-
-
?
additional information
?
-
-
Studies in the rat cells and mice suggest that Ins(1,4,5)P3 3-kinases likely contribute little to the synthesis of inositol pentakisphosphate and inositol hexakisphosphate
-
-
?
additional information
?
-
-
The 3-step pathway to InsP6 mediated by phospholipase C, IPMK and inositol kinase (Ipk1) in yeast contrasts with an alternative description of a 5-step pathway in human cells.
-
-
?
additional information
?
-
-
inositol polyphosphate multikinase is a multifunctional enzyme with PI3-kinase, IP3-kinase and catalytically independent activities. IPMK is a PI3-kinase which phosphorylates PIP2 into PIP3, serving as a physiologic activator of Akt/PKB. It also possesses IP3-kinase activity, converting IP3 into IP4 (1,3,4,5) or IP4 (1,4,5,6). Whether the phosphorylation of IP3 at the 3-position or the 6-position is physiologically regulated
-
-
?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
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Bone Marrow Failure Disorders
IP3 3-kinase B prevents bone marrow failure.
Brain Injuries
MicroRNA-23b alleviates neuroinflammation and brain injury in intracerebral hemorrhage by targeting inositol polyphosphate multikinase.
Brain Ischemia
Effects of focal cerebral ischemia on expression and activity of inositol 1,4,5-trisphosphate 3-kinase in rat cortex.
Brain Ischemia
Effects of focal cerebral ischemia on inositol 1,4,5-trisphosphate 3-kinase and 5-phosphatase activities in rat cortex.
Brain Ischemia
In situ hybridization of mRNA expression for IP3 receptor and IP3-3-kinase in rat brain after transient focal cerebral ischemia.
Breast Neoplasms
The natural anticancer agent plumbagin induces potent cytotoxicity in MCF-7 human breast cancer cells by inhibiting a PI-5 kinase for ROS generation.
Breast Neoplasms
Type I? phosphatidylinositol phosphate kinase regulates PD-L1 expression by activating NF-?B.
Carcinogenesis
Familial small-intestine carcinoids: Chromosomal alterations and germline inositol polyphosphate multikinase sequencing.
Carcinoid Tumor
A Hereditary Form of Small Intestinal Carcinoid Associated With a Germline Mutation in Inositol Polyphosphate Multikinase.
Carcinoid Tumor
Familial small-intestine carcinoids: Chromosomal alterations and germline inositol polyphosphate multikinase sequencing.
Carcinoma
Ribavirin and quercetin synergistically downregulate signal transduction and are cytotoxic in human ovarian carcinoma cells.
Carcinoma
Synergistic action of tiazofurin and genistein on growth inhibition and differentiation of K-562 human leukemic cells.
Carcinoma, Hepatocellular
1-Phosphatidylinositol 4-phosphate 5-kinase (EC 2.7.1.68): a proliferation- and malignancy-linked signal transduction enzyme.
Cerebral Hemorrhage
MicroRNA-23b alleviates neuroinflammation and brain injury in intracerebral hemorrhage by targeting inositol polyphosphate multikinase.
Cystic Fibrosis
Apical localization of ITPK1 enhances its ability to be a modifier gene product in a murine tracheal cell model of cystic fibrosis.
Friedreich Ataxia
The Friedreich's ataxia gene encodes a novel phosphatidylinositol-4- phosphate 5-kinase.
Gastrointestinal Stromal Tumors
Imatinib in combination with phosphoinositol kinase inhibitor buparlisib in patients with gastrointestinal stromal tumour who failed prior therapy with imatinib and sunitinib: a Phase 1b, multicentre study.
Graves Disease
Identification Of New Rare Variants Associated With Familial Autoimmune Thyroid Diseases By Deep Sequencing Of Linked Loci.
Heart Failure
Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases.
Hepatitis B
Immune recognition of linear antigenic regions within the hepatitis B pre-C and C-gene translation products using synthetic peptides.
Huntington Disease
Huntington's disease: Neural dysfunction linked to inositol polyphosphate multikinase.
Infections
Genome-Wide Screening Uncovers the Significance of N-Sulfation of Heparan Sulfate as a Host Cell Factor for Chikungunya Virus Infection.
Influenza, Human
Phosphatidylinositol 5-kinase stimulates apical biosynthetic delivery via an Arp2/3-dependent mechanism.
inositol-polyphosphate multikinase deficiency
Inositol polyphosphate multikinase deficiency leads to aberrant induction of synaptotagmin-2 in the forebrain.
Lung Neoplasms
TFAP2A Induced ITPKA Serves as an Oncogene and Interacts with DBN1 in Lung Adenocarcinoma.
Lupus Erythematosus, Systemic
Epigenome-wide association study of rheumatoid arthritis identifies differentially methylated loci in B cells.
Melanoma
Whole-genome landscapes of major melanoma subtypes.
Neoplasms
Amplified increase in signal transduction activity in cancer cells.
Neoplasms
Imatinib in combination with phosphoinositol kinase inhibitor buparlisib in patients with gastrointestinal stromal tumour who failed prior therapy with imatinib and sunitinib: a Phase 1b, multicentre study.
Neoplasms
MicroRNA-18a inhibits ovarian cancer growth via directly targeting TRIAP1 and IPMK.
Neoplasms
RNAi-based screening of the human kinome identifies Akt-cooperating kinases: a new approach to designing efficacious multitargeted kinase inhibitors.
Neural Tube Defects
The maternal ITPK1 gene polymorphism is associated with neural tube defects in a high-risk Chinese population.
Neuroinflammatory Diseases
MicroRNA-23b alleviates neuroinflammation and brain injury in intracerebral hemorrhage by targeting inositol polyphosphate multikinase.
Obesity
Inositol polyphosphate multikinase in adipocytes is dispensable for regulating energy metabolism and whole body metabolic homeostasis.
Sepsis
Inositol polyphosphate multikinase promotes Toll-like receptor-induced inflammation by stabilizing TRAF6.
Starvation
ITPK1 is an InsP6/ADP phosphotransferase that controls phosphate signaling in Arabidopsis.
Stroke
Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases.
Thyroiditis
Identification Of New Rare Variants Associated With Familial Autoimmune Thyroid Diseases By Deep Sequencing Of Linked Loci.
Triple Negative Breast Neoplasms
Type I? phosphatidylinositol phosphate kinase regulates PD-L1 expression by activating NF-?B.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
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Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
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evolution
IPMK is a member of the so-called IP-kinase family that includes IP3Ks and IP6Ks, evolutionary relationships and structure comparisons, overview. There has been co-evolution of Ins(1,4,5)P3 and PtdIns(4,5)P2 3-kinase activities
physiological function
-
IPMK is a pleiotropic enzyme. Gene transcription by p53 requires inositol polyphosphate multikinase as a co-activator. IPMK subsequently phosphorylates IP4 into IP5, and is the rate-limiting enzyme for this metabolite. IPMK serves as the gate-keeping enzyme for the synthesis of all higher inositol polyphosphate species, including inositol diphosphates, which are implicated in diverse physiologic processes. Independent of catalytic activity, IPMK binds to p53 and enhances its association with p300. The enhancement of p300s histone acetyltransferase activity by IPMK leads to increased acetylation of p53 and histone H3, as well as p53 association to target promoters. This augmentation of p53-dependent gene transcription enhances cell death. IPMK is also a major PI3 kinase, which acts together with the wortmannin-sensitive p110/p85 PI3 kinase, EC 2.7.1.153, to generatephosphatidylinositol-3,4,5-trisphosphate that activates Akt and protein synthesis. Both wild-type and catalytically inactive IPMK stabilize the mTOR-1 complex to facilitate protein translation
malfunction
IPMK depletion or catalytic inactivation selectively decreases RAD51 protein abundance and the nuclear export of RAD51 mRNA, thereby impairing homologous recombination. Depletion or catalytic inactivation of IPMK selectively inhibits the nuclear export of the poly(A)+ mRNAs that encode essential homologous recombination factors such as RAD51, CHK1, or FANCD2, decreasing protein abundance, whereas, in contrast, several genes involved in NHEJ are unaffected. IPMK inactivation inhibits RAD51 recombinase assembly, provokes sensitivity to genotoxic lesions repaired by homologous recombination, and causes structural chromosome aberrations typical of defective homologous recombination. Overexpression of catalytically inactive IPMK mutants is sufficient to reduce RAD51 foci formation
malfunction
knockdown of IPMK results in decreased activation of p53, decreased recruitment of p53 and p300 to target gene promoters, abrogated transcription of p53 target genes, and enhanced cell viability. Blocking the IPMK-p53 interaction decreases the extent of p53-mediated transcription. Depletion of IPMK results in decreased PUMA, Bax, and p21 abundance after treatment with etoposide, p53-null HCT116 cells transfected with IPMK shRNA do not exhibit decreased amounts of PUMA, Bax, or p21 mRNAs. In etoposide-treated HCT-116 cells, shRNA-mediated knockdown of IPMK reduces the binding of p300 to p53
malfunction
severe loss of IPMK in the striatum of Huntington's disease patients, the depletion reflects mHtt-induced impairment of COUP-TF-interacting protein 2 (Ctip2), a striatal-enriched transcription factor for IPMK, as well as alterations in IPMK protein stability. IPMK overexpression reverses the metabolic activity deficit in a cell model of Huntington's disease. IPMK depletion appears to mediate neural dysfunction, because intrastriatal delivery of IPMK abates the progression of motor abnormalities and rescues striatal pathology in transgenic murine models of Huntington's disease
metabolism
IPMK expression rescues mHtt-induced deficits in mitochondrial metabolic activity. Delivery of IPMK in a transgenic Huntington's disease model improves pathological changes and motor performance. The Ctip2-IPMK-Akt signaling pathway provides a previously unidentified therapeutic target for Huntington's disease
metabolism
the enzyme IPMK is involved in a transcript-selective mRNA export pathway controlled by phosphoinositide turnover that preserves genome integrity in humans
physiological function
inositol phosphate multikinase regulates transcript-selective nuclear mRNA export to preserve genome integrity. The transcript-selective nuclear export mechanism affecting certain human transcripts, enriched for functions in genome duplication and repair, is controlled by inositol polyphosphate multikinase, an enzyme catalyzing inositol polyphosphate and phosphoinositide turnover. Function for human IPMK in RAD51 assembly and DNA repair by homologous recombination, overview
physiological function
the enzyme stimulates tumor suppressor p53-mediated transcription by binding to p53 and enhancing its acetylation by the acetyltransferase p300 independently of its inositol phosphate and lipid kinase activities. IPMK acts as a transcriptional coactivator for p53 and that it is an integral part of the p53 transcriptional complex facilitating cell death. Tumor suppressor p53 is a critical transcriptional factor that senses and modulates cellular responses to injury and stress. Recombinantly expressed enzyme IPMK in the transfected cells binds to endogenous p53 upon treatment with etoposide, a DNA-damaging agent that canonically induces apoptosis by activating p53. IPMK enhances p53 acetylation and histone acetylation via p300, molecular mechanisms responsible for the stimulation of p53 transcriptional activity by IPMK, overview. IPMK does not require catalytic activity to enhance p53-mediated cell death
physiological function
human inositol phosphate multikinase (HsIPMK) critically contributes to intracellular signaling through its inositol-1,4,5-trisphosphate (Ins(1,4,5)P3) 3-kinase and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) 3-kinase activities. HsIPMK is both an inositol phosphate kinase and a PtdIns(4,5)P2 kinase
additional information
HsIPMK owns a catalytic pocket that is more constrained than those of the plant and yeast orthologues. Also unique to mammalian IPMK is a catalytically important proline-loop, and a preponderance of Gln residues in the active site. Description of two versions of Ins(1,4,5)P3 within the active site, first as a free inositol phosphate, and second as the headgroup of a soluble analogue of PtdIns(4,5)P2. The structure of the IPMK apoenzyme is determined by a molecular replacement approach using a model constructed from the template of yeast ScIPMK (PDB accession code 2IF8), and this apo-structure is used for further elucidation of the structures of crystal complexes with ADP plus either Ins(1,4,5)P3 or diC4-PtdIns(4,5)P2. Domains that are similar to the so-called N- and C-lobes that comprise the ATP-binding site. The C-terminal lobe comprising residues 136-149 and 175-416, which is an alphabeta-fold with five, central antiparallel beta-strands including beta4-6, beta8, and beta9, a pair of small antiparallel beta-strands (beta7 and beta10), and three alpha-helices (alpha5-alpha7). Also in the C-lobe of HsIPMK, a 310 helix is observed between the beta6 strand and alpha5 helix. His388 is at the catalytic center. Structure comparisons, overview
additional information
-
HsIPMK owns a catalytic pocket that is more constrained than those of the plant and yeast orthologues. Also unique to mammalian IPMK is a catalytically important proline-loop, and a preponderance of Gln residues in the active site. Description of two versions of Ins(1,4,5)P3 within the active site, first as a free inositol phosphate, and second as the headgroup of a soluble analogue of PtdIns(4,5)P2. The structure of the IPMK apoenzyme is determined by a molecular replacement approach using a model constructed from the template of yeast ScIPMK (PDB accession code 2IF8), and this apo-structure is used for further elucidation of the structures of crystal complexes with ADP plus either Ins(1,4,5)P3 or diC4-PtdIns(4,5)P2. Domains that are similar to the so-called N- and C-lobes that comprise the ATP-binding site. The C-terminal lobe comprising residues 136-149 and 175-416, which is an alphabeta-fold with five, central antiparallel beta-strands including beta4-6, beta8, and beta9, a pair of small antiparallel beta-strands (beta7 and beta10), and three alpha-helices (alpha5-alpha7). Also in the C-lobe of HsIPMK, a 310 helix is observed between the beta6 strand and alpha5 helix. His388 is at the catalytic center. Structure comparisons, overview
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D144N
site-directed mutagenesis
D144N/K146A
site-directed mutagenesis
H388A
site-directed mutagenesis, the mutant shows no Ins(1,4,5)P3 3-kinase activity and reduced Ins(1,3,4,5)P4 6-kinase activity compared to wild-type
K129A/S235A
catalytically inactive mutant
K146A
site-directed mutagenesis
K160A
site-directed mutagenesis, the mutant shows no Ins(1,4,5)P3 3-kinase activity and reduced Ins(1,3,4,5)P4 6-kinase activity compared to wild-type
K167A
site-directed mutagenesis, the mutant shows reduced Ins(1,4,5)P3 3-kinase activity and Ins(1,3,4,5)P4 6-kinase activity compared to wild-type
K327Q/K328Q
site-directed mutagenesis, generation of an IPMK mutant with inactivated nuclear localization signal, NLS, whose intracellular distribution is unaffected by inhibition of conventional protein import
Q163A
site-directed mutagenesis, the mutant shows no Ins(1,4,5)P3 3-kinase activity and reduced Ins(1,3,4,5)P4 6-kinase activity compared to wild-type
Q163K
site-directed mutagenesis, the mutant shows reduced Ins(1,4,5)P3 3-kinase activity and increased Ins(1,3,4,5)P4 6-kinase activity compared to wild-type
Q163R
site-directed mutagenesis, the mutant shows reduced Ins(1,4,5)P3 3-kinase activity and increased Ins(1,3,4,5)P4 6-kinase activity compared to wild-type
Q164A
site-directed mutagenesis, the mutant shows reduced Ins(1,4,5)P3 3-kinase activity and Ins(1,3,4,5)P4 6-kinase activity compared to wild-type
Q164K
site-directed mutagenesis, the mutant shows reduced Ins(1,4,5)P3 3-kinase activity and increased Ins(1,3,4,5)P4 6-kinase activity compared to wild-type
Q164R
site-directed mutagenesis, the mutant shows reduced Ins(1,4,5)P3 3-kinase activity and increased Ins(1,3,4,5)P4 6-kinase activity compared to wild-type
Q196A
site-directed mutagenesis, the mutant shows reduced Ins(1,4,5)P3 3-kinase activity and Ins(1,3,4,5)P4 6-kinase activity compared to wild-type
Q196K
site-directed mutagenesis, the mutant shows reduced Ins(1,4,5)P3 3-kinase activity and increased Ins(1,3,4,5)P4 6-kinase activity compared to wild-type
Q196R
site-directed mutagenesis, the mutant shows reduced Ins(1,4,5)P3 3-kinase activity and increased Ins(1,3,4,5)P4 6-kinase activity compared to wild-type
Q78A
site-directed mutagenesis, the mutant shows no Ins(1,4,5)P3 3-kinase activity and reduced Ins(1,3,4,5)P4 6-kinase activity compared to wild-type
R82A
site-directed mutagenesis, the mutant shows no Ins(1,4,5)P3 3-kinase activity and reduced Ins(1,3,4,5)P4 6-kinase activity compared to wild-type
additional information
genetic or RNA interference-mediated, and shRNA-mediated knockdown of enzyme IPMK
additional information
overexpression of catalytically inactive IPMK mutants is sufficient to reduce RAD51 foci formation
additional information
-
overexpression of catalytically inactive IPMK mutants is sufficient to reduce RAD51 foci formation
additional information
generation of the core catalytic domain of the enzyme that contains residues 50 to 416, from which an internal domain comprising residues 263 to 377 is deleted. The deletion is necessary to obtain crystals, it is replaced with a simple Gly-Gly-Ser-Gly-Gly linker. This deletion does not compromise catalytic activity, it is a non-catalytic region of the protein. It contains a nuclear localization sequence, flanked by residues that host protein kinase phosphorylation sites that regulate nuclear localization sequence functionality. Gln residues at positions 163, 164, and 196 are mutated each to Arg and Lys, both of which have side chains that are larger and also positively charged at physiological pH. The results are quite dramatic: in each case, the rate of Ins(1,4,5)P3 3-kinase activity declines, but in contrast, the rate of Ins(1,3,4,5)P4 6-kinase activity is not impaired, three of these mutants show increased 6-kinase activity, analysis of the structural basis, overview
additional information
-
generation of the core catalytic domain of the enzyme that contains residues 50 to 416, from which an internal domain comprising residues 263 to 377 is deleted. The deletion is necessary to obtain crystals, it is replaced with a simple Gly-Gly-Ser-Gly-Gly linker. This deletion does not compromise catalytic activity, it is a non-catalytic region of the protein. It contains a nuclear localization sequence, flanked by residues that host protein kinase phosphorylation sites that regulate nuclear localization sequence functionality. Gln residues at positions 163, 164, and 196 are mutated each to Arg and Lys, both of which have side chains that are larger and also positively charged at physiological pH. The results are quite dramatic: in each case, the rate of Ins(1,4,5)P3 3-kinase activity declines, but in contrast, the rate of Ins(1,3,4,5)P4 6-kinase activity is not impaired, three of these mutants show increased 6-kinase activity, analysis of the structural basis, overview
additional information
-
construction of an N-terminal deletion mutant comprising residues 266-371, the mutant enzyme is inhibited by aurintricarboxylic acid, gossypol, 3',4',7,8-tetrahydroxyflavone, epigallocatechin-3-gallate, chlorogenic acid, and rose bengal, but not by quercetin, epicatechin-3-gallate, ellagic acid, hypericin, and myricetin in contrary to the wild-type
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Chang, S.C.; Miller, A.L.; Feng, Y.; Wente, S.R.; Majerus, P.W.
The human homolog of the rat inositol phosphate multikinase is an inositol 1,3,4,6-tetrakisphosphate 5-kinase
J. Biol. Chem.
277
43836-43843
2002
Homo sapiens
brenda
Chang, S.C.; Majerus, P.W.
Inositol polyphosphate multikinase regulates inositol 1,4,5,6-tetrakisphosphate
Biochem. Biophys. Res. Commun.
339
209-216
2006
Homo sapiens
brenda
Nalaskowski, M.M.; Deschermeier, C.; Fanick, W.; Mayr, G.W.
The human homologue of yeast ArgRIII protein is an inositol phosphate multikinase with predominantly nuclear localization
Biochem. J.
366
549-556
2002
Homo sapiens (Q8NFU5), Homo sapiens
brenda
Xia, H.J.; Yang, G.
Inositol 1,4,5-trisphosphate 3-kinases: functions and regulations
Cell Res.
15
83-91
2005
Arabidopsis thaliana, Homo sapiens, Saccharomyces cerevisiae
brenda
Mayr, G.W.; Windhorst, S.; Hillemeier, K.
Antiproliferative plant and synthetic polyphenolics are specific inhibitors of vertebrate inositol-1,4,5-trisphosphate 3-kinases and inositol polyphosphate multikinase
J. Biol. Chem.
280
13229-13240
2005
Homo sapiens
brenda
Riley, A.M.; Deleu, S.; Qian, X.; Mitchell, J.; Chung, S.; Adelt, S.; Vogel, G.; Potter, B.V.; Shears, S.B.
On the contribution of stereochemistry to human ITPK1 specificity: Ins(1,4,5,6)P4 is not a physiologic substrate
FEBS Lett.
580
324-330
2006
Homo sapiens
brenda
Resnick, A.C.; Saiardi, A.
Inositol polyphosphate multikinase: metabolic architect of nuclear inositides
Front. Biosci.
13
856-866
2008
Arabidopsis thaliana, Saccharomyces cerevisiae, Drosophila melanogaster, Homo sapiens, Rattus norvegicus, Solanum tuberosum
brenda
Xu, R.; Snyder, S.
Gene transcription by p53 requires inositol polyphosphate multikinase as a co-activator
Cell Cycle
12
1819-1820
2013
Homo sapiens
brenda
Wickramasinghe, V.O.; Savill, J.M.; Chavali, S.; Jonsdottir, A.B.; Rajendra, E.; Gruener, T.; Laskey, R.A.; Babu, M.M.; Venkitaraman, A.R.
Human inositol polyphosphate multikinase regulates transcript-selective nuclear mRNA export to preserve genome integrity
Mol. Cell
51
737-750
2013
Homo sapiens (Q8NFU5), Homo sapiens
brenda
Ahmed, I.; Sbodio, J.I.; Harraz, M.M.; Tyagi, R.; Grima, J.C.; Albacarys, L.K.; Hubbi, M.E.; Xu, R.; Kim, S.; Paul, B.D.; Snyder, S.H.
Huntingtons disease: neural dysfunction linked to inositol polyphosphate multikinase
Proc. Natl. Acad. Sci. USA
112
9751-9756
2015
Homo sapiens (Q8NFU5), Homo sapiens
brenda
Xu, R.; Sen, N.; Paul, B.D.; Snowman, A.M.; Rao, F.; Vandiver, M.S.; Xu, J.; Snyder, S.H.
Inositol polyphosphate multikinase is a coactivator of p53-mediated transcription and cell death
Sci. Signal.
6
ra22
2013
Homo sapiens (Q8NFU5)
brenda
Wang, H.; Shears, S.B.
Structural features of human inositol phosphate multikinase rationalize its inositol phosphate kinase and phosphoinositide 3-kinase activities
J. Biol. Chem.
292
18192-18202
2017
Homo sapiens (Q8NFU5), Homo sapiens
brenda