2.7.1.151: inositol-polyphosphate multikinase
This is an abbreviated version!
For detailed information about inositol-polyphosphate multikinase, go to the full flat file.
Word Map on EC 2.7.1.151
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2.7.1.151
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phosphatidylinositol
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phospholipase
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phosphoinositide
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4,5-bisphosphate
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4-phosphate
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5-phosphatase
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1,3,4,5-tetrakisphosphate
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bacteriorhodopsin
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insp3
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pip2
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ptdins4,5p2
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4-kinase
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hexakisphosphate
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pikfyve
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ptdins4p
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pentakisphosphate
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1,3,4-trisphosphate
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3hinositol
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phosphatidylinositol-4-phosphate
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photocycle
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diphosphoinositol
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inositide
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3,4,5-trisphosphate
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5/6-kinase
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polyphosphoinositide
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medicine
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light-driven
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arf6
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agriculture
- 2.7.1.151
- phosphatidylinositol
- phospholipase
- phosphoinositide
- 4,5-bisphosphate
- 4-phosphate
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5-phosphatase
- 1,3,4,5-tetrakisphosphate
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bacteriorhodopsin
- insp3
- pip2
-
ptdins4,5p2
-
4-kinase
- hexakisphosphate
- pikfyve
-
ptdins4p
- pentakisphosphate
- 1,3,4-trisphosphate
-
3hinositol
- phosphatidylinositol-4-phosphate
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photocycle
-
diphosphoinositol
-
inositide
- 3,4,5-trisphosphate
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5/6-kinase
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polyphosphoinositide
- medicine
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light-driven
- arf6
- agriculture
Reaction
Synonyms
1,3,4,6-tetrakisphosphate 5-kinase, 5-kinase, Arg82, ArgRIII, ARGSIII, AtIpk2a, AtIpk2b, AtIpk2beta, HsIPMK, Impk, inositol 1,4,5-trisphosphate 3-kinase, inositol phosphate multikinase, inositol phosphate multikinase 2, inositol polyphosphate 6-/3-kinase, inositol polyphosphate kinase, inositol polyphosphate multikinase, Ins(1,4,5)P3 3-kinase, InsP4 5-kinase, IP3 3-kinase, IP3/IP4 6-/3-kinase, IP3K, IPK, Ipk2, Ipk2/Impk/IP3K, Ipk2a, Ipk2beta/IP3K, IPKII, IPMK, ITPK1, Kcs1, Kcs1p, More, phosphoinositol kinase, PI3K, StIPMK
ECTree
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General Information
General Information on EC 2.7.1.151 - inositol-polyphosphate multikinase
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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
malfunction
metabolism
physiological function
additional information
immediate early gene induction by electroconvulsive stimulation is virtually abolished in the brains of IPMK-deleted mice, which also display deficits in spatial memory. Dominant-negative constructs, which prevent IPMK-CBP binding, substantially decrease immediate early gene induction
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
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
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inositol polyphosphate multikinase IPMK physiologically generates phosphatidylinositol trisphosphate as well as water soluble inositol phosphates. IPMK deletion reduces growth factor-elicited Akt signaling and cell proliferation caused uniquely by loss of its phosphatidylinositol 3-kinase activity. IPMK appears to act as a molecular switch, inhibiting or stimulating Akt via its inositol phosphate kinase or inositol trisphosphate-kinase activities, respectively
physiological function
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inositol polyphosphate multikinase IPMK regulates glucose signaling to AMP-activated kinase in a pathway whereby glucose activates phosphorylation of IPMK at residue Tyr174 enabling the enzyme to bind to AMP-activated kinase and regulate its activation. Refeeding fasted mice rapidly and markedly stimulates transcriptional enhancement of IPMK expression while down-regulating AMP-activated kinase. AMP-activated kinase is up-regulated in mice with genetic depletion of hypothalamic IPMK. IPMK physiologically binds AMP-activated kinase, with binding enhanced by glucose treatment. Regulation by glucose of phospho-AMP-activated kinase in hypothalamic cell lines is prevented by blocking AMP-activated kinase-IPMK binding
physiological function
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inositol polyphosphate multikinase regulates amino acid signaling to mammalian target of rapamycin in complex with raptor, mTORC1. This regulation is independent of IPMK's catalytic function, instead reflecting its binding with mammalian target of rapamycin, mTOR, and raptor, which maintains the mTOR-raptor association. Inositol polyphosphate multikinase appears to be a physiologic mTOR cofactor, serving as a determinant of mTORC1 stability and amino acid-induced mTOR signaling
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
inositol polyphosphate multikinase is a transcriptional coactivator required for immediate early gene induction. Inositol polyphosphate multikinase acts noncatalytically as a transcriptional coactivator to mediate induction of numerous immediate early genes, IEGs. Neural activity stimulates binding of IPMK to the histone acetyltransferase CBP and enhances its recruitment to IEG promoters, but IPMK regulation of CBP recruitment and IEG induction does not require its catalytic activities. The enzyme's epigenetic regulation of immediate early genes may influence diverse nonneural and neural biologic processes
physiological function
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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
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
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
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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