Pathway for inositol 1,3,4-trisphosphate and 1,4-bisphosphate metabolism.

Inhorn, Roger C.; Bansal, Vinay S.; Majerus, Philip W.

doi:10.1073/pnas.84.8.2170

Cited by 109 publications

(66 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This agrees with previous reports in which Ins(4)P was shown to be the predominant inositol monophosphate formed [33][34][35]. However, there are also reports of the production of Ins(l)P or mixtures of Ins(l)P and Ins(4)P in which Ins(l)P is the predominant form [36,37].…”

Section: Discussionsupporting

confidence: 79%

Subcellular localization of the enzymes that dephosphorylate myo-inositol polyphosphates in human platelets

Vedia

Nolan

Lapetina

1988

Biochemical Journal

View full text Add to dashboard Cite

The phosphatase-induced hydrolysis of [3H]inositol 1,4-bisphosphate [Ins(1,4)P2)] and [3H]inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] was studied in platelet subcellular fractions. The activity that hydrolyses Ins(1,4)P2 is cytosolic, whereas the activity that hydrolyses Ins(1,4,5)P3 is present in both particulate and cytosolic fractions. The cytosolic Ins(1,4)P2 phosphatase hydrolyses the 1-phosphate of Ins(1,4)P2, whereas the cytosolic and membrane-bound Ins(1,4,5)P3 phosphatases hydrolyse the 5-phosphate of Ins(1,4,5)P3. In the presence of ATP, it is possible to observe a cytosolic Ins(1,4,5)P3 3-kinase that phosphorylates Ins(1,4,5)P3 to inositol 1,3,4,5-tetrakisphosphate. Apparent Km values for the particulate and the cytosolic Ins(1,4,5)P3 phosphatases are 100 tM and 40,/M respectively. A large proportion of the membraneassociated Ins(1,4,5)P3 phosphatase can be extracted with 1 M-NaCl, and the Mr of this enzyme, as determined by hydrodynamic studies, is 49000, whereas that of the cytosolic enzyme is 59000. The Km values for the cytosolic Ins(1,4)P2 phosphatase is 40 ,UM; this enzyme has an Mr of49 000. The highest specific activity of the Ins(1,4,5)P3 phosphatase is present in a highly purified plasma-membrane fraction.

show abstract

Section: Discussionsupporting

confidence: 79%

Subcellular localization of the enzymes that dephosphorylate myo-inositol polyphosphates in human platelets

Vedia

Nolan

Lapetina

1988

Biochemical Journal

View full text Add to dashboard Cite

show abstract

“…Biochemical analysis of these proteins demonstrated a Mg 2ϩ -dependent, Li ϩ -sensitive phosphomonoesterase activity on 3Ј phosphoadenosine 5Ј phosphate (PAP) and 3Ј phosphoadenosine 5Ј phosphosulfate (PAPS) (11)(12)(13). Additionally, SAL1 has been reported (13) to possess 1ptase activity which removes the 1-position phosphate from either inositol 1,4-bisphosphate (Ins(1,4)P 2 ) or Ins(1,3,4)P 3 (15,16). As SAL1 overexpression confers salt tolerance on yeast and complements the methionine auxotrophy of hal2 mutants (13), roles were ascribed for both hydrolytic activities in the functioning of SAL1.…”

mentioning

confidence: 99%

Cloning and Characterization of a Mammalian Lithium-sensitive Bisphosphate 3′-Nucleotidase Inhibited by Inositol 1,4-Bisphosphate

Spiegelberg

Xiong

Smith

et al. 1999

Journal of Biological Chemistry

101

View full text Add to dashboard Cite

Discovery of a structurally conserved metal-dependent lithium-inhibited phosphomonoesterase protein family has identified several potential cellular targets of lithium as used to treat manic depression. Here we describe identification of a novel family member using a "computer cloning" strategy. Human and murine cDNA clones encoded proteins sharing 92% identity and were highly expressed in kidney. Native and recombinant protein harbored intrinsic magnesium-dependent bisphosphate nucleotidase activity (BPntase), which removed the 3-phosphate from 3-5 bisphosphate nucleosides and 3-phosphoadenosine 5-phosphosulfate with K m and V max values of 0.5 M and 40 mol/min/mg. Lithium uncompetitively inhibited activity with a K i of 157 M. Interestingly, BPntase was competitively inhibited by inositol 1,4-bisphosphate with a K i of 15 M. Expression of mammalian BPntase complemented defects in hal2/met22 mutant yeast. These data suggest that BPntase's physiologic role in nucleotide metabolism may be regulated by inositol signaling pathways. The presence of high levels of BPntase in the kidney are provocative in light of the roles of bisphosphorylated nucleotides in regulating salt tolerance, sulfur assimilation, detoxification, and lithium toxicity. We propose that inhibition of human BPntase may account for lithium-induced nephrotoxicity, which may be overcome by supplementation of current therapeutic regimes with inhibitors of nucleotide biosynthesis, such as methionine.Lithium is a major drug used to treat manic depression, yet its molecular mechanism of action has not been conclusively elucidated. Insight into lithium's pharmacological activity has come with the identification of a magnesium-dependent phosphomonoesterase family whose members are inhibited by lithium at subtherapeutic concentrations (1). Despite relatively low overall sequence similarity, in some cases undetectable, the family shows a conserved three-dimensional core structure. Functional and structural studies of three members, fructose 1,6-bisphosphatase (fbptase) 1 , inositol monophosphatase (impase), and inositol polyphosphate 1-phosphatase (1ptase), indicate that residues involved in metal binding and catalysis are conserved within a sequence motif D-X n -EE-X n -DP(i/l)D(s/g/ a)T-X n -WD-X 11 -GG (2-7). Of interest, several studies indicate that lithium interacts at one or more of the metal binding sites (6,8,9). 2 Together, these data support the idea that the signature motif confers the common enzymatic characteristics of the family, including lithium sensitivity.The lithium-sensitive family includes proteins with multiple cellular roles. The roles of fbptase in gluconeogenesis, and impase and 1ptase in inositol signaling, are well established. Additionally, this family includes HAL2(MET22), SAL1, and cysQ, gene products implicated in sulfur assimilation and salt tolerance in yeast, plants, and bacteria (10 -14). Met22p and isoallelic Hal2p were identified as yeast proteins involved in methionine biosynthesis (10) and sodium tolerance (11, 12). S...

show abstract

“…Precedent for the latter explanation comes from monitoring agonist-induced IP 3 changes in which cellular studies frequently use lithium treatment to inhibit IP phosphatases, thereby enabling accumulation of signaling intermediates that are stable and easily quantified (31,32). Because pharmacological traps are not readily available for the IPK-mediated pathways, we examined whether genetic perturbation in combination with metabolic labeling would enable visualization of flux through these pathways.…”

mentioning

confidence: 99%

Alterations in an inositol phosphate code through synergistic activation of a G protein and inositol phosphate kinases

Otto

Kelly

Chiou

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

In mammals, many cellular stimuli evoke a response through G protein activation of phospholipase C, which results in the lipidderived production of inositol 1,4,5-trisphosphate (IP3). Although it is well established that IP3 is converted to numerous inositol phosphates (IPs) and pyrophosphates (PP-IPs) through the action of up to six classes of inositol phosphate kinases (IPKs), it is not clear that these metabolites are influenced by G protein signaling. Here we report that activation of G␣q leads to robust stimulation of IP3 to IP8 metabolism. To expose flux through these pathways, genetic perturbation was used to alter IP homeostasis. Coupled expression of a constitutively active G␣qQL and one or more IPK gene products synergistically generated dramatic changes in the patterns of intracellular IP messengers. Many distinct IP profiles were observed through the expression of different combinations of IPKs, including changes in previously unappreciated pools of IP 5 and IP6, two molecules widely viewed as stable metabolites. Our data link the activation of a trimeric G protein to a plethora of metabolites downstream of IP3 and provide a framework for suggesting that cells possess the machinery to produce an IPK-dependent IP code. We imply, but do not prove, that agonist-induced alterations in such a code would theoretically be capable of enhancing signaling complexity and specificity. The essential roles for IPKs in organism development and cellular adaptation are consistent with our hypothesis that such an IP code may be relevant to signaling pathways.Gq ͉ metabolomics ͉ phospholipase C ͉ signal transduction ͉ G protein-coupled receptor I n mammals, hundreds of G protein-coupled receptors (GPCR) and receptor tyrosine kinases (RTKs) are present and link to numerous intracellular signaling modules that, in combination, enable selective cellular responses. One of the most commonly activated signaling modules is the generation of the second messengers inositol 1,4,5-trisphosphate (IP 3 ) and 1,2-diacylglycerol by the action of phospholipase C isozymes (PLCs) on phosphatidylinositol 4,5-bisphosphate (PIP 2 ) (1-5). The ubiquity of PLC activation in response to a wide range of stimuli supports its central role in signaling, but also emphasizes that the production of two messengers alone, IP 3 and diacylglycerol, is insufficient to encode the breadth of specific cellular responses necessary for survival and adaptation. Therefore, it has been postulated that further signaling diversity could theoretically arise from the conversion of IP 3 to numerous inositol tetrakisphosphate (IP 4 ), inositol pentakisphosphate (IP 5 ), inositol hexakisphosphate (IP 6 ), and inositol pyrophosphate (PP-IP) molecules (2, 6-9). The production of these regulators occurs through the action of up to six classes of evolutionarily conserved IP kinase (IPK) gene products that include: IPMK/IPK2 (10-14), IPK1 (15-17), , ITPK/IP56K (21, 22), IP6K/ IHPK (23-25), and VIP1 (25-27) (Fig. 1). Genetic and biochemical studies of IPKs have provided v...

show abstract

Pathway for inositol 1,3,4-trisphosphate and 1,4-bisphosphate metabolism.

Cited by 109 publications

References 32 publications

Subcellular localization of the enzymes that dephosphorylate myo-inositol polyphosphates in human platelets

Subcellular localization of the enzymes that dephosphorylate myo-inositol polyphosphates in human platelets

Cloning and Characterization of a Mammalian Lithium-sensitive Bisphosphate 3′-Nucleotidase Inhibited by Inositol 1,4-Bisphosphate

Alterations in an inositol phosphate code through synergistic activation of a G protein and inositol phosphate kinases

Contact Info

Product

Resources

About