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At least 739 records · Page 41Linked to original sources
PubMed2000

Inositol polyphosphate kinase activity of Arg82/ArgRIII is not required for the regulation of the arginine metabolism in yeast.

Arg82, a nuclear regulator of diverse cellular processes in yeast, is an inositol polyphosphate kinase. Some defects such as the regulation of arginine metabolism observed in an arg82Delta, result from a lack of Mcm1 and Arg80 stability. We show here that neither the kinase activity of Arg82 nor inositol phosphates are required for the control of arginine metabolism. Arg82 mutations keeping kinase active affect the expression of arginine genes, whereas mutations in the kinase domain do not impair this metabolic control.

Arginine↗
PubMed2001

The transcriptional regulator, Arg82, is a hybrid kinase with both monophosphoinositol and diphosphoinositol polyphosphate synthase activity.

The Arg82 gene of Saccharomyces cerevisiae encodes a transcriptional regulator that phosphorylates inositol 1,4,5-trisphosphate [Saiardi et al. (1999) Curr. Biol. 9, 1323-1326]. However, some controversy has surrounded the nature of the reaction products. We now show that Arg82 phosphorylates inositol 1,3,4,5-tetrakisphosphate to inositol pentakisphosphate, which is itself converted to two isomers of diphosphoinositol tetrakisphosphate, one of which has never previously been identified. One of the diphosphoinositol phosphates was further phosphorylated by a yeast cell lysate. We propose that Arg82 is an ancestral precursor of two distinct and specific enzyme families: inositol 1,4,5-trisphosphate kinases and diphosphoinositol polyphosphate synthases.

Amino Acid Motifs↗
PubMed2004

Uridine 5'-polyphosphates (p4U and p5U) and uridine(5')polyphospho(5')nucleosides (Up(n)Ns) can be synthesized by UTP:glucose-1-phosphate uridylyltransferase from Saccharomyces cerevisiae.

UTP:glucose-1-phosphate uridylyltransferase (EC 2.7.7.9) from Saccharomyces cerevisiae can transfer the uridylyl moiety from UDP-glucose onto tripolyphosphate (P(3)), tetrapolyphosphate (P(4)), nucleoside triphosphates (p(3)Ns) and nucleoside 5'-polyphosphates (p(4)Ns) forming uridine 5'-tetraphosphate (p(4)U), uridine 5'-pentaphosphate (p(5)U) and dinucleotides, such as Ap(4)U, Cp(4)U, Gp(4)U, Up(4)U, Ap(5)U and Gp(5)U. Unlike UDP-glucose, UDP-galactose was not a UMP donor and ADP was not a UMP acceptor. This is the first example of an enzyme that may be responsible for accumulation of dinucleoside tetraphosphates containing two pyrimidine nucleosides in vivo. Occurrence of such dinucleotides in S. cerevisiae and Escherichia coli has been previously reported (Coste et al., J. Biol. Chem. 262 (1987) 12096-12103).

Dinucleoside Phosphates↗
PubMed1998

T4 DNA ligase synthesizes dinucleoside polyphosphates.

T4 DNA ligase (EC 6.5.1.1), one of the most widely used enzymes in genetic engineering, transfers AMP from the E-AMP complex to tripolyphosphate, ADP, ATP, GTP or dATP producing p4A, Ap3A, Ap4A, Ap4G and Ap4dA, respectively. Nicked DNA competes very effectively with GTP for the synthesis of Ap4G and, conversely, tripolyphosphate (or GTP) inhibits the ligation of DNA by the ligase. As T4 DNA ligase has similar requirements for ATP as the mammalian DNA ligase(s), the latter enzyme(s) could also synthesize dinucleoside polyphosphates. The present report may be related to the recent finding that human Fhit (fragile histidine triad) protein, encoded by the FHIT putative tumor suppressor gene, is a typical dinucleoside 5',5''-P1,P3-triphosphate (Ap3A) hydrolase (EC 3.6.1.29).

Acid Anhydride Hydrolases↗
PubMed1999

The human and rat forms of multiple inositol polyphosphate phosphatase: functional homology with a histidine acid phosphatase up-regulated during endochondral ossification.

We have derived the full-length sequences of the human and rat forms of the multiple inositol polyphosphate phosphatase (MIPP); their structural and functional comparison with a chick histidine acid phosphatase (HiPER1) has revealed new information: (1) MIPP is approximately 50% identical to HiPER1, but the ER-targeting domains are divergent; (2) MIPP appears to share the catalytic requirement of histidine acid phosphatases, namely, a C-terminal His residue remote from the RHGxRxP catalytic motif; (3) rat MIPP mRNA is up-regulated during chondrocyte hypertrophy. The latter observation provides a context for proposing that MIPP may aid bone mineralization and salvage the inositol moiety prior to apoptosis.

Acid Phosphatase↗
PubMed1977

Simultaneous analysis of bases, nucleosides and nucleoside mono- and polyphosphates by high-performance liquid chromatography.

A single-column high-performance liquid chromatographic system for the simultaneous separation of bases, nucleosides and nucleoside mono- and polyphosphates has been developed, in which a strong porous anion-exchange resin (Aminex A-14) is used. The chromatographic run, carried out at 55 degrees and at alkaline pH by using a linear gradient both of ionic strength and pH, takes less than 225 min. The quantitative application of the described procedure to the analysis of cell nucleotide pools is reported.

Animals↗
PubMed2001

Porous calcium polyphosphate scaffolds for bone substitute applications -- in vitro characterization.

Porous structures were formed by gravity sintering calcium polyphosphate (CPP) particles of either 106-150 or 150-250 microm size to form samples with 30-45 vol% porosity with pore sizes in the range of 100 microm (40-140 microm). Tensile strength of the samples assessed by diametral compression testing indicated relatively high values for porous ceramics with a maximum strength of 24.1 MPa for samples made using the finer particles (106-150 microm). X-ray diffraction studies of the sintered samples indicated the formation of beta-CPP from the starting amorphous powders. In vitro aging in 0.1 M tris-buffered solution (pH 7.4) or 0.05 M potassium hydrogen phthalate buffered solution (pH 4.0) at 37 degreesC for periods up to 30d indicated an initial rapid loss of strength and P elution by 1 d followed by a more gradual continuing strength and P loss resulting in strengths at 30d equal to about one-third the initial value. The observed structures, strengths and in vitro degradation characteristics of the porous CPP samples suggested their potential usefulness as bone substitute materials pending subsequent in vivo behaviour assessment.

Bone Substitutes↗
PubMed2002

Porous calcium polyphosphate scaffolds for bone substitute applications in vivo studies.

Porous rods (6 mm in length and 4 mm in diameter) of calcium polyphosphate (CPP) made by gravity sintering of particles in the size ranges of 45-105, 105-150. and 150-250 microm and with initial volume percent porosity in the range of 35-45% were implanted in the distal femur of New Zealand white rabbits. In an initial experiment, four rabbits implanted with rods made from coarse particles (150-250 microm) were sacrificed at each of the following time points: 2 days, 2 weeks, 6 weeks and 12 weeks. In a subsequent experiment, 10 rabbits were implanted with rods made by sintering 45-105 microm particles and another 10 were made by using particles of 105-150 microm. These rabbits were sacrificed at 6 weeks (five rabbits) and 1 year (five rabbits). No adverse reaction was found histologically at any time point in either experiment. These experiments show that CPP macroporous rods can support bone ingrowth and that between 12 weeks and 1 year, the amount of bones formed is equivalent to the natural bone volume found at similar sites. The degradation of the CPP material is inversely proportional to the original particle size and is rapid initially (within the first 6 weeks) and slows down thereafter. In conclusion, this material seems to promote rapid bone ingrowth and can be tailored to degrade at a given rate in vivo to some degree through appropriate selection of the starting particle size.

Animals↗
PubMed2003

Chondrocyte interactions with porous titanium alloy and calcium polyphosphate substrates.

Chondrocytes maintain their phenotype and form cartilagenous tissue when cultured on calcium polyphosphate (CPP) or titanium alloy (Ti alloy), porous three-dimensional materials. To understand how these materials may influence chondrocyte phenotype and matrix synthesis, the early interactions of cultured cells with CPP and titanium alloy were examined. These were compared to chondrocytes grown in monolayer culture on tissue culture polystyrene, conditions in which cultured chondrocytes dedifferentiate and do not form cartilagenous tissue. Scanning electron microscopy of cells up to 72 h in culture showed that bovine chondrocytes on CPP, Ti alloy, and polystyrene were an admixture of round and spread cells. The spread cells on CPP and titanium alloy were not entirely flattened but maintained a polygonal shape. In contrast, spread chondrocytes in monolayer culture were flatter and significantly larger, a difference that was maintained even in the absence of serum. All cells cultured on CPP and Ti alloy exhibited subcortical ring-like distribution of actin filaments whereas the flattened cells on polystyrene showed actin filaments distributed throughout the cytoplasm. Cells on CPP and Ti alloy synthesized significantly less collagen and proteoglycans than cells cultured on polystyrene at 72 h of culture. In summary the cells on the porous three-dimensional materials differed from those on polystyrene in terms of cell morphology and size, actin cytoskeleton organization, and synthesis of selected matrix macromolecules. The data suggests that CPP and titanium alloy may mediate their effect by limiting cell spreading in part by favoring the maintenance of a ring-like actin distribution.

Actin Cytoskeleton↗
PubMedDate not supplied

Dinucleoside polyphosphates-friend or foe?

Despite being known for over 30 years, the functions of the dinucleoside polyphosphates, such as diadenosine 5',5"'-P(1), P(4)-tetraphosphate (Ap(4)A) and diadenosine 5',5"'-P(1), P(3)-triphosphate (Ap(3)A), are still unclear. On the one hand, they may have important signalling functions, both inside and outside the cell (friend), while on the other hand, they may simply be the unavoidable by-products of certain biochemical reactions, which, if allowed to accumulate, would be potentially toxic through their structural similarity to ATP and other essential mononucleotides (foe). Here, the occurrence, synthesis, degradation, and proposed functions of these compounds are briefly reviewed, along with some new data and recent evidence supporting roles for Ap(3)A and Ap(4)A in the cellular decision making processes leading to proliferation, quiescence, differentiation, and apoptosis. Hypotheses are forwarded for the involvement of Ap(4)A in the intra-S phase DNA damage checkpoint and for Ap(3)A and the pFhit (fragile histidine triad gene product) protein in tumour suppression. It is concluded that the roles of friend and foe are not incompatible, but are distinguished by the concentration range of nucleotide achieved under different circumstances.

Adenosine Triphosphate↗
PubMed1998

The hydrolytic activity of bovine adrenal medullary plasma membranes towards diadenosine polyphosphates is due to alkaline phosphodiesterase-I.

A hydrolase activity directed against diadenosine 5',5"'-P1, P4-tetraphosphate (Ap4A) has been solubilised and partially purified from the plasma membrane fraction of bovine adrenal medullary chromaffin tissue in order to determine its relationship to alkaline phosphodiesterase-I/nucleotide pyrophosphatase (PDase-I, EC 3.1.4.1). Activity with the specific dinucleoside tetraphosphatase (EC 3.6.1. 17) substrate Ap4A and with the non-specific PDase-I substrate thymidine 5'-monophosphate p-nitrophenyl ester had Km and Vmax values of 2.0 microM and 600 pmol/min/mg protein and 0.2 mM and 26 nmol/min/mg protein respectively and co-chromatographed upon gel filtration and ion-exchange chromatography. Activity with the fluorescent substrates etheno-Ap4A and 4-methylumbelliferyl phenylphosphonate co-electrophoresed on native polyacrylamide gels. No activity was detected which exclusively hydrolysed Ap4A. Immunoblotting of the most purified fraction with an antibody against mouse PC-1, one of the major PDase-I family members, detected bands of 240, 120 and 62 kDa corresponding to PC-1 dimer, monomer and proteolytic fragment. Therefore, the activity previously described as bovine adrenal chromaffin cell ecto(diadenosine polyphosphate hydrolase) (ecto-ApnAase) is a PDase-I, probably bovine PC-1.

Acid Anhydride Hydrolases↗
PubMed1993

Evaluation of new high-performance calcium polyphosphate bioceramics as bone graft materials.

The purpose of this study was to evaluate the ability of a recently developed porous calcium polyphosphate bioceramic (CPB) to function as a bone graft substitute. After six weeks, postsurgical extraction of the mandibular first and second molars, alveolar ostectomies were performed bilaterally in five dogs. The ridge forms were then restored using the CPB implant material on one side and the autogenous bone obtained from the contralateral ostectomy site on the other. The graft and implant sites were retrieved after 4 months and decalcified and undecalcified sections were prepared for special staining (modified Attwood) and subsequent light microscopy and histomorphometry. In addition, the undecalcified sections were prepared for histometry using backscattered electron imaging (BSEI). Histologically, the CPB implants showed extensive vascularization and cellularity within an "invading" loose connective tissue matrix. On the opposite side, the loose connective tissue of the autografts showed hypovascularity and hypocellularity. Neither the implants nor the autografts showed any histologic evidence of an inflammatory reaction. Using light microscopic histomorphometry, the implants showed a higher incidence of union than the autografts. On BSEI histometry, the CPB implants showed significantly greater new bone formation than the autografts. This study reveals that porous CPB possesses certain characteristics essential for the "ideal" implantable bone substitute necessary for the repair of craniofacial and other bony defects.

Animals↗
PubMed2001

Molecular cloning of a novel isoform of diphosphoinositol polyphosphate phosphohydrolase: a potential target of lithium therapy.

The mechanisms underlying the therapeutic effects of lithium are largely unknown but may involve progressive adaptive alterations at the level of gene expression. Using differential display PCR, we identify a novel cDNA fragment, the expression of which was increased in the rat frontal cortex after 5 weeks of lithium administration. A full-length cDNA (2954-nt) was cloned by arrayed cDNA library screening, and sequencing of the clone revealed an open reading frame of 537-bp encoding a 179-residue protein. Amino acid sequence comparisons revealed that our clone is a member of the Nudix hydrolase family, with the highest percentage of homology (95%) being with a subtype of human diphosphoinositol polyphosphate phosphohydrolase, hDIPP2. Northern blot analysis revealed that chronic lithium treatment significantly increased rDIPP2 mRNA levels in frontal cortex, but not in hippocampus, midbrain, and cerebellum. The effect of lithium on rDIPP2 mRNA expression was not shared by two other anticonvulsant mood stabilizers, carbamazepine and valproate. Time-course studies showed that 1-week of lithium had no effect on rDIPP2 mRNA abundance in the frontal cortex. Our results suggest that DIPP2 may represent a biologically relevant target of lithium therapy, further supporting the notion that abnormalities in inositol phosphate metabolism may be significant in the pathophysiology and pharmacotherapy of bipolar disorder.

Acid Anhydride Hydrolases↗
PubMed1998

Synaptic defects and compensatory regulation of inositol metabolism in inositol polyphosphate 1-phosphatase mutants.

Phosphoinositides function as important second messengers in a wide range of cellular processes. Inositol polyphosphate 1-phosphatase (IPP) is an enzyme essential for the hydrolysis of the 1-phosphate from either Ins(1,4)P2 or Ins(1,3,4)P3. This enzyme is Li+ sensitive, and is one of the proposed targets of Li+ therapy in manic-depressive illness. Drosophila ipp mutants accumulate IP2 in their system and are incapable of metabolizing exogenous Ins(1,4)P2. Notably, ipp mutants demonstrate compensatory upregulation of an alternative branch in the inositol-phosphate metabolism tree, thus providing a means of ensuring continued availability of inositol. We demonstrate that ipp mutants have a defect in synaptic transmission resulting from a dramatic increase in the probability of vesicle release at larval neuromuscular junctions. We also show that Li+ phenocopies this effect in wild-type synapses. Together, these results support a role for phosphoinositides in synaptic vesicle function in vivo and mechanistically question the "lithium hypothesis."

Animals↗
PubMed2001

A null mutation in inositol polyphosphate 4-phosphatase type I causes selective neuronal loss in weeble mutant mice.

Weeble mutant mice have severe locomotor instability and significant neuronal loss in the cerebellum and in the hippocampal CA1 field. Genetic mapping was used to localize the mutation to the gene encoding inositol polyphosphate 4-phosphatase type I (Inpp4a), where a single nucleotide deletion results in a likely null allele. The substrates of INPP4A are intermediates in a pathway affecting intracellular Ca(2+) release but are also involved in cell cycle regulation through binding the Akt protooncogene; dysfunction in either may account for the neuronal loss of weeble mice. Although other mutations in phosphoinositide enzymes are associated with synaptic defects without neuronal loss, weeble shows that Inpp4a is critical for the survival of a subset of neurons during postnatal development in mice.

Alleles↗
PubMed2000

The phosphatidylinositol polyphosphate 5-phosphatase SHIP1 associates with the dok1 phosphoprotein in bcr-Abl transformed cells.

The initial phase of chronic myelogenous leukemia (CML) is triggered by constitutive protein tyrosine kinase activity of the chimeric kinase p210(bcr-abl) (Bcr-Abl). A major substrate of Bcr-Abl was recently identified as the RasGAP-associated 62 kDa docking protein Dok1. Here, we report complex formation between endogenous Dok1 and the SH2 domain-containing phosphatidylinositol polyphosphate 5-phosphatase SHIP1 in hematopoietic cells expressing Bcr-Abl. Expression of Bcr-Abl induced tyrosine phosphorylation of both Dok1 and SHIP1 and the formation of a Dok1/SHIP1 complex. Tyr(P) SHIP1 was also bound to Shc in Bcr-Abl expressing cells. A small amount of Shc/SHIP1/Dok1 trimolecular complex was detected and this was due to binding of Dok1 to SHIP1 that was bound to Shc. In contrast, association of Dok1 with SHIP1 or RasGAP was mutually exclusive. Both the SH2 domain of SHIP1 and the PTB domain of Dok1 were required for complex formation between the two proteins. Neither the specific activity of SHIP1 as an inositol phosphate 5-phosphatase nor the subcellular localization of SHIP1 appeared to be altered by tyrosine phosphorylation. However, the Dok1/SHIP1 complex was only detected in the cytosolic fraction of Bcr-Abl transformed hematopoietic cells. We propose that interaction between Dok1 and SHIP1 modulates the ability of these two proteins to interact with other cytosolic binding partners.

Animals↗