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PubMed1995

Structure of the genes encoding the alpha- and beta-subunits of castor pyrophosphate-dependent phosphofructokinase.

Full-length genomic clones encoding the alpha- and beta-subunits of the pyrophosphate-dependent phosphofructokinase (PFP) from the castor plant have been isolated and sequenced. The gene (PFP alpha) encoding PFP alpha is approx. 5.8 kb in length and contains 19 exons, which collectively encode a protein of 617 amino acids (aa) having a deduced M(r) of 67,360. PFP beta is approx. 4.6-kb long and contains 16 exons. Together, these exons encode a protein (PFP beta), of 552 aa with a deduced M(r) of 60,114. The intron-exon splice junctions in both genes contain the consensus sequences typical for plants. An alignment of intron placement in castor PFP alpha and PFP beta with introns in the 5' portion of the gene encoding the ATP-dependent phosphofructokinase (PFK) from rabbit muscle, indicates that only one intron occupies the same position in all three genes. Furthermore, within castor PFP alpha and PFP beta, only two introns are identically placed. Within the promoter regions of castor PFP alpha and PFP beta, there are short sequences having high homology to each other (up to 65%). The results demonstrate, for the first time, that there is little homology between PFP and PFK, nor are PFP alpha and PFP beta closely related. This lack of homology suggests PFP did not evolve from PFK, but rather, that PFP and PFK have probably evolved from a common ancestral gene.

Amino Acid Sequence↗
PubMed1995

Chemical cross-linking of MvaI and EcoRII enzymes to DNA duplexes containing monosubstituted pyrophosphate internucleotide bond.

DNA duplexes containing a monosubstituted pyrophosphate internucleotide group, instead of a phosphodiester bond, were used as cross-linking reagent for the affinity modification of the restriction endonucleases EcoRII and MvaI (R.EcoRII and R.MvaI). An active group was introduced into the enzyme's recognition site or between the recognition site and flanking sequence. The substrate properties of such DNA duplexes were determined. Cross-linking specificity was demonstrated by competition experiments with unmodified substrate, as well as by the absence of cross-linking to an active duplex lacking a recognition site. It was shown that the nucleophilicity of the buffer solution and the presence of the enzyme cofactor Mg2+ dramatically affected the cross-linking yield.

Base Sequence↗
PubMed1988

Stabilization of stannous pyrophosphate kits with gentisic acid.

We evaluated the ability of gentisic acid, an antioxidant, to stabilize stannous pyrophosphate (Sn:PPi) kits and extend the shelf-life of the kit after reconstitution. In vitro studies showed that gentisic acid (0.5 mg/mL) stabilized the stannous ion against oxidation by various levels of exogenous hydrogen peroxide. In patients who received stabilized Sn:PPi for in vivo red blood cell labelling, the left ventricle-to-background activity ratio was significantly higher than that in patients who received a standard formation of Sn:PPi. Gentisic acid is now used routinely in the Sn:PPi kit formulation in this institution.

Drug Stability↗
PubMed1996

Specific inhibition of basic calcium phosphate and calcium pyrophosphate crystal-induction of metalloproteinase synthesis by phosphocitrate.

Calcium pyrophosphate dihydrate (CPPD) and basic calcium phosphate (BCP) crystal deposition diseases are a group of heterogeneous arthritides which are a significant source of morbidity in the elderly. Both crystals induced mitogenesis and metalloproteinase (MP) synthesis and secretion by fibroblasts and chondrocytes which may promote degradation of intra-articular tissue. We have previously shown that phosphocitrate (PC), an inhibitor of hydroxyapatite crystallization, specifically blocks BCP crystal-induced mitogenesis in 3T3 cells. This led us to examine the effect of PC on BCP and CPPD crystal induction of MP synthesis in human fibroblasts. PC (10(-3) to 10(-4) M) specifically inhibited the crystal-induced collagenase and stromelysin mRNA accumulation while having no effect on epidermal growth factor-induced or basal levels of mRNA for both enzymes. Western blots (collagenase) of conditioned media confirmed that PC blocked crystal-induced proteinase secretion as well. Moreover, PC (10(-3) M) also blocked the crystal induction of c-fos and c-jun. Since FOS and JUN proteins form a transacting activator (AP-1) for expression of collagenase and stromelysin genes, PC may block the synthesis of both enzymes by inhibiting the transcription of c-fos and c-jun.

1-Methyl-3-isobutylxanthine↗
PubMed1996

Carbocyclic analogues of D-ribose-5-phosphate: synthesis and behavior with 5-phosphoribosyl alpha-1-pyrophosphate synthetases.

The synthesis of cyclopentyl and cyclopentenyl analogues of the alpha-anomer of D-ribose-5-phosphate from D-ribonolactone and D-ribose is described. These analogues, which have the same absolute configuration as D-ribose-5-phosphate, were incubated with PRPP synthetases in an attempt to prepare the corresponding carbocyclic PRPP analogues. The carbocyclic ribose-5-phosphate analogues were found to be inhibitors, rather than substrates, for 5-phosphoribosyl alpha-1-pyrophosphate synthetases of both bacterial and human origin. The inhibitory behaviour of the analogues is described.

Humans↗
PubMed1985

Effect of pyrophosphate and two diphosphonates on 45Ca and 32Pi uptake and mineralization by matrix vesicle-enriched fractions and by hydroxyapatite.

Inorganic pyrophosphate (PPi) and two diphosphonates, ethane-1-hydroxy-1, 1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl2MDP), were found to inhibit in vitro mineralization induced by matrix vesicle-enriched fractions from chicken epiphyseal cartilage. Inhibitor concentrations from 0.20 to 20 microM caused a dosage-dependent decrease in 45Ca and 32Pi uptake by the vesicle fraction. These inhibitors were also tested in a hydroxyapatite (HA)-seeded system to help distinguish between effects on the mineral vs nonmineral portions of the vesicle fraction. The order of inhibition of the HA-seeded system was EHDP greater than PPi greater than Cl2MDP, except for inhibitor concentrations of 0.20 microM where EHDP was the least inhibitory. This variation may be due to differences in the binding of the inhibitors to HA crystals. In general, inhibition of HA mineralization was greatest during later time periods, whereas vesicle ion uptake was affected more during early stages of incubation. The differential effects of the three inhibitors were most obvious at the 2.0 microM concentration. With PPi substantial inhibition of HA-seeded mineralization was observed even in late stages of the study; in contrast, with time the vesicle fraction overcame this inhibition. This suggests that alkaline phosphatase, an enzyme notably enriched in matrix vesicles, catalyzed the hydrolysis of PPi, reducing its concentration to a level where mineralization could proceed. Our findings show that matrix vesicle-induced mineralization differs significantly from apatite-induced mineralization. The data support the concept that vesicle alkaline phosphatase acts, at least in part, to remove physiological crystal growth inhibitors.

Alkaline Phosphatase↗
PubMed2005

Rehabilitation of orthopedic and rheumatologic disorders. 4. Rheumatoid arthritis and calcium pyrophosphate deposition disease.

UNLABELLED: This self-directed learning module highlights a clinical vignette of 2 patients: (1) a woman with bilateral, distal, upper-limb pain assessed by differential diagnosis, laboratory work-up, and treatment of rheumatologic disorders frequently seen in the physiatric practice setting and (2) a 57-year-old man with an acute recurring monoarthritis of the knee and addresses clinical presentation, assessment, medical management, and rehabilitation approaches. It is part of the chapter on rehabilitation of orthopedic and rheumatologic disorders in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article specifically focuses on 2 aspects: (1) the differential diagnosis of polyarthralgia, distal upper-limb pain, criteria for classification of rheumatoid arthritis, synovial fluid analysis, and comprehensive treatment of rheumatoid arthritis, both pharmacologic and nonpharmacologic and (2) the differential diagnosis, clinical diagnostic considerations, current pharmacotherapy, invasive procedure options, and orthotic and exercise interventions for a patient with calcium pyrophosphate dehydrate-induced monoarthritis of the knee. OVERALL ARTICLE OBJECTIVES: (a) Clinical evaluation, diagnosis, management, and rehabilitation strategies in persons with initial presentations of inflammatory distal upper-limb pain and (b) clinical evaluation of an individual with crystal-induced monoarthritis and differentiation of the pathophysiology, assessment, and treatment of chondrocalcinosis.

Adult↗
PubMed2003

Diacylglycerol pyrophosphate phosphatase in Saccharomyces cerevisiae.

Diacylglycerol pyrophosphate (DGPP) phosphatase in the yeast Saccharomyces cerevisiae is a Mg(2+)-independent and N-ethylmaleimide-insensitive 34-kDa vacuolar membrane-associated enzyme. It catalyzes the dephosphorylation of DGPP to form phosphatidate (PA) and then removes the phosphate from PA to form diacylglycerol (DAG). The enzyme is a member of the lipid phosphate phosphatase superfamily that contains a three-domain lipid phosphatase motif required for catalytic activity. Expression of the DPP1 gene, which encodes DGPP phosphatase, is induced by zinc depletion, by inositol supplementation, and when cells enter the stationary phase. Induction by zinc depletion is mediated by the transcription factor Zap1p, which binds to a zinc-responsive element in the DPP1 promoter. Repression of DPP1 expression is mediated by the transcription factor Gis1p, which binds to three post-diauxic shift elements in the promoter. Regulation of DPP1 correlates with the expression of DGPP phosphatase activity and the cellular levels of DGPP and PA.

Catalysis↗
PubMed2006

Signalling diacylglycerol pyrophosphate, a new phosphatidic acid metabolite.

Diacylglycerol pyrophosphate (DGPP) is a novel phospholipid that has been found in plants and yeast but not in higher animals. It is produced through phosphorylation of phosphatidic acid (PA) by the novel enzyme PA kinase (PAK). In plants, DGPP is virtually absent in non-stimulated cells but its concentration increases within minutes in response to various stimuli, including osmotic stress and pathogen attack, implying a role in stress signalling. DGPP is broken down by the enzyme DGPP phosphatase (DPP). DPP-encoding genes have been cloned from Arabidopsis thaliana and Saccharomyces cerevisiae (DPP1). In S. cerevisiae, the expression of DPP1 is regulated coordinately with the majority of genes encoding enzymes involved in phospholipid biosynthesis.

Arabidopsis↗
PubMed2005

Kinetics of pyrophosphate-driven proton uptake by acidocalcisomes of Leptomonas wallacei.

In this work, we show the kinetics of pyrophosphate-driven H+ uptake by acidocalcisomes in digitonin-permeabilized promastigotes of Leptomonas wallacei. The vacuolar proton pyrophosphatase activity was optimal in the pH range of 7.5-8.0, was inhibited by imidiodiphosphate, and was completely dependent on K+ and PPi. H+ was released with the addition of Ca2+, suggesting the presence of a Ca2+/H+ antiport. In addition, X-ray elemental mapping associated with energy-filtering transmission electron microscopy showed that most of the Ca, Na, Mg, P, K, Fe, and Zn were located in acidocalcisomes. L. wallacei immunolabeled with antibodies against Trypanosoma cruzi pyrophosphatase show intense fluorescence in cytoplasmatic organelles of size and distribution similar to the acidocalcisomes. Altogether, the results show that L. wallacei acidocalcisomes possess a H+-pyrophosphatase with characteristics of type I V-H+-PPase. However, we did not find any evidence, either for the presence of H+-ATPases or for Na+/H+ exchangers in these acidocalcisomes.

Animals↗
PubMed2005

Synthesis and biological evaluation of 1-amino-1,1-bisphosphonates derived from fatty acids against Trypanosoma cruzi targeting farnesyl pyrophosphate synthase.

We have investigated the effect of a series of 1-amino-1,1-bisphosphonates derived from fatty acids against proliferation of the clinically more relevant form of Trypanosoma cruzi, the causative agent of American trypanosomiasis (Chagas' disease). Some of these drugs were potent inhibitors against the intracellular form of the parasite, exhibiting IC50 values at low micromolar level. Cellular activity was associated with the inhibition of enzymatic activity of T. cruzi farnesyl pyrophosphate synthase. As bisphosphonate-containing drugs are FDA-approved for the treatment of bone resorption disorders, their potential innocuousness makes them good candidates to control tropical diseases.

Animals↗
PubMed2004

Pyruvate phosphate dikinase and pyrophosphate metabolism in the glycosome of Trypanosoma cruzi epimastigotes.

Pyruvate phosphate dikinase (PPDK) was recently reported in trypanosomatids, but its metabolic function is not yet known. The present work deals with the cellular localization and the function of the Trypanosoma cruzi enzyme. First, we show by digitonin titration and cell fractionation that the enzyme was essentially present in the glycosome matrix of the epimastigote form. Second, we address the issue of the direction of the reaction inside the glycosome for one part, our bibliographic survey evidenced a quite exergonic DeltaGo' (at least -5.2 kcal/mol at neutral pH and physiologic ionic strength); for another part, no pyrophosphatase (PPase) could be detected in fractions corresponding to the glycosomes; therefore, glycosomal PPDK likely works in the direction of pyruvate production. Third, we address the issue of the origin of the glycosomal pyrophosphate (PPi): several synthetic pathways known to produce PPi are already considered to be glycosomal. This work also indicates the presence of an NADP(+)-dependent beta-oxidation of palmitoyl-CoA in the glycosome. Several pyruvate-consuming activities, in particular alanine dehydrogenase (ADH) and pyruvate carboxylase (PC), were detected in the glycosomal fraction. PPDK appears therefore as a central enzyme in the metabolism of the glycosome of T. cruzi by providing a link between glycolysis, fatty acid oxidation and biosynthetic PPi-producing pathways. Indeed, PPDK seems to replace pyrophosphatase in its classical thermodynamic role of displacing the equilibrium of PPi-producing reactions, as well as in its role of eliminating the toxic PPi.

Alanine Dehydrogenase↗
PubMed2006

Geranylgeranyl-pyrophosphate (GGPP) synthase is down-regulated during differentiation of osteoblastic cell line MC3T3-E1.

Isoprenylation of geranylgeranyl-pyrophosphate (GGPP) is critical for activation of small GTPases. We examined the roles of GGPP synthase (GGPPS) during the differentiation induced by the cell-to-cell contact in osteoblastic cell line MC3T3-E1 cells. We found that (1) both mRNA and protein expression of GGPPS was reduced with decrement of its activity during the differentiation, (2) GGOH, which is converted to GGPP in the cells, inhibited differentiation. These results suggest that the decrement of GGPP is critical for the cell-to-cell contact-induced differentiation, in which the down-regulation of GGPPS might be involved.

Animals↗
PubMed2004

Selective in vitro effects of the farnesyl pyrophosphate synthase inhibitor risedronate on Trypanosoma cruzi.

We present the results of the first detailed study of the molecular and cellular basis of the antiproliferative effects of the bisphosphonate risedronate (Ris) on Trypanosoma cruzi, the causative agent of Chagas' disease. Ris and related compounds, which block poly-isoprenoid biosynthesis at the level of farnesyl pyrophosphate synthase, are currently used for the treatment of bone resorption disorders, but also display selective activity against trypanosomatid and apicomplexan parasites. Ris induced a dose-dependent effect on growth of the extracellular epimastigote form of T. cruzi; complete growth arrest and cell lysis ensued at 150 microM. Growth inhibition was associated with depletion of the parasite's endogenous sterols, but complete growth arrest and loss of cell viability took place before full depletion of these compounds, suggesting that disappearance of other essential poly-isoprenoids is involved in its anti-parasitic action. Ris had a variety of effects on cellular ultrastructure, including mitochondrial swelling, disorganisation of other organelles, such as reservosomes and the kinetoplast, together with the appearance of autophagic vesicles and progressive vacuolization of the cytoplasm. Ris had selective antiproliferative effects against the clinically relevant amastigote form of T. cruzi, and at 100 microM, was able to prevent completely the development of T. cruzi infection of murine muscle heart or Vero cells, and to cure cultures which were already infected. Ris induced drastic ultrastructural alterations in the intracellular parasites and blocked amastigote to trypomastigote differentiation, with no biochemical or ultrastructural effects on the host cells, which fully recovered their normal structure and activity after treatment. Ris is, therefore, a promising lead compound for the development of new drugs against T. cruzi.

Alkyl and Aryl Transferases↗
PubMed2004

Familial calcium pyrophosphate dihydrate deposition disease. A Tunisian kindred.

INTRODUCTION: Familial calcium pyrophosphate dihydrate deposition disease (CPDD) is uncommon, with about 50 affected families identified to date in the world. Genetic studies in familial CPDD are focusing on the ANKH gene. We report a new Tunisian kindred with CPDD. PATIENTS AND METHODS: The development of CPDD in a patient who was only 35 years of age prompted a family study. A medical history, physical examination, and radiographs were performed in 103 family members older than 18 years. RESULTS: Fifteen family members had CPDD. There were 10 men and five women, with a mean age of 59.4 years. Onset was usually in the third or fourth decade. Four clinical patterns were found: Five patients had pseudogout, five had pseudoosteoarthritis, three had asymptomatic disease, and two had pseudorheumatoid arthritis. Inheritance was autosomal dominant with low penetrance. No associations with specific HLA antigens were found. The disease was mild. These characteristics fit the description of Gaucher type 1 familial CPDD. CONCLUSION: Inherited autosomal dominant CPDD with low penetrance was found in 15 members of a Tunisian kindred. The disease was mild. We are planning a genetic study including tests for ANKH gene mutations in this kindred.

Adult↗
PubMed2004

Concerted regulation of inorganic pyrophosphate and osteopontin by akp2, enpp1, and ank: an integrated model of the pathogenesis of mineralization disorders.

Tissue-nonspecific alkaline phosphatase (TNAP) hydrolyzes the mineralization inhibitor inorganic pyrophosphate (PP(i)). Deletion of the TNAP gene (Akp2) in mice results in hypophosphatasia characterized by elevated levels of PP(i) and poorly mineralized bones, which are rescued by deletion of nucleotide pyrophosphatase phosphodiesterase 1 (NPP1) that generates PP(i). Mice deficient in NPP1 (Enpp1(-/-)), or defective in the PP(i) channeling function of ANK (ank/ank), have decreased levels of extracellular PP(i) and are hypermineralized. Given the similarity in function between ANK and NPP1 we crossbred Akp2(-/-) mice to ank/ank mice and found a partial normalization of the mineralization phenotypes and PP(i) levels. Examination of Enpp1(-/-) and ank/ank mice revealed that Enpp1(-/-) mice have a more severe hypermineralized phenotype than ank/ank mice and that NPP1 but not ANK localizes to matrix vesicles, suggesting that failure of ANK deficiency to correct hypomineralization in Akp2(-/-) mice reflects the lack of ANK activity in the matrix vesicle compartment. We also found that the mineralization inhibitor osteopontin (OPN) was increased in Akp2(-/-), and decreased in ank/ank mice. PP(i) and OPN levels were normalized in [Akp2(-/-); Enpp1(-/-)] and [Akp2(-/-); ank/ank] mice, at both the mRNA level and in serum. Wild-type osteoblasts treated with PP(i) showed an increase in OPN, and a decrease in Enpp1 and Ank expression. Thus TNAP, NPP1, and ANK coordinately regulate PP(i) and OPN levels. The hypomineralization observed in Akp2(-/-) mice arises from the combined inhibitory effects of PP(i) and OPN. In contrast, NPP1 or ANK deficiencies cause a decrease in the PP(i) and OPN pools that leads to hypermineralization.

Alkaline Phosphatase↗
PubMed1976

Technetium stannous pyrophosphate myocardial scintigrams in the recognition of myocardial infarction in patients undergoing coronary artery revascularization.

Myocardial imaging using technetium 99m stannous pyrophosphate (99mTc-PYP) has been utilized preoperatively and three to five days postoperatively to detect myocardial infarction in 48 patients undergoing aortocoronary bypass grafting, including 7 having valve replacement (5 aortic, 2 mitral) in addition to revascularization. In the total group of patients operated on there were 3 deaths (6%). Preoperatively, 26 patients had unstable angina and 10 had severe left main coronary artery disease. Eleven of the 48 (23%) were women. ECG and enzyme-proved infarctions occurred in 6 of the 48 patients (12%), but the addition of 99mTc-PYP myocardial imaging demonstrated scintigraphic evidence of infarction in 15 patients (31%), including 2 who died in the operating room. The 99mTc-PYP myocardial imaging technique, which has proved safe, simple, and relatively inexpensive in these patients, suggests that the incidence of infarction after coronary bypass operations is somewhat higher than has been previously recognized from just ECG and enzyme changes. This technique also has been of value in helping to exclude myocardial infarction in difficult clinical situations such as postoperative arrhythmias and the postpericardiotomy syndrome.

Adult↗
PubMed2003

Fluorescence study of ligand binding to potato tuber pyrophosphate-dependent phosphofructokinase: evidence for competitive binding between fructose-1,6-bisphosphate and fructose-2,6-bisphosphate.

The intrinsic fluorescence of potato tuber pyrophosphate:fructose-6-phosphate 1-phosphotransferase (PFP) was used as an indicator of conformational changes due to ligand binding. Binding of the substrates and the allosteric activator fructose-2,6-bisphosphate was quantitatively compared to their respective kinetic effects on enzymatic activity. PFP exhibited a relatively high affinity for its isolated substrates, relative to the enzyme's respective K(m) (substrate) values. There are two distinct types of fructose-1,6-bisphosphate interaction with PFP, corresponding to catalytic and activatory binding. Activatory fructose-1,6-bisphosphate binding shares several characteristics with fructose-2,6-bisphosphate binding, indicating that both ligands compete for the same allosteric activator site. Activation by fructose-1,6-bisphosphate or fructose-2,6-bisphosphate was exerted primarily on the forward (glycolytic) reaction by greatly increasing the enzyme's affinity for fructose-6-phosphate. Binding of substrates and effectors to PFP and PFP kinetic properties were markedly influenced by assay pH. Results indicate an increased glycolytic role for PFP during cytosolic acidification that accompanies anoxia stress.

Binding, Competitive↗