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PubMed2006

Crystal structure of type-III geranylgeranyl pyrophosphate synthase from Saccharomyces cerevisiae and the mechanism of product chain length determination.

Geranylgeranyl pyrophosphate synthase (GGPPs) catalyzes a condensation reaction of farnesyl pyrophosphate with isopentenyl pyrophosphate to generate C(20) geranylgeranyl pyrophosphate, which is a precursor for carotenoids, chlorophylls, geranylgeranylated proteins, and archaeal ether-linked lipid. For short-chain trans-prenyltransferases that synthesize C(10)-C(25) products, bulky amino acid residues generally occupy the fourth or fifth position upstream from the first DDXXD motif to block further elongation of the final products. However, the short-chain type-III GGPPs in eukaryotes lack any large amino acid at these positions. In this study, the first structure of type-III GGPPs from Saccharomyces cerevisiae has been determined to 1.98 A resolution. The structure is composed entirely of 15 alpha-helices joined by connecting loops and is arranged with alpha-helices around a large central cavity. Distinct from other known structures of trans-prenyltransferases, the N-terminal 17 amino acids (9-amino acid helix A and the following loop) of this GGPPs protrude from the helix core into the other subunit and contribute to the tight dimer formation. Deletion of the first 9 or 17 amino acids caused the dissociation of dimer into monomer, and the Delta(1-17) mutant showed abolished enzyme activity. In each subunit, an elongated hydrophobic crevice surrounded by D, F, G, H, and I alpha-helices contains two DDXXD motifs at the top for substrate binding with one Mg(2+) coordinated by Asp(75), Asp(79), and four water molecules. It is sealed at the bottom with three large residues of Tyr(107), Phe(108), and His(139). Compared with the major product C(30) synthesized by mutant H139A, the products generated by mutant Y107A and F108A are predominantly C(40) and C(30), respectively, suggesting the most important role of Tyr(107) in determining the product chain length.

Amino Acid Motifs↗

PubMed2000

Iron bioavailability in infants from an infant cereal fortified with ferric pyrophosphate or ferrous fumarate.

BACKGROUND: Infant cereals are commonly fortified with insoluble iron compounds with low relative bioavailability, such as ferric pyrophosphate, because of organoleptic changes that occur after addition of water-soluble iron sources. OBJECTIVE: Our objective was to compare iron bioavailability from ferric pyrophosphate with an alternative iron source that is soluble in dilute acid, ferrous fumarate, and to evaluate the influence of ascorbic acid on iron bioavailability from ferrous fumarate in infants. DESIGN: Iron bioavailability was measured as the incorporation of stable iron isotopes into erythrocytes 14 d after administration of labeled test meals (25 g dry wheat and soy infant cereal, 100 g water, and 2.5 mg Fe as [57Fe]ferric pyrophosphate or [57Fe]ferrous fumarate). Ascorbic acid was added to all test meals (25 mg in study 1 or 25 or 50 mg in study 2). Infants were fed each test meal on 4 consecutive days under standardized conditions. The 2 different test meals within each study were administered 2 wk apart in a crossover design. RESULTS: Geometric mean iron bioavailability was significantly higher from [57Fe]ferrous fumarate than from [57Fe]ferric pyrophosphate [4.1% (range: 1.7-14.7%) compared with 1.3% (range: 0. 7-2.7%); n = 8, P = 0.008]. In this study, doubling the ascorbic acid content did not further enhance iron bioavailability; the geometric means (range) were 3.4% (1.9-6.6%) and 4.2% (1.2-18.7%) for the test meals with 25 and 50 mg ascorbic acid added, respectively (n = 9). CONCLUSION: Iron bioavailability from iron-fortified infant cereals can be improved by using an iron compound with high relative bioavailability and by ensuring adequate ascorbic acid content of the product.

Biological Availability↗

PubMed1992

Selective cleavage of pyrophosphate linkages.

Pyrophosphate linkages have a number of important roles in biology and are also formed chemically with great ease. They often are unwanted products, such as in the nonenzymatic oligomerization of mononucleotides. We have found that Zr(4+)- and Th(4+)-ions catalyze the symmetrical hydrolysis of pyrophosphate linkages. Oligonucleotide analogs linked by pyrophosphate bonds are substantially degraded in the presence of these metals, even at 0 degrees C. Conditions are described which permit the decapping of a pyrophosphate capped oligonucleotide. Oligodeoxynucleotides can be decapped by this procedure without cleavage of phosphodiester linkages. Oligoribonucleotides are susceptible to partial hydrolysis and require purification by HPLC after decapping.

Chromatography, High Pressure Liquid↗

PubMed2004

Targeting extracellular pyrophosphates underpins the high selectivity of nisin.

The spread of infectious diseases and the increase in antibiotic resistance represent a life-threatening global development that calls for new approaches to control microorganisms. Of all potential targets, the essential and unique pathway of bacterial cell wall synthesis, targeted by the first known antibiotic penicillin, remains a perfect candidate for the development of new antibiotics. Here we show that the lantibiotic nisin exercises its antibacterial action by targeting peptidoglycan intermediates' extracellular pyrophosphate, unique to bacterial cell wall precursors. We show that nisin sequesters cell wall precursors found in the outer leaflet of bacterial plasma membranes, Lipid II and undecaprenyl pyrophosphate, into stable complexes. We propose a model of antibacterial action for nisin in which the terminal amino group of Ile1 targets the pyrophosphate groups of the bacterial cell wall precursors, where it docks via a hydrogen bond. The pyrophosphate moiety, a highly conserved chemical group different from the L-Lys-D-Ala-D-Ala docking motif for vancomycin, has no biochemical analogs with comparable properties and is unlikely to be susceptible to bacterial adaptations akin to those responsible for resistance to penicillins and vancomycin.

Amino Acid Sequence↗

PubMed1996

Cervical myelopathy caused by calcium pyrophosphate dihydrate crystal deposition in facet joints. A case report.

STUDY DESIGN: This report illustrates a case of cervical myelopathy caused by degenerative changes of the facet joints in which calcium pyrophosphate dihydrate crystals were found histologically. OBJECTIVES: To evaluate the treatment of this patient, which involved the principles of laminoplasty and posterolateral fusion, and to analyze surgical specimens and preoperative radiographs taken after the patient's surgery. SUMMARY OF BACKGROUND DATA: Calcium pyrophosphate dihydrate deposition occurs in cartilage, ligaments, tendons, and joint capsules. Radiographic changes of the cervical facet joints caused by such deposition have already been reported in cadaveric studies. Cases with neurologic compromise rarely occur. METHODS: Surgical specimens that were obtained from the cervical facet joints, i.e., capsule and synovium, were analyzed histopathologically. RESULTS: The preoperative radiographic study showed severe degenerative changes of the cervical facet joints, and analysis of the surgical specimens indicated the presence of calcium pyrophosphate dihydrate crystals. CONCLUSIONS: The cervical facet joints can be involved in calcium pyrophosphate dihydrate crystal deposition and this involvement may accelerate the degenerative changes of the facet joints.

Adult↗

PubMed2001

Foramen magnum syndrome secondary to calcium pyrophosphate crystal deposition in the transverse ligament of the atlas.

STUDY DESIGN: This report illustrates two rare cases of foramen magnum syndrome caused by a retro-odontoid mass in which calcium pyrophosphate dihydrate crystals were found. OBJECTIVES: To analyze the preoperative studies and the diagnostic criteria and to discuss the surgical treatment. The present cases will be compared with previous ones described in the literature. SUMMARY OF BACKGROUND DATA: Deposition of calcium pyrophosphate dihydrate crystals occurs into the fibrous and hyaline cartilage of the joints and intervertebral discs of the spine. Half of the patients known to have a chondrocalcinosis had asymptomatic calcification in the odontoid region. Ten patients were published in the literature as having a spinal cord syndrome secondary to calcium pyrophosphate dihydrate deposition in the odontoid region. METHODS: In both cases the preoperative studies were analyzed, and the retro-odontoid mass was resected and histologically examined. Both had an anterior transoral approach and have been followed for 1 year. RESULTS: According to the preoperative radiographs the diagnosis was suspected and confirmed histologically. Transoral approach was done with no need in either case for a posterior stabilization. CONCLUSIONS: Compression of the spinal cord by calcium pyrophosphate dihydrate deposition may occur. The preoperative diagnosis may be highly suspected after radiographic study and histologically confirmed. Transoral resection is the treatment of choice. Posterior stabilization should be considered only in cases of craniovertebral instability.

Aged↗

PubMed2000

LEFPS1, a tomato farnesyl pyrophosphate gene highly expressed during early fruit development.

Farnesyl pyrophosphate synthase (FPS) catalyzes the synthesis of farnesyl pyrophosphate, a key intermediate in sterol and sesquiterpene biosynthesis. Using a polymerase chain reaction-based approach, we have characterized LeFPS1, a tomato (Lycoperscion esculentum cv Wva 106) fruit cDNA, which encodes a functional FPS. We demonstrate that tomato FPSs are encoded by a small multigenic family with genes located on chromosomes 10 and 12. Consistent with farnesyl pyrophosphate requirement in sterol biosynthesis, FPS genes are ubiquitously expressed in tomato plants. Using an LeFPS1 specific probe, we show that the corresponding gene can account for most of FPS mRNA in most plant organs, but not during young seedling development, indicating a differential regulation of FPS genes in tomato. FPS gene expression is also under strict developmental control: FPS mRNA was mainly abundant in young organs and decreased as organs matured with the exception of fruits that presented a biphasic accumulation pattern. In this latter case in situ hybridization studies have shown that FPS mRNA is similarly abundant in all tissues of young fruit. Taken together our results suggest that several FPS isoforms are involved in tomato farnesyl pyrophosphate metabolism and that FPS genes are mostly expressed in relation to cell division and enlargement.

Alkyl and Aryl Transferases↗

PubMed1984

Kinetic properties of pyrophosphate:fructose-6-phosphate phosphotransferase from germinating castor bean endosperm.

Pyrophosphate:fructose-6-phosphate phosphotransferase (PFP) was purified over 500-cold from endosperm of germinating castor bean (Ricinus commiunis L. var. Hale). The kinetic properties of the purified enzyme were studied. PFP was specific for pyrophosphate and had a requirement for a divalent metal ion. The pH optimum for activity was 7.3 to 7.7. The enzyme had similar activities in the forward and reverse directions and exhibited hyperbolic kinetics with all substrates. Kinetic constants were determined in the presence of fructose 2,6-bisphosphate, which stimulated activity about 20-fold and increased the affinity of the enzyme for fructose 6-phosphate, fructose 1,6-bisphosphate, and pyrophosphate up to 10-fold. Half-maximum activation of PFP by fructose 2,6-bisphosphate was obtained at 10 nanomolar. The affinity of PFP for this activator was reduced by decreasing the concentration of fructose 6-phosphate or increasing that of phosphate. Phosphate inhibited PFP when the reaction was measured in the reverse direction, i.e. fructose 6-phosphate production. In the presence of fructose 2,6-bisphosphate, phosphate was a mixed inhibitor with respect to both fructose 6-phosphate and pyrophosphate when the reaction was measured in the forward direction, i.e. fructose 1,6-bisphosphate production. The possible roles of fructose 2,6-bisphosphate, fructose 6-phosphate, and phosphate in the control of PFP are discussed.

Journal Article↗

PubMed2001

Binding of phosphate and pyrophosphate ions at the active site of human angiogenin as revealed by X-ray crystallography.

Human angiogenin (Ang) is an unusual homolog of bovine pancreatic RNase A that utilizes its ribonucleolytic activity to induce the formation of new blood vessels. The pyrimidine-binding site of Ang was shown previously to be blocked by glutamine 117, indicating that Ang must undergo a conformational change to bind and cleave RNA. The mechanism and nature of this change are not known, and no Ang-inhibitor complexes have been characterized structurally thus far. Here, we report crystal structures for the complexes of Ang with the inhibitors phosphate and pyrophosphate, and the structure of the complex of the superactive Ang variant Q117G with phosphate, all at 2.0 A resolution. Phosphate binds to the catalytic site of both Ang and Q117G in essentially the same manner observed in the RNase A-phosphate complex, forming hydrogen bonds with the side chains of His 13, His 114, and Gln 12, and the main chain of Leu 115; it makes an additional interaction with the Lys 40 ammonium group in the Ang complex. One of the phosphate groups of pyrophosphate occupies a similar position. The other phosphate extends toward Gln 117, and lies within hydrogen-bonding distance from the side-chain amide of this residue as well as the imidazole group of His 13 and the main-chain oxygen of Leu 115. The pyrimidine site remains obstructed in all three complex structures, that is, binding to the catalytic center is not sufficient to trigger the conformational change required for catalytic activity, even in the absence of the Gln 117 side chain. The Ang-pyrophosphate complex structure suggests how nucleoside pyrophosphate inhibitors might bind to Ang; this information may be useful for the design of Ang antagonists as potential anti-angiogenic drugs.

Binding Sites↗

PubMed1986

Pyrophosphate-caused inhibition of the aminoacylation of tRNA by the leucyl-tRNA synthetase from Neurospora crassa.

Inorganic pyrophosphate inhibits the aminoacylation of tRNALeu by the leucyl-tRNA synthetase from Neurospora crassa giving very low Kapp.i, PPi values of 3-20 microM. The inhibition by pyrophosphate, together with earlier kinetic data, suggest a reaction mechanism where leucine, ATP and tRNA are bound to the enzyme in almost random order, and pyrophosphate is dissociated before the rate-limiting step. A kinetic analysis of this mechanism shows that the measured Kapp.i values do not give the real dissociation constant but it is about 0.4 mM. Other dissociation constants are 90 microM for leucine, 2.2 mM for ATP and 1 microM for tRNALeu. At the approximate conditions of the living cell (2 mM ATP, 100 microM leucine and 150 microM PPi) the leucyl-tRNA synthetase is about 85% inhibited by pyrophosphate.

Adenosine Triphosphate↗

PubMed1991

Inorganic-pyrophosphate-dependent phosphorylation of spinach thylakoid proteins.

It has been shown for the first time that several photosystem-II thylakoid proteins and the main chlorophyll-a/b light-harvesting complex can be phosphorylated with inorganic pyrophosphate as phosphate donor. With pyrophosphate, as with ATP, the protein-kinase reaction is dependent on light or a strong reducing agent. The reaction which can be demonstrated in well-washed spinach thylakoids is dependent on electron transport and is controlled by the redox state of the plastoquinone pool. It is suggested that the pyrophosphate-dependent thylakoid protein phosphorylation is mediated by the same kinase which is responsible for the ATP-dependent protein phosphorylation. This pyrophosphate-dependent kinase activity may be derived from an evolutionary precursor from which ATP-dependent protein phosphorylation also developed.

Adenosine Triphosphate↗

PubMed1985

Biochemical studies in paraplegic renal stone patients. 2. Urinary excretion of citrate, inorganic pyrophosphate, silicate and urate.

The urinary excretions of citrate, inorganic orthophosphate and pyrophosphate, silicate and urate were measured in 17 paraplegic patients with renal calculous disease associated with urinary infection, in 16 paraplegics with no history of urinary calculus and in 14 healthy control subjects. The paraplegics excreted less citrate, orthophosphate and pyrophosphate than the control subjects. The stone-formers excreted more urate than the paraplegics without stone disease, but less than the control subjects. There were significant positive correlations between urinary orthophosphate and pyrophosphate and between urinary silicate and 24-h urine volume. The possible roles of increased urate and diminished excretion of citrate and inorganic pyrophosphate in the aetiology of renal calculosis in paraplegic patients deserve further investigation.

Adult↗

PubMed1990

Desorption of acquired enamel pellicle in vivo by pyrophosphate.

Soluble pyrophosphate (PP) has been introduced in dentifrices to inhibit the formation of dental calculus. The mechanism of inhibition is probably an adsorption of the pyrophosphate ions to the Ca-sites on the enamel surfaces and a blocking of the active sites for crystal growth. It has been shown in a recently published study that PP reduced the protein adsorption to hydroxyapatite (HA) in vitro and also inhibited the pellicle formation in vivo. The aim of the present study was to examine the desorption potential of pyrophosphate on the acquired enamel pellicle in vivo. Enamel fragments were carried in the mouth to collect pellicle material and some of the enamel surfaces were then treated with PP. Pellicle formation was examined by SEM of the enamel surfaces. The results showed that pyrophosphate desorbed the acquired enamel pellicle effectively. The clinical consequences of this effect is unknown, but it could possibly explain some aspects of hypersensitivity of teeth observed in some individuals using dentifrices containing PP.

Adsorption↗

PubMed2006

Pyruvate-phosphate dikinase of oxymonads and parabasalia and the evolution of pyrophosphate-dependent glycolysis in anaerobic eukaryotes.

In pyrophosphate-dependent glycolysis, the ATP/ADP-dependent enzymes phosphofructokinase (PFK) and pyruvate kinase are replaced by the pyrophosphate-dependent PFK and pyruvate phosphate dikinase (PPDK), respectively. This variant of glycolysis is widespread among bacteria, but it also occurs in a few parasitic anaerobic eukaryotes such as Giardia and Entamoeba spp. We sequenced two genes for PPDK from the amitochondriate oxymonad Streblomastix strix and found evidence for PPDK in Trichomonas vaginalis and other parabasalia, where this enzyme was thought to be absent. The Streblomastix and Giardia genes may be related to one another, but those of Entamoeba and perhaps Trichomonas are distinct and more closely related to bacterial homologues. These findings suggest that pyrophosphate-dependent glycolysis is more widespread in eukaryotes than previously thought, enzymes from the pathway coexists with ATP-dependent more often than previously thought and may be spread by lateral transfer of genes for pyrophosphate-dependent enzymes from bacteria.

Amino Acid Sequence↗

PubMed1966

Conversion of mevalonic acid to gamma, gamma-dimethylallyl pyrophosphate by Mycoplasma.

Henrikson, Carl V. (University of South Dakota, Vermillion), and Paul F. Smith. Conversion of mevalonic acid to gamma,gamma-dimethylallyl pyrophosphate by Mycoplasma. J. Bacteriol. 92:701-706. 1966.-Three representative strains of Mycoplasma, M. laidlawii strain B, Mycoplasma sp. avian strain J, and M. hominis type 2 strain O7, were examined for the presence or absence of enzymes associated with the biosynthetic pathway from mevalonic acid to gamma,gamma-dimethylallyl pyrophosphate. M. laidlawii served as a control organism, since it is capable of de novo biosynthesis of carotenoids. All four enzymes, namely, adenosine triphosphate (ATP)-mevalonate 5-phosphotransferase (EC 2.7.1.36), ATP-5-phosphomevalonate phosphotransferase (EC 2.7.4.2), ATP-5-pyrophosphomevalonate carboxy-lyase (EC 4.1.1.33), and isopentenylpyrophosphate Delta(3),Delta(2)-isomerase (EC 5.3.3.2), were demonstrated in this organism. Mycoplasma sp. avian strain J, which contains all enzymes necessary for the biosynthesis of mevalonic acid, lacks the first three of the above enzymes but contains isopentenyl pyrophosphate Delta(3),Delta(2)-isomerase. M. hominis, which lacks the enzymes necessary for the biosynthesis of mevalonic acid, also is deficient in the enzymes involved in its conversion to gamma,gamma-dimethylallyl pyrophosphate.

Carbon Isotopes↗

PubMed1977

Assessment of diagnostic value of technetium-99m pyrophosphate myocardial scintigraphy in 80 patients with possible acute myocardial infarction.

The diagnostic value of technetium-99m-pyrophosphate (Tc-pyrophosphate) myocardial scintigraphy was determined in 80 consecutive patients who had been admitted to the coronary care unit in order to rule out an acute myocardial infarction. Scintigraphic findings obtained within 5 days of admission were correlated with the final cardiac diagnosis determined for each patient. Significant myocardial uptake of Tc-pyrophosphate (positive scans) occurred in 13 of 22 patients (59%) who had enzyme and/or electrocardiographic proven acute myocardial infarct: 3 out of 5 with transmural myocardial infarct, 9 of 16 with nontransmural myocardial infarct, and 1 patient with left bundle-branch block. Of 58 patients who showed no evidence of acute myocardial infarction, positive scans occurred in 14 of 33 patients who had unstable angina pectoris (42%), 0 of 6 who had congestive heart failure, 6 of 9 who had other acute cardiac syndromes, and in 0 of 10 who had noncardiac chest pain. In the patients with unstable angina pectoris positive scans could not be predicted on the basis of the history, electrocardiographic findings or the arteriographically determined severity of the coronary artery disease. Blood levels of Tc-99m activity measured in 21 cardiac patients and in 6 volunteers did not correlate with the uptake intensity of Tc-pyrophosphate. These findings suggest caution in the use of this imaging method for the diagnosis of acute myocardial infarct in patients admitted with 'rule out myocardial infarction'.

Acute Disease↗

PubMedDate not supplied

Diagnosis of calcium pyrophosphate dihydrate deposition disease by fine needle aspiration biopsy: a case report.

BACKGROUND: Calcium pyrophosphate dihydrate deposition disease is a relatively rare disease with variable clinical presentations. CASE: A 73-year-old man presented with worsening lower back pain and fever. Fine needle aspiration biopsy of the lumbar vertebral bodies (L3-L4) revealed abundant neutrophils admixed with small, birefringent, rhomboid crystals in Diff-Quik-stained smears. These crystals were confirmed as calcium pyrophosphate dihydrate on cell block sections. A diagnosis of osteomyelitis and calcium pyrophosphate dihydrate deposition disease was rendered. The patient was treated with antibiotics and responded well. CONCLUSION: Calcium pyrophosphate dihydrate deposition disease can be diagnosed by fine needle aspiration biopsy, and an accurate diagnosis can be greatly facilitated by cell block sections. However, such a diagnosis may be neglected if the specimen is not carefully inspected.

Aged↗

PubMed1976

Whole-body autoradiography of 99Tcm-labelled pyrophosphate and related compounds in young rats.

The distribution of 99Tcm-labelled pyrophosphate in young rats was analysed by wholebody autoradiography and compared with those observed for 99Tcm-pertechnetate, 32P-labelled pyrophosphate and 85Sr-chloride. 99Tcm-labelled pyrophosphate was rapidly accumulated in bone and dentine and was similar to 32P-labelled pyrophosphate and 85Sr-chloride. The uptake of these substances in developing enamel was rather low in contrast to 99Tcm-pertechnetate, which had no affinity for bone.

Animals↗