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PubMed1985

[Biosynthesis of thiamine triphosphate and identification of thiamine diphosphate-binding proteins in the rat liver hyaloplasm].

The nature of the thiamine diphosphate binding proteins from rat liver hyaloplasm was studied. When [14C]thiamine was used as a marker, a [14C]thiamine diphosphate-containing electrophoretically homogeneous protein preparation was isolated from the liver soluble fraction and classified as transketolase. No other non-enzymatic proteins which bind thiamine diphosphate and can serve as substrates in the reaction of thiamine diphosphate synthesis in the hyaloplasm were found. It was shown that the phosphate group is transferred by rat liver thiamine diphosphate kinase to the free (but not to the protein-bound) thiamine diphosphate as it was believed earlier.

Animals↗
PubMed1991

Saccharomyces cerevisiae nucleoside-diphosphate kinase: purification, characterization, and substrate specificity.

Nucleoside-diphosphate kinase is an enzyme which catalyzes the phosphorylation of nucleoside diphosphates into the corresponding triphosphates for nucleic acid biosynthesis. In this communication, we describe the purification and characterization of nucleoside-diphosphate kinase from yeast. The purified protein appears to be homogeneous by sodium dodecyl sulfate-polyacrylamide gel analysis, with a molecular weight of about 17,000-18,000. An estimate from the fast protein liquid chromatography Superose 12 gel filtration shows a native molecular weight of about 68,000 to 70,000. The results suggest that yeast nucleoside-diphosphate kinase is composed of four subunits. Substrate specificity studies show that the relative activity of nucleoside diphosphates (NDP) as phosphate acceptors is in the order of dTDP greater than CDP greater than UDP greater than dUDP greater than GDP greater than or equal to dGDP greater than dCDP greater than dADP greater than ADP; and the relative activity of triphosphate donors is in the order of UTP greater than dTTP greater than CTP greater than dCTP greater than dATP greater than ATP greater than or equal to dGTP greater than GTP. The Km and Vm of dTDP, dGDP, dCDP, dUDP, CDP, and UDP have been determined. The rate constant studies indicate that the purified NDP kinase prefers using, to a slight extent, dTDP (approximately 800 min-1) as the substrate rather than other tested deoxyribo- and ribonucleotides (350-450 min-1). The broad substrate specificity and kinetic data suggest that the enzyme is involved in both DNA and RNA metabolism.

Molecular Weight↗
PubMed1987

Dissociation of the aggregating effect and the inhibitory effect upon cyclic adenosine monophosphate accumulation by adrenaline and adenosine diphosphate in human platelets.

Recent evidence indicates that adrenaline and adenosine diphosphate each have separate stimulus-response pathways for induction of aggregation and inhibition of cAMP accumulation. We have used a natural model to test the validity of this evidence, i.e. patients from two kindreds with an inherited bleeding disorder due to absent aggregation to adrenaline and no secondary wave response to large concentrations of adenosine diphosphate. Our studies showed that the inhibitory effect of adrenaline and adenosine diphosphate on PGE1-induced increase of cAMP in the patients was not different from that of the controls both for adrenaline and adenosine diphosphate. These results therefore support the present evidence that both adrenaline and adenosine diphosphate apply separate pathways in these two platelet functions.

Adenosine Diphosphate↗
PubMed2000

Inositol trisphosphate and cyclic adenosine diphosphate-ribose increase quantal transmitter release at frog motor nerve terminals: possible involvement of smooth endoplasmic reticulum.

The release of chemical transmitter from nerve terminals is critically dependent on a transient increase in intracellular Ca2+. The increase in Ca2+ may be due to influx of Ca2+ from the extracellular fluid or release of Ca2+ from intracellular stores such as mitochondria. Whether Ca2+ utilized in transmitter release is liberated from organelles other than mitochondria is uncertain. Smooth endoplasmic reticulum is known to release Ca2+, e.g., on activation by inositol trisphosphate or cyclic adenosine diphosphate-ribose, so the possibility exists that Ca2+ from this source may be involved in the events leading to exocytosis. We examined this hypothesis by testing whether inositol trisphosphate and cyclic adenosine diphosphate-ribose modified transmitter release. We used liposomes to deliver these agents into the cytoplasmic compartment and binomial analysis to determine their effects on the quantal components of transmitter release. Administration of inositol trisphosphate (10(-4)M) caused a rapid, 25% increase in the number of quanta released. This was due to an increase in the number of functional release sites, as the other quantal parameters were unaffected. The effect was reversed with 40 min of wash. Virtually identical results were obtained with cyclic adenosine diphosphate-ribose (10(-4)M). Inositol trisphosphate caused a 10% increase in quantal size, whereas cyclic adenosine diphosphate-ribose had no effect. The results suggest that quantal transmitter release can be increased by Ca2+ released from smooth endoplasmic reticulum upon stimulation by inositol trisphosphate or cyclic adenosine diphosphate-ribose. This may involve priming of synaptic vesicles at the release sites or mobilization of vesicles to the active zone. Inositol trisphosphate may have an additional action to increase the content of transmitter within the vesicles. These findings raise the possibility of a role of endogenous inositol phosphate and smooth endoplasmic reticulum in the regulation of cytoplasmic Ca2+ and transmitter release.

Adenosine Diphosphate Ribose↗
PubMed2006

Farnesyl diphosphate synthase: the art of compromise between substrate selectivity and stereoselectivity.

Farnesyl diphosphate (FPP) synthase catalyzes the consecutive head-to-tail condensations of isopentenyl diphosphate (IPP, C5) with dimethylallyl diphosphate (DMAPP, C5) and geranyl diphosphate (GPP, C10) to give (E,E)-FPP (C15). The enzyme belongs to a genetically distinct family of chain elongation enzymes that install E-double bonds during each addition of a five-carbon isoprene unit. Analysis of the C10 and C15 products from incubations with avian FPP synthase reveals that small amounts of neryl diphosphate (Z-C10) and (Z,E)-FPP are formed along with the E-isomers during the C5 --> C10 and C10 --> C15 reactions. Similar results were obtained for FPP synthase from Escherichia coli, Artemisia tridentata (sage brush), Pyrococcus furiosus, and Methanobacter thermautotrophicus and for GPP and FPP synthesized in vivo by E. coli FPP synthase. When (R)-[2-2H]IPP was a substrate for chain elongation, no deuterium was found in the chain elongation products. In contrast, the deuterium in (S)-[2-2H]IPP was incorporated into all of the products. Thus, the pro-R hydrogen at C2 of IPP is lost when the E- and Z-double bond isomers are formed. The synthesis of Z-double bond isomers by FPP synthase during chain elongation is unexpected for a highly evolved enzyme and probably reflects a compromise between optimizing double bond stereoselectivity and the need to exclude DMAPP from the IPP binding site.

Artemisia↗
PubMed1974

Mutants of group D1 Salmonella carrying the somatic antigen of group A organisms: evidence for the lack of cytidine diphosphate paratose-2-epimerase activity.

The mutant strains of Salmonella durban that possessed O antigen 2, 12 of group A Salmonella were defective in the cytidine diphosphate paratose-2-epimerase activity. The enzyme preparation of the mutant strains catalyzed the conversion of cytidine diphosphate glucose into cytidine diphosphate paratose but not into cytidine diphosphate tyvelose. The defect in the epimerase activity was also confirmed by the use of purified cytidine diphosphate paratose as a substrate. The specificity of dideoxyhexosyl transferase catalyzing the formation of the group-specific determinant is discussed.

Agglutination Tests↗
PubMed1997

Receptor-independent activation of cardiac adenylyl cyclase by GDP and membrane-associated nucleoside diphosphate kinase. A new cardiotonic mechanism?

Regulation of adenylyl cyclase activity by guanine nucleoside tri- and diphosphates as well as by stimulatory and inhibitory receptors was studied in canine cardiac sarcolemmal membranes. Guanosine triphosphate (GTP) increased adenylyl cyclase activity by a maximum of 80%, with an EC50 value of 0.7 mumol/l. The addition of the beta-adrenoceptor agonist, isoprenaline (100 mumol/l), caused a further, about 100%, increase in GTP-stimulated activity. The nucleoside diphosphate (GDP) also activated cardiac adenylyl cyclase, but in a biphasic manner. At low concentrations (EC50 0.12 mumol/ l). GDP increased enzyme activity by about 80%, followed by a plateau at 0.5-2 mumol/l and a second increase to a maximum of 60% with an EC50 value of 14 mumol/l. The stable GDP analog, guanosine 5'-O-(2-thio)diphosphate (GDP beta S), also increased cardiac adenylyl cyclase activity, but in a monophasic manner, by a maximum of 150%, with an EC50 of 0.4 mumol/l. Addition of uracil diphosphate (UDP) (3 mmol/l), which completely inhibited transphosphorylation of GDP to GTP, did not reduce adenylyl cyclase stimulation by low concentrations of GDP, whereas enzyme stimulation by high GDP concentrations was almost completely attenuated. Furthermore, pretreatment of the membranes with cholera toxin led to an increased stimulation of adenylyl cyclase activity by high concentrations of GDP. These findings suggest that the second phase of adenylyl cyclase stimulation by GDP is due to transphosphorylation of GDP to GTP, associated with activation of Gs proteins, and that stimulation by GDP itself (first phase) and endogenously formed GTP (second phase) is additive. However, in contrast to exogenously added GTP, beta-adrenoceptor activation did not enhance GDP-stimulated adenylyl cyclase activity. Furthermore, in the presence of 1 mumol/l GDP, the addition of GTP did not cause any further increase in enzyme activity. On the other hand, the muscarinic acetylcholine receptor agonist carbachol inhibited both GTP- and GDP-activated adenylyl cyclase. The inhibition of GDP-stimulated activity was lost when formation of GTP from GDP was blocked. The contrasting effects of endogenously formed GTP and exogenous GTP suggest that the formation of GTP from GDP is closely linked to the activation site of adenylyl cyclase, i.e. the stimulatory Gs protein. This receptor-independent activation can apparently bypass beta-adrenoceptor-dependent activation of cardiac adenylyl cyclase.

Adenylyl Cyclases↗
PubMed1999

Glucosylation of glycosylphosphatidylinositol membrane anchors: identification of uridine diphosphate-glucose as the direct donor for side chain modification in Toxoplasma gondii using carbohydrate analogues.

Toxoplasma gondii is an obligate intracellular parasite of the phylum apicomplexa and a common and often life-threatening opportunistic infection associated with AIDS. A family of parasite-specific glycosylphosphatidylinositols containing a novel glucosylated side chain has been shown to be highly immunogenic in humans (Striepen et al. (1997) J. Mol. Biol. 266, 797-813). In contrast to trypanosomes in T. gondii side chain modification takes place before addition to protein in the endoplasmic reticulum. The biosynthesis of these modifications was studied in an in vitro system prepared from hypotonically lysed T. gondii parasites. Radiolabeled glucose-containing glycosylphosphatidylinositol precursors were synthesized by T. gondii membrane preparations upon incubation with uridine diphosphate-[3H]glucose. Synthesis of glucosylated glycolipids took place only in the presence of exogenous uridine diphosphate-glucose and was stimulated by unlabeled uridine diphosphate-glucose in a dose-dependent manner. In contrast to glycosylphosphatidylinositol mannosylation, glucosylation was shown to be insensitive to amphomycin treatment. In addition, the glucose analogue 2-deoxy-D-glucose was used to trace the glycosylphosphatidylinositol glucosylation pathway. Detailed analysis of glycolipids synthesized in vitro in the presence of UDP and GDP derivatives of D-glucose and 2-deoxy-D-glucose ruled out an involvement of dolichol phosphate-glucose and demonstrates direct transfer of glucose from uridine diphosphate-glucose.

Animals↗
PubMed2006

Cloning of deoxynucleoside monophosphate kinase genes and biosynthesis of deoxynucleoside diphosphates.

The genes encoding four deoxynucleoside monophosphate kinase (dNMP kinase) enzymes, including ADK1 for deoxyadenylate monophosphate kinase (AK), GUK1 for deoxyguanylate monophosphate kinase (GK), URA6 for deoxycytidylate monophosphate kinase (CK), and CDC8 for deoxythymidylate monophosphate kinase (TK), were isolated from the genome of Saccharomyces cerevisiae ATCC 2610 strain and cloned into E. coli strain BL21(DE3). Four recombinant plasmids, pET17b-JB1 containing ADK1, pET17b-JB2 containing GUK1, pET17b-JB3 containing URA6, and pET17b-JB4 containing CDC8, were constructed and transformed into E. coli strain for over-expression of AK, GK, CK, and TK. The amino acid sequences of these enzymes were analyzed and a putative conserved peptide sequence for the ATP active site was proposed. The four deoxynucleoside diphosphates (dNDP) including deoxyadenosine diphosphate (dADP), deoxyguanosine diphosphate (dGDP), deoxycytidine diphosphate (dCDP), and deoxythymidine diphosphate (dTDP), were synthesized from the corresponding deoxynucleoside monophosphates (dNMP) using the purified AK, GK, CK, and TK, respectively. The effects of pH and magnesium ion concentration on the dNDP biosynthesis were found to be important. A kinetic model for the synthetic reactions of dNDP was developed based on the Bi-Bi random rapid equilibrium mechanism. The kinetic parameters including the maximum reaction velocity and Michaelis-Menten constants were experimentally determined. The study on dNDP biosynthesis reported in this article are important to the proposed bioprocess for production of deoxynucleoside triphosphates (dNTP) that are used as precursors for in vitro DNA synthesis. There is a significant advantage of using enzymatic biosyntheses of dNDP as compared to the chemical method that has been in commercial use.

Amino Acid Sequence↗
PubMed2004

Crystal structure of the C67A mutant of isopentenyl diphosphate isomerase complexed with a mechanism-based irreversible inhibitor.

Isopentenyl diphosphate:dimethylallyl diphosphate (IPP:DMAPP) isomerase is a key enzyme in the biosynthesis of isoprenoids. The mechanism of the isomerization reaction involves protonation of the unactivated carbon-carbon double bond in the substrate. Analysis of the 1.97 A crystal structure of the inactive C67A mutant of E. coli isopentenyl diphosphate:dimethylallyl diphosphate isomerase complexed with the mechanism-based inactivator 3,4-epoxy-3-methyl-1-butyl diphosphate is in agreement with an isomerization mechanism involving Glu 116, Tyr 104, and Cys 67. In particular, the results are consistent with a mechanism where Glu116 is involved in the protonation step and Cys67 in the elimination step.

Binding Sites↗
PubMed1994

Isolation and characterization of idsA: the gene for the short chain isoprenyl diphosphate synthase from Methanobacterium thermoautotrophicum.

The gene that encodes the bifunctional short chain isoprenyl diphosphate synthase (idsA) for synthesis of farnesyl diphosphate and geranylgeranyl diphosphate in Methanobacterium thermoautotrophicum, a strict archaebacterial anaerobe, was isolated from a genomic DNA library by colony-lift hybridization and sequenced. Amino acid sequences were obtained for the N-terminus of the enzyme and for internal peptide fragments generated by proteolysis and treatment with cyanogen bromide. Degenerate primers based on the amino acid sequences were used in PCR to synthesize a 220-bp probe from genomic DNA. The probe was radiolabeled and used to isolate idsA. DNA sequencing revealed a 975-bp open reading frame located within an operon. The encoded 325-amino-acid protein contained five conserved regions found in eubacterial and eukaryotic farnesyl diphosphate and geranylgeranyl diphosphate synthases, including aspartate-rich motifs commonly found in prenyltransferases.

Alkyl and Aryl Transferases↗
PubMed1995

Significance of Phe-220 and Gln-221 in the catalytic mechanism of farnesyl diphosphate synthase of Bacillus stearothermophilus.

Farnesyl diphosphate synthase [EC 2.5.1.10] from Bacillus stearothermophilus was specifically altered at two amino acid residues by using site-directed mutagenesis. The highly conserved Phe and Gln residues at the sequential amino acid positions 220-221 in an upstream part of the putative substrate binding site were replaced with Ala and Glu, respectively. These mutageneses (F220A and Q221E) resulted in 10(-5) and 10(-3) decreases in catalytic activity of farnesyl diphosphate synthesis, respectively. Michaelis constants of the Q221E mutant for the allylic substrates (dimethylallyl- and geranyl diphosphates) increased approximately 25- and 2-folds, respectively, compared to wild type, whereas those for the homoallylic substrate (isopentenyl diphosphate) were not altered much. These results suggest that the Phe-Gln motif is involved not only in the binding of allylic substrates but also in the catalysis by farnesyl diphosphate synthase.

Alkyl and Aryl Transferases↗
PubMed2001

Refolding and characterization of a yeast dehydrodolichyl diphosphate synthase overexpressed in Escherichia coli.

Dehydrodolichyl diphosphate synthase (DDPPs) catalyzes the sequential condensation of isopentenyl diphosphate with farnesyl diphosphate to synthesize long-chain dehydrodolichyl diphosphate, which serves as a precursor of glycosyl carrier in glycoprotein biosynthesis in eukaryotes. To perform kinetic and structural studies of DDPPs, we have expressed yeast DDPPs using Escherichia coli as the host cell. Thioredoxin and His tag were utilized to increase the solubility of the recombinant protein and facilitate its purification using Ni-nitrilotriacetic acid (NTA) column. The protein was overexpressed in E. coli but mostly existed in pellet in the absence of detergent. The low quantity of soluble DDPPs was purified using Ni-NTA, Mono Q anion-exchange, and size-column chromatographies. The protein in the pellet was solubilized with 7 M urea and purified using Ni-NTA under denaturing condition. The protein refolding was achieved via the stepwise dialysis to remove the denaturant in the presence of 6 mM beta-mercaptoethanol. Detergent n-octyl-beta-d-glucopyranoside and Triton X-100 increased the solubility of the DDPPs so that refolding can be performed at higher protein concentration. Alternatively, on-column refolding was carried out in a single step to obtain the active protein in large quantities. beta-Mercaptoethanol and Triton were both required in this quick refolding process. The kinetic studies indicated that the soluble and refolded DDPPs have comparable activities (k(cat) = 2 x 10(-4) s(-1)). Unlike its bacterial homologue, undecaprenyl diphosphate synthase, yeast DDPPs activity was not enhanced by Triton.

Alkyl and Aryl Transferases↗
PubMed1994

Cloning of an Arabidopsis thaliana cDNA coding for farnesyl diphosphate synthase by functional complementation in yeast.

A cDNA encoding farnesyl diphosphate synthase, an enzyme that synthesizes C15 isoprenoid diphosphate from isopentenyl diphosphate and dimethylallyl diphosphate, was cloned from an Arabidopsis thaliana cDNA library by complementation of a mutant of Saccharomyces cerevisiae deficient in this enzyme. The A. thaliana cDNA was also able to complement the lethal phenotype of the erg20 deletion yeast mutant. As deduced from the full-length 1.22 kb cDNA nucleotide sequence, the polypeptide contains 343 amino acids and has a relative molecular mass of 39,689. The predicted amino acid sequence presents about 50% identity with the yeast, rat and human FPP synthases. Southern blot analyses indicate that A. thaliana probably contains a single gene for farnesyl diphosphate synthase.

Alkyl and Aryl Transferases↗
PubMed1993

A thiamin diphosphate binding fold revealed by comparison of the crystal structures of transketolase, pyruvate oxidase and pyruvate decarboxylase.

BACKGROUND: The crystal structures of three thiamin diphosphate-dependent enzymes that catalyze distinct reactions in basic metabolic pathways are known. These enzymes--transketolase, pyruvate oxidase and pyruvate decarboxylase--also require metal ions such as Ca2+ and Mg2+ as cofactors and have little overall sequence similarity. Here, the crystal structures of these three enzymes are compared. RESULTS: The three enzymes share a similar pattern of binding of thiamin diphosphate and the metal ion cofactors. The enzymes function as multisubunit proteins, with each polypeptide chain folded into three alpha/beta domains. Two of these domains are involved in binding of the thiamin diphosphate and the metal ion. These domains have the same topology of six parallel beta-strands and surrounding alpha-helices. The thiamin diphosphate is bound in a cleft, formed by two domains from two different subunits. Only a few residues are conserved in all three enzymes and these are responsible for proper binding of the cofactors. CONCLUSIONS: Despite considerable differences in quaternary structure and lack of overall sequence homology, thiamin diphosphate binds to the three enzymes in a very similar fashion, and a general thiamin-binding fold can be revealed.

Amino Acid Sequence↗
PubMed2004

Temperature-dependent modulation of farnesyl diphosphate/geranylgeranyl diphosphate synthase from hyperthermophilic archaea.

Enzyme characteristics of trans-prenyl diphosphate synthase (Tk-IdsA) from Thermococcus kodakaraensis, which catalyzes the consecutive trans-condensation of isopentenyl diphosphate (C(5)) units with allylic diphosphate, were examined. Product analysis revealed that Tk-IdsA is a bifunctional enzyme, farnesyl diphosphate (FPP, C(15))/geranylgeranyl diphosphate (GGPP, C(20)) synthase, and mainly yields both C(15) and C(20). The FPP/GGPP product ratio increases with the rise of the reaction temperature. The kinetic parameters obtained at 70 and 90 degrees C demonstrated that the rise of the temperature elevates the k(0) value for the C(10) allylic substrate to more than those for the C(5) and C(15) allylic substrates. These data suggest that Tk-IdsA contributes to adjust the membrane composition to the cell growth temperature by modulating its substrate and product specificities. Mutation study indicated that the aromatic side chain of Tyr-81 acts as a steric hindrance to terminate the chain elongation and defines the final product length.

Alkyl and Aryl Transferases↗
PubMed2002

Chemical formation of 4-hydroxy-2,5-dimethyl-3[2H]-furanone from D-fructose 1,6-diphosphate.

The selective chemical formation of 4-hydroxy-2,5-dimethyl-3[2H]-furanone (HDF) from D-fructose 1,6-diphosphate in the presence of reduced nicotinamide-adenine-dinucleotides (NAD(P)H) was investigated by means of HPLC-DAD and HPLC-UV-MS/MS. The temperature optimum for HDF formation was 30 degrees C, whereas the pH value (pH 3-10) and chemical nature of the buffer had no significant influence. A linear correlation of reaction time and D-fructose 1,6-diphosphate concentration with the obtained HDF yield was observed. Proteins appeared to have a stabilizing effect. The NAD(P)H were mandatory, even in the presence of protein, implying a non-enzymatic hydride-transfer to an unknown intermediate which finally leads to the selective formation of HDF. The hydride-transfer was confirmed by the application of selectively pro-4R or pro-4S deuterium labeled NADH resulting in each case in the formation of HDF exhibiting a deuterium labeling of approx 30% and employment of [4R,S-(2)H(2)]-NADH led to a deuterium labeling of approx 66%. The incubation of [1-(13)C]-D-fructose 1,6-diphosphate with [4R,S-(2)H(2)]-NADH revealed that the hydride is transferred to C-5 or C-6 of the D-fructose 1,6-diphosphate skeleton. Thus, a chemical HDF formation from D-fructose 1,6-diphosphate under physiological reaction conditions was shown and for the first time to our knowledge a non-enzymatic hydride-transfer from NADH to a carbohydrate structure was demonstrated.

Deuterium↗
PubMed2001

5-aminoisoquinolinone, a potent inhibitor of poly (adenosine 5'-diphosphate ribose) polymerase, reduces myocardial infarct size.

This study investigates the effects of a novel, water-soluble inhibitor of the activity of poly (adenosine 5'-diphosphate ribose) polymerase, 5-aminoisoquinolinone [5-aminoisoquinolin-1(2H)-one], on (i) poly (adenosine 5'-diphosphate ribose) polymerase activity in rat cardiac myoblasts and (ii) the infarct size caused by regional myocardial ischaemia and reperfusion in the rat. Exposure of H9c2 cells to hydrogen peroxide (H2O2, 1 mM) caused a significant increase in poly (adenosine 5'-diphosphate ribose) polymerase activity and an 80-90% reduction in mitochondrial respiration (cellular injury). Pretreatment of these cells with 5-aminoisoquinolinone (0.003-1 mM) caused a concentration-dependent inhibition of poly (adenosine 5'-diphosphate ribose) polymerase activity (IC50: approximately 4.5 microM, n=6-9) and cell injury (EC50: approximately 4.45 microM, n=9). In a rat model of myocardial infarction, left anterior descending coronary artery occlusion (25 min) and reperfusion (2 h) resulted in an infarct size of 50+/-3%. Administration (1 min before reperfusion) of 5-aminoisoquinolinone reduced myocardial infarct size in a dose-related fashion. Thus, 5-aminoisoquinolinone is a potent inhibitor of poly (adenosine 5'-diphosphate ribose) polymerase activity in cardiac myoblasts and reduces myocardial infarct size in vivo.

Animals↗