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At least 145 records · Page 8Linked to original sources
PubMed2003

R208X mutation in CLN2 gene associated with reduced cerebrospinal fluid pterins in a girl with classic late infantile neuronal ceroid lipofuscinosis.

Clinical picture of neuronal ceroid lipofuscinosis with late infantile onset (LINCL) is characterized by myoclonic seizures and psychomotor regression. We present a case of classic LINCL and reduced cerebrospinal fluid (CSF) pterins in a girl of normal psychomotor development and born to non-consanguineous parents. She first presented with febrile seizures at the age of four. At that time, brain computed tomography finding was normal, but electroencephalogram showed hypsarrhythmia. At the age of five, tremor, generalized ataxia, and motor and mental regression appeared. Brain magnetic resonance imaging showed cerebellar atrophy. Electron microscopy examination showed storage of intracytoplasmic curvilinear inclusions in neurons, fibroblasts, and secretory cells of the skin and rectal mucosa. Tripeptidyl peptidase I (TPP-I) activity in leukocytes was very low (5.4 nmol/h/mg protein; range in homozygote cases of LINCL, 0.4-26.0). Molecular genetic studies showed a homozygous mutation, R208X, in exon 6 of CLN2 gene. CSF analysis revealed very low neopterin (7.3 nmol/L; normal range, 9-30) and biopterin (4.1 nmol/L; normal range, 10-30), reduced homovanillic acid (266 nmol/L; normal range, 211-871), and low homovanillic acid/5-hydroxyindoleacetic acid ratio (1.21; normal ratio, 1.5-3.5). Treatment with L-Dopa/Carbidopa (4 mg/kg) and antiepileptics was introduced, but without significant effect. It seems that low CSF pterins and impaired dopamine turnover are secondary manifestations of classical LINCL caused by homozygous inheritance of the R208X mutation in CLN2 gene.

Age Factors↗
PubMedDate not supplied

[Juvenile hormone in diapausing Pieris brassicae and mutations. Tetrahydrofolic acid and pterins incubated in chrysalids, provoking ontogenic and mutagenic genetic information alterations in Drosophila melanogaster].

Study of AMPc phosphodiesterase shows presence of JH in diapausing chrysalids and antogonistic action of FH and pterines. Study of farnesoldeshydrogenase and farnesal deshydrogenase in Dm shows that FH4 and pterines inhibite FDH, active ADH. Conclusion is JH in diapause chrysalides is active factor with FH4 provoking genesis of pigmentary mutation, cellular proliferation or growth deficiencies. Comparison with JH+FH4+ teromes incubated in Bar (Muller 5) mutants of Dm in place of diapausing chrysalids reproduce larval deficiences, mosaics and mutations observed in precedent experiments.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1991

Effects of amobarbital on pterins and dinucleotides contents in rat brain.

The effects of amobarbital (50 mg.kg-1 ip) on the brain concentrations of biopterin, pterin, reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) were studied by a reverse phase high performance liquid chromatography with fluorescent detector. Amobarbital increased FAD concentrations in 5 brain areas and pterin concentration in the cortex, but decreased biopterin concentrations in the cortex and hippocampus.

Amobarbital↗
PubMedDate not supplied

Influence of light on activity of adenylate kinase and pterin-protein complexes from pea chloroplasts.

The activity of adenylate kinase (AK) and of pterin-protein complexes (PPC), whose proteins have adenylate kinase activity comparable to that of the enzyme was studied. It was established that light inhibits adenylate kinase activity and that this effect is partially eliminated by phosphate ions. The forward and reverse reactions catalyzed by AK and PPC were studied and it was found that the activity of native protein complexes is different in the forward and reverse reactions. The thermostable protein both of adenylate kinase and of the pterin-protein complexes had identical activity in the ADP dismutation and the reverse reaction.

Adenosine Diphosphate↗
PubMed1979

Pterin deaminase from Bacillus megaterium. Purification and properties.

A pterin deaminase catalyzing the hydrolytic deamination of various pteridines was found in the bacterium, Bacillus megaterium, and partially purified from bacterial extract. The specific activity was raised 90-fold over that of the crude extract. The pH optimum is around 7.3, and the Km value for 6-carboxypterin is 1.3 mM. The molecular weight of the enzyme was estimated by gel filtration to be about 110,000. The enzyme deaminated pterin, 6-carboxypterin, biopterin, 6-methylpterin, 7-methylpterin, xanthopterin, 6-hydroxymethylpterin, sepiapterin, isosepiapterin, folic acid, and 6,7-dimethylpterin to their corresponding lumazines, whereas guanine, 7-carboxypterin, leucopterin, isoxanthopterin, and 6-methylisoxanthopterin did not serve as substrates. The enzyme was inhibited by PCMB and 8-azaguanine.

Aminohydrolases↗
PubMed1994

Delineation of the catalytic core of phenylalanine hydroxylase and identification of glutamate 286 as a critical residue for pterin function.

Rat phenylalanine hydroxylase was expressed in Escherichia coli. High level expression was achieved when the transformed E. coli were incubated at 27 degrees C for 24 h. A series of truncated fragments were expressed. The smallest fragment that gave an active soluble protein was from Leu142 to Phe410. This fragment corresponds closely to the region where there is highest homology between the three aromatic amino acid hydroxylases. The circular dichroism spectra of the phenylalanine hydroxylase catalytic core suggested that it contains around 50% alpha-helix. The core fragment is monomeric in dilute solutions but self-associates at higher concentrations. The E. coli expression system was used to generate a number of mutations in phenylalanine hydroxylase from position 264 to 290. This region had been previously shown to be important for pterin binding. Characterization of the mutant phenylalanine hydroxylase molecules identified Glu286 as an amino acid critical for pterin function in phenylalanine hydroxylase.

Amino Acid Sequence↗
PubMed1998

Human white blood cells and hair follicles are good sources of mRNA for the pterin carbinolamine dehydratase/dimerization cofactor of HNF1 for mutation detection.

Pterin carbinolamine dehydratase/dimerization cofactor of HNF1 (PCD/DCoH) is a protein that has a dual function. It is a pterin 4alpha-carbinolamine dehydratase that is involved in the regeneration of the cofactor tetrahydrobiopterin during the phenylalanine hydroxylase- catalyzed hydroxylation of phenylalanine. In addition, it is the dimerization cofactor of HNF1 that is able to activate the transcriptional activity of HNF1. Deficiencies in the gene for this dual functional protein result in hyperphenylalaninemia. Here we report for the first time that the PCD/DCoH mRNA is present in human white blood cells and hair follicles. Taking advantage of this finding, a sensitive, rapid and convenient method for screening mutations occurring in the coding region of this gene has been described.

Cloning, Molecular↗
PubMed1986

Identification of a dephosphorylated oxidation product of the molybdenum cofactor as 2-(1,2-dihydroxyethyl)thieno[3,2-g]pterin.

A new method was developed for the synthesis of 2-(1,2-dihydroxyethyl)thieno[3,2-g]pterin and related 2-substituted thienopterins. A dephosphorylated fluorescent oxidation product of the molybdenum cofactor isolated from xanthine oxidase (EC 1.2.3.2) was identified as 2-(1,2-dihydroxyethyl)thieno[3,2-g]pterin by comparison of electronic and fluorescence spectra and TLC behaviors with those of the synthetic compound.

Chromatography, Thin Layer↗
PubMed2001

Conformation of the substrate and pterin cofactor bound to human tryptophan hydroxylase. Important role of Phe313 in substrate specificity.

Tryptophan hydroxylase (TPH) carries out the 5-hydroxylation of L-Trp, which is the rate-limiting step in the synthesis of serotonin. We have prepared and characterized a stable N-terminally truncated form of human TPH that includes the catalytic domain (Delta90TPH). We have also determined the conformation and distances to the catalytic non-heme iron of both L-Trp and the tetrahydrobiopterin cofactor analogue L-erythro-7,8-dihydrobiopterin (BH2) bound to Delta90TPH by using 1H NMR spectroscopy. The bound conformers of the substrate and the pterin were then docked into the modeled three-dimensional structure of TPH. The resulting ternary TPH-BH2-L-Trp structure is very similar to that previously determined by the same methods for the complex of phenylalanine hydroxylase (PAH) with BH2 and L-Phe [Teigen, K., et al. (1999) J. Mol. Biol. 294, 807-823]. In the model, L-Trp binds to the enzyme through interactions with Arg257, Ser336, His272, Phe318, and Phe313, and the ring of BH2 interacts mainly with Phe241 and Glu273. The distances between the hydroxylation sites at C5 in L-Trp and C4a in the pterin, i.e., 6.1 +/- 0.4 A, and from each of these sites to the iron, i.e., 4.1 +/- 0.3 and 4.4 +/- 0.3 A, respectively, are also in agreement with the formation of a transient iron-4a-peroxytetrahydropterin in the reaction, as proposed for the other hydroxylases. The different conformation of the dihydroxypropyl chain of BH2 in PAH and TPH seems to be related to the presence of nonconserved residues, i.e., Tyr235 and Pro238 in TPH, at the cofactor binding site. Moreover, Phe313, which seems to interact with the substrate through ring stacking, corresponds to a Trp residue in both tyrosine hydroxylase and PAH (Trp326) and appears to be an important residue for influencing the substrate specificity in this family of enzymes. We show that the W326F mutation in PAH increases the relative preference for L-Trp as the substrate, while the F313W mutation in TPH increases the preference for L-Phe, possibly by a conserved active site volume effect.

Binding Sites↗
PubMed1999

Essential thiol requirement to restore pterin- or substrate-binding capability and to regenerate native enzyme-type high-spin heme spectra in the Escherichia coli-expressed tetrahydrobiopterin-free oxygenase domain of neuronal nitric oxide synthase.

Nitric oxide (NO) synthases (NOS) are thiolate-ligated heme-, tetrahydrobiopterin (BH(4))-, and flavin-containing monooxygenases which catalyze the NADPH-dependent conversion of L-arginine (L-Arg) to NO AND citrulline. NOS consists of two domains: an N-terminal oxygenase (heme- and BH(4)-bound) domain and a C-terminal reductase (FMN- and FAD-bound) domain. In this study, we have spectroscopically examined the binding of L-Agr and BH(4) to the dimeric, BH(4)-free ferric neuronal NOS (NNOS) oxygenase domain expressed in Escherichia coli separately from the reductase domain. Addition of L-Arg or its analogue inhibitors (N(G)()-methyl-L-Arg, N(G)()-nitro-L-Arg) and BH(4), together with dithiothreitol (DTT), to the pterin-free ferric low-spin oxygenase domain (gamma(MAX): 419, 538, 568 NM) and incubation for 2-3 days at 4 degrees C converted the domain to a native enzyme-type, predominantly high-spin state (gamma(MAX): approximately 395, approximately 512, approximately 650 NM). 7,8-Dihydrobiopterin and other thiols (E.G., beta-mercaptoethanol, cysteine, and glutathione, with less effectiveness) can replace BH(4) and DTT, respectively. the UV-visible absorption spectrum of L-Arg-bound ferric full length NNOS, which exhibits a relatively intense band at approximately 650 NM (epsilon equals 7.5-8 MM(-)(1) CM(-)(1)) due to the presence of a neutral flavin semiquinone, can then be quantitatively reconstructed by combining the spectra of equimolar amounts of the oxygenase and reductase domains. Of particular note, the heme spin-state conversion does not occur in the absence of a thiol even after prolonged (35-48 H) incubation of the oxygenase domain with BH(4) and/or L-Arg under anaerobic conditions. Thus, DTT (or other thiols) plays a significant role(s) beyond keeping BH(4) in its reduced form, In restoring the pterin- and/or substrate-binding capability of the E. coli-expressed, BH(4) free, dimeric NNOS oxygenase domain. Our results in combination with recently available X-ray crystallography and site-directed mutagenesis data suggest that the observed DTT effects arise from the involvement of an intersubunit disulfide bond or its rearrangement in the NOS dimer.

Binding Sites↗
PubMed1989

Oxidation--reduction midpoint potentials of the flavin, haem and Mo-pterin centres in spinach (Spinacia oleracea L.) nitrate reductase.

Oxidation-reduction midpoint potentials have been determined for the flavin, cytochrome b557 and Mo-pterin prosthetic groups of spinach (Spinacia oleracea L.) assimilatory nitrate reductase using visible, c.d. and room-temperature e.p.r. potentiometric titrations. At pH 7 and 25 degrees C, the midpoint potential for the FAD/FADH2 couple was determined by c.d. potentiometry to be -280 +/- 10 mV (n = 2). The redox potential for reduction of the haem was determined by visible potentiometry to be -123 +/- 10 mV (n = 1), significantly lower than the previously published value of -60 mV [Fido, Hewitt, Notton, Jones & Nasrulhaq-Boyce (1979) FEBS Lett. 99, 180-182]. Potentials for the Mo(VI)/Mo(V) and Mo(V)/Mo(IV) redox couples, determined by room-temperature e.p.r. potentiometry, were found to be +2 +/- 20 and -6 +/- 20 mV respectively. These values are very similar to the values previously determined for the FAD, haem and Mo-pterin centres in assimilatory nitrate reductase isolated from the unicellular green alga Chlorella vulgaris and indicate a close thermodynamic similarity between the two enzymes.

Bacterial Proteins↗
PubMed2004

Inactivation of the Leishmania tarentolae pterin transporter (BT1) and reductase (PTR1) genes leads to viable parasites with changes in folate metabolism and hypersensitivity to the antifolate methotrexate.

The protozoan parasite Leishmania is a folate and pterin auxotroph. The main biopterin transporter (BT1) and pterin reductase (PTR1) have already been characterized in Leishmania. In this study, we have succeeded in generating a BT1 and PTR1 null mutant in the same Leishmania tarentolae strain. These cells are viable with growth properties indistinguishable from wildtype cells. However, in response to the inactivation of BT1 and PTR1, at least one of the folate transporter genes was deleted, and the level of the folylpolyglutamate synthetase activity was increased, leading to increased polyglutamylation of both folate and methotrexate (MTX). Secondary events following gene inactivation should be considered when analyzing a phenotype in Leishmania. The BT1/PTR1 null mutant is hypersensitive to MTX, but in a step-by-step fashion, we could induce resistance to MTX in these cells. Several resistance mechanisms were found to co-exist including a reduced folate and MTX accumulation, demonstrating that cells with no measurable biopterin uptake but also greatly reduced folate uptake are viable, despite their auxotrophy for each of these substrates. The resistant cells have also amplified the gene coding for the MTX target dihydrofolate reductase. Finally, we found a marked reduction in MTX polyglutamylation in resistant cells. These studies further highlight the formidable ability of Leishmania cells to bypass the blockage of key metabolic pathways.

Animals↗
PubMed1994

Increased systemic, but not regional, neopterin production following intraperitoneal administration of interleukin-2 and lack of effect of pterins upon the lymphokine-activated killer cell phenomenon.

Circulating neopterin is derived from monocytes and/or macrophages that produce it upon stimulation by interferon-gamma released from activated T cells. Neopterin production has been proposed as a marker of biological response in the clinical administration of a number of cytokines. Changes in neopterin production as indicated by urinary neopterin excretion were studied in four patients with ovarian carcinoma receiving intraperitoneal interleukin-2 and lymphokine-activated killer cells. Neopterin production increased approximately threefold during treatment with interleukin-2 at doses which represent or exceed the maximum tolerated dose by this route of administration. Increased neopterin apparently was derived from systemic, not regional, tissues. The physiologic role(s) of pterins in immune responses is uncertain. In an in vitro system, the presence of neopterin or tetrahydrobiopterin or the pterin synthesis inhibitor, N-acetyl serotonin, did not modulate cytotoxic effects of lymphokine-activated killer cells.

Biopterins↗
PubMed1999

PhhB, a Pseudomonas aeruginosa homolog of mammalian pterin 4a-carbinolamine dehydratase/DCoH, does not regulate expression of phenylalanine hydroxylase at the transcriptional level.

Pterin 4a-carbinolamine dehydratase is bifunctional in mammals. In addition to playing a catalytic role in pterin recycling in the cytoplasm, it plays a regulatory role in the nucleus, where it acts as a dimerization-cofactor component (called DCoH) for the transcriptional activator HNF-1alpha. A thus far unique operon in Pseudomonas aeruginosa contains a gene encoding a homolog (PhhB) of the regulatory dehydratase, together with genes encoding phenylalanine hydroxylase (PhhA) and aromatic aminotransferase (PhhC). Using complementation of tyrosine auxotrophy in Escherichia coli as a functional test, we have found that the in vivo function of PhhA requires PhhB. Strikingly, mammalian DCoH was an effective substitute for PhhB, and either one was effective in trans. Surprisingly, the required presence of PhhB for complementation did not reflect a critical positive regulatory effect of phhB on phhA expression. Rather, in the absence of PhhB, PhhA was found to be extremely toxic in E. coli, probably due to the nonenzymatic formation of 7-biopterin or a similar derivative. However, bacterial PhhB does appear to exert modest regulatory effects in addition to having a catalytic function. PhhB enhances the level of PhhA two- to threefold, as was demonstrated by gene inactivation of phhB in P. aeruginosa and by comparison of the levels of expression of PhhA in the presence and absence of PhhB in Escherichia coli. Experiments using constructs having transcriptional and translational fusions with a lacZ reporter indicated that PhhB activates PhhA at the posttranscriptional level. Regulation of PhhA and PhhB is semicoordinate; both PhhA and PhhB are induced coordinately in the presence of either L-tyrosine or L-phenylalanine, but PhhB exhibits a significant basal level of activity that is lacking for PhhA. Immunoprecipitation and affinity chromatography showed that PhhA and PhhB form a protein-protein complex.

Escherichia coli↗
PubMed2003

Inhibition of THP-1 cell-mediated low-density lipoprotein oxidation by the macrophage-synthesised pterin, 7,8-dihydroneopterin.

Human macrophages release the pterin, 7,8-dihydroneopterin when exposed to the immune stimulant gamma-interferon (IFN-gamma). Previous in vitro studies have shown 7,8-dihydroneopterin is a potent antioxidant, which inhibits copper- and peroxyl-radical mediated low-density lipoprotein (LDL) oxidation. Using THP-1 cells, a human derived monocyte-like cell line, we have found that low micromolar concentrations of 7,8-dihydroneopterin inhibit cell mediated oxidation of LDL, as measured by electrophoretic mobility, alpha-tocopherol loss, and lipid oxidation. Stimulation of the THP-1 cells with IFN-gamma caused a significant reduction in the cells' ability to oxidise LDL. The extracellular pterin concentration increased from 0 to 16 nM with IFN-gamma stimulation, while the intracellular concentration increased from 0.21 to 1.69 nmol/mg cell protein.

Cell Line↗
PubMed1995

The identification of the pterin-binding domain in the nitric oxide synthase's sequence.

Comparative studies of primary sequences of nitric oxide synthase (NOS) and pterin-dependent enzymes has shown that the biopterin-dependent site of NOS is localized between the regions responsible for calmodulin and FMN binding. On the example of NOS from rat brain it was demonstrated that this biopterin-binding site is located in the region 750-769. Pairwise alignment of amino acids sequences of NOS from rat brain and rat xantine dehydrogenase revealed that the two proteins are 39.7% identical.

Amino Acid Oxidoreductases↗
PubMed1997

Pterin-6-aldehyde, an inhibitor of xanthine oxidase, has superoxide anion radical scavenging activity.

Superoxide anion radical (O2.-) scavenging activity of neopterin (NP) and its photodegraded products was studied. NP did not affect O2.- release in hypoxanthine/xanthine oxidase (HPX/XOD) reaction system, but pterin-6-aldehyde (P6A), one of photodegraded products of NP, suppressed it. The identification of P6A was successful by confirming inhibiting property of xanthine oxidase. In neutrophil/phorbol myristate acetate reaction system, NP did not affect the O2.- release but P6A suppressed it. The suppression by P6A was not associated with oxygen uptake, which indicated that P6A did not inhibit the generation of O2.- but directly scavenged it. These findings suggest that P6A has ameliorating effects on ischemic-reperfusion injury in which O2.-, which is generated both in HPX/XOD reaction and in activated neutrophil, is one of the major substances to damage the tissues.

Biopterins↗
PubMed2001

Evidence that bacterial cyanide oxygenase is a pterin-dependent hydroxylase.

The soluble cell-free fraction (150,000g high-speed supernatants [HSS]) of Pseudomonas fluorescens NCIMB 11764 contains putative cyanide oxygenase (CNO) responsible for initiating cyanide oxidation and assimilation as a nitrogenous growth substrate. CNO activity, assayed either by cyanide-dependent O(2) or NADH uptake, or by conversion of radioactive K(14)CN to (14)CO(2), was detected at micromolar concentrations (apparent half-saturation constant, 4 microM). Results demonstrating that CNO requires a protein-enriched cell fraction and a low MW redox factor (<500 Da) for which reduced biopterin could substitute are presented. The properties of CNO are consistent with those of a pterin hydroxylase.

Bacterial Proteins↗