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At least 19 recordsLinked to original sources
PubMed1992

7-substituted pterins in humans with suspected pterin-4a-carbinolamine dehydratase deficiency. Mechanism of formation via non-enzymatic transformation from 6-substituted pterins.

A recently described new form of hyperphenylalaninemia is characterized by the excretion of 7-substituted isomers of biopterin and neopterin and 7-oxo-biopterin in the urine of patients. It has been shown that the 7-substituted isomers of biopterin and neopterin derive from L-tetrahydrobiopterin and D-tetrahydroneopterin and are formed during hydroxylation of phenylalanine to tyrosine with rat liver dehydratase-free phenylalanine hydroxylase. We have now obtained identical results using human phenylalanine hydroxylase. The identity of the pterin formed in vitro and derived from L-tetrahydrobiopterin as 7-(1',2'-dihydroxypropyl)pterin was proven by gas-chromatography mass spectrometry. Tetrahydroneopterin and 6-hydroxymethyltetrahydropterin also are converted to their corresponding 7-substituted isomers and serve as cofactors in the phenylalanine hydroxylase reaction. Dihydroneopterin is converted by dihydrofolate reductase to the tetrahydro form which is biologically active as a cofactor for the aromatic amino acid monooxygenases. The 6-substituted pterin to 7-substituted pterin conversion occurs in the absence of pterin-4a-carbinolamine dehydratase and is shown to be a nonenzymatic process. 7-Tetrahydrobiopterin is both a substrate (cofactor) and a competitive inhibitor with 6-tetrahydrobiopterin (Ki approximately 8 microM) in the phenylalanine hydroxylase reaction. For the first time, the formation of 7-substituted pterins from their 6-substituted isomers has been demonstrated with tyrosine hydroxylase, another important mammalian enzyme which functions in the hydroxylation of phenylalanine and tyrosine.

Biotransformation↗
PubMed1991

The major pterin in Tetrahymena pyriformis is 6-(D-threo-1,2,3-trihydroxypropyl)-pterin (D-monapterin) and not 6-(L-threo-1,2-dihydroxypropyl)-pterin (ciliapterin).

The major pterin in Tetrahymena pyriformis, strain W, earlier suggested to be L-threo-biopterin and named ciliapterin [1] is now identified as D-threo-neopterin (D-monapterin). This is the first example of a natural D-monapterin. This compound was characterized by its chromatographic behavior, its fluorescence properties and by its oxidation product with alkaline permanganate. The final identification was obtained by comparison with an authentic material using an exchange ligand chromatography method with D-phenylalanine as chiral modifier and Cu (II) as metal ion. D-monapterin is also present as the major pterin in Tetrahymena pyriformis strains GL and ST, and in Tetrahymena thermophila.

Animals↗
PubMed1981

Folic acid and pterin deaminases in Dictyostelium discoideum: kinetic properties and regulation by folic acid, pterin, and adenosine 3',5'-phosphate.

Kinetic data obtained for deamination of pterin by the extracellular fraction from Dictyostelium discoideum yielded apparently linear Lineweaver-Burk plots for pterin. The Michaelis constant for pterin was 30 microM. The data for folic acid deamination yielded convex Lineweaver-Burk plots. Convex Lineweaver-Burk plots could result from the presence of two types of enzymes with different affinities. The data for folic acid deamination were analyzed mathematically for two types of enzymes. This analysis produced Michaelis constants for folic acid of 1.8 and 23 microM competition studies suggested that an enzyme with low affinity nonspecifically catalyzed the deamination of folic acid and pterin, whereas an enzyme with high affinity was a specific folic acid deaminase. A specific folic acid deaminase with high affinity appeared to be present on the surface of D. discoideum cells. The Michaelis constant for this enzyme was 2.6 microM. Cells growing in nutrient broth and cells starved in phosphate buffer released folic acid and pterin deaminases. The quantity of deaminase activities released by the cells appeared to be controlled by chemoattractants. Starving cells that were supplied with folic acid, pterin, or adenosine 3',5'-phosphate increased their extracellular folic acid and pterin deaminase activities to a larger extent than did cell suspensions to which no chemoattractants were added. Administration of folic acid or pterin to starving cells caused increases of the activity of extracellular adenosine 3',5'-phosphate phosphodiesterase and repressed increases of the activity of phosphodiesterase inhibitor.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1975

Studies on the degradation of pterine and pterine-6-carboxylic acid by Pseudomonas fluorescens UK-1.

Pseudomonas fluorescens UK-1 has been incubated in basal mineral medium which was 0.5mM in pterine or pterine-6-carboxylic acid. During incubation the test organism splits the pteridine ring by liberating carbon dioxide from position 2. Glucose added to the medium greatly enhances both the growth of the organism and the carbon dioxide formation. Despite the structural similarities between pterine and pterine-6-carboxylic acid, only the degradation products derived from pterine are fluorescent in UV-light. Among the degradation products lumazine, pyrazine-2-carboxylic acid, and pyrazine-2-carboxamide have been identified. Also the activities of pterine deaminase and a carbon dioxide-liberating enzyme have been determined.

Aminohydrolases↗
PubMed1990

Chromophore function and interaction in Escherichia coli DNA photolyase: reconstitution of the apoenzyme with pterin and/or flavin derivatives.

Native DNA photolyase, as isolated from Escherichia coli, contains a neutral flavin radical (FADH.) plus a pterin chromophore (5,10-methenyltetrahydropteroylpolyglutamate) and can be converted to its physiologically significant form by reduction of FADH. to fully reduced flavin (FADH2) with dithionite or by photoreduction. Either FADH2 or the pterin chromophore in dithionite-reduced native enzyme can function as a sensitizer in catalysis. Various enzyme forms (EFADox, EFADH., EFADH2, EPteFADox, EPteFADH., EPteFADH2, EPte) containing stoichiometric amounts of FAD in either of its three oxidation states and/or 5,10-methenyltetrahydrofolate (Pte) have been prepared in reconstitution experiments. Studies with EFADox and EPte showed that these preparations retained the ability to bind the missing chromophore. The results suggest that there could be considerable flexibility in the biological assembly of holoenzyme since the order of binding of the enzyme's chromophores is apparently unimportant, the binding of FAD is unaffected by its redox state, and enzyme preparations containing only one chromophore are reasonably stable. The same catalytic properties are observed with dithionite-reduced native enzyme or EFADH2. These preparations do not exhibit a lag in catalytic assays whereas lags are observed with preparations containing FADox or FADH. in the presence or absence of pterin. Photochemical studies show that these lags can be attributed to enzyme activation under assay conditions in a reaction involving photoreduction of enzyme-bound FADox or FADH. to FADH2. EPte is catalytically inactive, but catalytic activity is restored upon reconstitution of EPte with FADox. The results show that pterin is not required for dimer repair when FADH2 acts as the sensitizer but that FADH2 is required when dimer repair is initiated by excitation of the pterin chromophore. The relative intensity of pterin fluorescence in EPte, EPteFADH., EPteFADox, or EPteFADH2 has been used to estimate the efficiency of pterin singlet quenching by FADH. (93%), FADox (90%), or FADH2 (58%). Energy transfer from the excited pterin to flavin is energetically feasible and may account for the observed quenching of pterin fluorescence and also explain why photoreduction of FADox or FADH. is accelerated by the pterin chromophore. An irreversible photobleaching of the pterin chromophore is accelerated by FADH2 in a reaction that is accompanied by a transient oxidation of FADH2 to FADH.. Both pterin bleaching and FADH2 oxidation are inhibited by substrate.

Apoenzymes↗
PubMed1992

pH-dependence of the structure and degradation of 8-alkyl-substituted pterins.

Structures of 8-(2-hydroxyethyl)pterins (8-11) investigated using 1H- and 13C-NMR and UV/vis spectroscopies showed a complex dependence on pH, solvent and 6,7-substitution pattern. In acid, only one cation was observed for all the pterins. In neutral aqueous solution, only one neutral form, the normal quinonoid tautomer, was observed for 7-unsubstituted pterins 9 & 11, but two neutral tautomeric forms, quinonoid and 7-exo-methylene, were observed for 7-CH3 substituted pterins 8 & 10 with 70% and 92%, respectively, of quinonoid. The neutral pterins in MeOH, however, showed a different distribution of structural forms: quinonoid and a five-membered intramolecular ether forms were observed for 7-unsubstituted pterins 9 & 11 as 60% and 25%, respectively, of quinonoid, while quinonoid and 7-exomethylene forms were observed for 7-CH3 substituted pterins 8 & 10 as 10% and 50%, respectively, of quinonoid. In base, for 7-unsubstituted pterins 9 & 11 only the intramolecular ether forms were observed, while for the 7-CH3 substituted pterins 8 & 10 two anion forms, the 7-exo-methylene and intramolecular ether, were observed in the ratio 2:1. Investigation of the distinctive proton-resonance pattern of the ethanomoiety of the intramolecular ether anion of 9 using 600 MHz NMR and spectrum simulation, indicated all four protons have different chemical environments. One conformation of the cyclic-ether ring satisfying the experimental data has been deduced, and the conformational energetics of the ring studied further using AM1 semiempirical quantum chemical calculations. Structural distributions of 8-methylpterins 12-15 were also studied in base only. These showed the 7-unsubstituted pterins 13 & 15 existed solely as the hydrated anion forms, while the 7-CH3 substituted pterins 12 & 14 existed predominantly as the 7-exo-methylene anions. Spectroscopic investigations of the degradation processes of 8-(2-hydroxyethyl)pterins and 8-methylpterins in base indicated a complex pattern of oxidation, ring opening and elimination reactions as a function of time. Using authentic samples, the 7-oxo compounds 16 & 17 and ethanolamine were identified, and evidence for ring-opened forms was obtained by comparison with the relevant 2,5-diamino-6-alkyl-aminopyrimidin-4(3H)-ones 1 & 2. Characteristically different degradation pathways for 7-CH3 and 7-unsubstituted compounds were established.

Ethers, Cyclic↗
PubMed1997

Photoinduced hydroxylation of deoxyguanosine in DNA by pterins: sequence specificity and mechanism.

Pterin-sensitized DNA photodamage has been characterized by a DNA sequencing technique. Exposure of double-stranded DNA to 365-nm light in the presence of pterin, 6-carboxypterin, biopterin, neopterin, and folic acid produced sequence-specific DNA lesions, whereas photoinduced DNA lesions were not observed in the presence of xanthopterin or isoxanthopterin. The DNA photodamage induced by these pterin derivatives occurred specifically at the guanine located 5' to guanine. High-pressure liquid chromatography (HPLC) analysis revealed that the pterin-sensitized DNA photodamage was predominantly due to the formation of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG). The DNA photodamage with pterin was not enhanced in D2O, suggesting that lO2 is not the main active species. Electron spin resonance (ESR) spin destruction experiments demonstrated that the photoexcited pterins reacted specifically with dGMP to produce pterin anion radicals. In addition, the reactivities of the photoexcited pterin derivatives with dGMP were found to correlate well with their efficiencies of DNA photodamage induction. These results indicate that the photoexcited pterins specifically oxidize deoxyguanosine in DNA to produce 8-oxo-dG through an electron transfer reaction. With denatured single-stranded DNA, the extent of pterin-sensitized photodamage was decreased and the damage occurred at most guanine residues without specificity for those located 5' to guanine. The mechanism of pterin-induced sequence-specific guanine photodamage could be explained on the basis of a recent theoretical study [Sugiyama. H., & Saito, I. (1996) J. Am. Chem. Soc. 118, 7063-7068] concerning the ionization potentials of stacked dinucleotide base pairs. Sepiapterin, a model compound for the dihydropterins, induced similar sequence-specific photolesions in double-stranded DNA. However, DNA photodamage by sepiapterin was more extensive in the presence of Cu(II), and the sites of the photolesions were different from those induced in the absence of Cu(II). These data may provide a basis for the elucidation of the molecular mechanism of solar UV carcinogenesis.

Base Sequence↗
PubMed2000

Crystal structure and site-specific mutagenesis of pterin-bound human phenylalanine hydroxylase.

The crystal structure of the dimeric catalytic domain (residues 118-424) of human PheOH (hPheOH), cocrystallized with the oxidized form of the cofactor (7,8-dihydro-L-biopterin, BH(2)), has been determined at 2.0 A resolution. The pterin binds in the second coordination sphere of the catalytic iron (the C4a atom is 6.1 A away), and interacts through several hydrogen bonds to two water molecules coordinated to the iron, as well as to the main chain carbonyl oxygens of Ala322, Gly247, and Leu249 and the main chain amide of Leu249. Some important conformational changes are seen in the active site upon pterin binding. The loop between residues 245 and 250 moves in the direction of the iron, and thus allows for several important hydrogen bonds to the pterin ring to be formed. The pterin cofactor is in an ideal orientation for dioxygen to bind in a bridging position between the iron and the pterin. The pterin ring forms an aromatic pi-stacking interaction with Phe254, and Tyr325 contributes to the positioning of the pterin ring and its dihydroxypropyl side chain by hydrophobic interactions. Of particular interest in the hPheOH x BH(2) binary complex structure is the finding that Glu286 hydrogen bonds to one of the water molecules coordinated to the iron as well as to a water molecule which hydrogen bonds to N3 of the pterin ring. Site-specific mutations of Glu286 (E286A and E286Q), Phe254 (F254A and F254L), and Tyr325 (Y325F) have confirmed the important contribution of Glu286 and Phe254 to the normal positioning of the pterin cofactor and catalytic activity of hPheOH. Tyr325 also contributes to the correct positioning of the pterin, but has no direct function in the catalytic reaction, in agreement with the results obtained with rat TyrOH [Daubner, S. C., and Fitzpatrick, P. F. (1998) Biochemistry 37, 16440-16444]. Superposition of the binary hPheOH.BH(2) complex onto the crystal structure of the ligand-free rat PheOH (which contains the regulatory and catalytic domains) [Kobe, B., Jennings, I. G., House, C. M., Michell, B. J., Goodwill, K. E., Santarsiero, B. D., Stevens, R. C., Cotton, R. G. H., and Kemp, B. E. (1999) Nat. Struct. Biol. 6, 442-448] reveals that the C2'-hydroxyl group of BH(2) is sufficiently close to form hydrogen bonds to Ser23 in the regulatory domain. Similar interactions are seen with the hPheOH.adrenaline complex and Ser23. These interactions suggest a structural explanation for the specific regulatory properties of the dihydroxypropyl side chain of BH(4) (negative effector) in the full-length enzyme in terms of phosphorylation of Ser16 and activation by L-Phe.

Binding Sites↗
PubMed1990

Nutritional requirements of wild-type and folate transport-deficient Leishmania donovani for pterins and folates.

The nutritional requirements for folates and pterins were assessed for two strains of Leishmania donovani promastigotes, a wild-type (D1700) parental strain and a mutant derivative (MTXA5) which possesses a markedly diminished capacity to transport both [3H]folate and [3H]methotrexate (MTX). Both L. donovani strains have an absolute growth requirement for an exogenous pterin, since their proliferation could not be sustained in completely defined medium lacking either a pterin or a folate. Supplementation of the growth medium by many of a spectrum of folates and pterins could support growth of the wild-type cell line. Surprisingly, however, the MTXA5 strain could not thrive in folate-deficient medium fortified with any of the pterins that promoted wild-type cell division, including biopterin and neopterin. The relationship between the incapacity of MTXA5 cells to transport folate and methotrexate and their inability to multiply in folate-deficient medium supplemented with pterins was evaluated using genetic approaches. First, an independently generated MTX-resistant mutant, MTXB4, was isolated in 1 mM MTX. The phenotype of the MTXB4 cells was like that of MTXA5 cells since they were unable to transport [3H]MTX and [3H]folate or grow in folate-deficient medium supplemented with pterins. Second, three revertants of the MTXA5 cells were selected for their ability to grow in 1 microM biopterin. All three revertants had regained [3H]folate and [3H]MTX transport capability concomitant with growth sensitivity to methotrexate toxicity. These observations provide genetic evidence that the competence of L. donovani to transport [3H]folate and [3H]MTX and the capability of the organisms to utilize pterins as a nutritional factor are influenced by a common genetic locus.

Affinity Labels↗
PubMed1998

Crystal structure of tyrosine hydroxylase with bound cofactor analogue and iron at 2.3 A resolution: self-hydroxylation of Phe300 and the pterin-binding site.

TyrOH is a non-heme iron enzyme which uses molecular oxygen to hydroxylate tyrosine to form L-dihydroxyphenylalanine (L-DOPA), and tetrahydrobiopterin to form 4a-hydroxybiopterin, in the rate-limiting step of the catecholamine biosynthetic pathway. The 2.3 A crystal structure of the catalytic and tetramerization domains of rat tyrosine hydroxylase (TyrOH) in the presence of the cofactor analogue 7,8-dihydrobiopterin and iron shows the mode of pterin binding and the proximity of its hydroxylated 4a carbon to the required iron. The pterin binds on one face of the large active-site cleft, forming an aromatic pi-stacking interaction with Phe300. This phenylalanine residue of TyrOH is found to be hydroxylated in the meta position, most likely through an autocatalytic process, and to consequently form a hydrogen bond to the main-chain carbonyl of Gln310 which anchors Phe300 in the active site. The bound pterin forms hydrogen bonds from N-8 to the main-chain carbonyl of Leu295, from O-4 to Tyr371 and Glu376, from the C-1' OH to the main-chain amides of Leu294 and Leu295, and from the C-2' hydroxyl to an iron-coordinating water. The part of the pterin closest to the iron is the O-4 carbonyl oxygen at a distance of 3.6 A. The iron is 5.6 A from the pterin 4a carbon which is hydroxylated in the enzymatic reaction. No structural changes are observed between the pterin bound and the nonliganded enzyme. On the basis of these structures, molecular oxygen could bind in a bridging position optimally between the pterin C-4a and iron atom prior to substrate hydroxylation. This structure represents the first report of close interactions between pterin and iron in an enzyme active site.

Animals↗
PubMed1981

Urinary excretion levels of unconjugated pterins in cancer patients and normal individuals.

Urinary excretion levels of seven unconjugated pterins in healthy individuals and in cancer patients, most of whom were undergoing chemotherapy, were measured utilizing a newly developed high-pressure liquid chromatographic system. Excretion of pterins in the control group appears to be under strict metabolic control as the values obtained were confined within a small range. When the mean excretion levels in control subjects were compared with those in cancer patients, we found a significant increase in the excretion of xanthopterin, neopterin and pterin and a significant decrease in isoxanthopterin by cancer patients. Biopterin levels, on the other hand, were found only slightly but not significantly increased, whereas pterin-6-carboxylic acid and 6-hydroxymethylpterin were found to be excreted in approximately equal amounts in both groups. Urinary excretion levels of pterins were monitored for a period of nine months in a patient being treated with chemotherapy for metastatic ovarian carcinomatosis. We found that the excretion pattern of pterins appeared to correlate with the clinical status of the patient. These results indicate that a definite imbalance in pterin, and possibly folate metabolism, is associated with the presence of malignant diseases.

Adult↗
PubMed2001

Pterin interactions with distinct reductase activities of NO synthase.

Besides oxidizing L-arginine, neuronal NO synthase (NOS) NADPH-dependently reduces various electron acceptors, including cytochrome c and tetrazolium salts. The latter NADPH diaphorase reaction is used as a NOS-specific histochemical stain. Both reductase activities have been utilized to analyse electron transfer mechanisms within NOS. Basal L-arginine turnover by homodimeric NOS is enhanced by exogenous tetrahydrobiopterin, and the intra-subunit electron flow may include intermediate trihydrobiopterin. In the present work we have investigated the possible role of the tetrahydrobiopterin binding site of NOS in its reductase activities by examining the effects of anti-pterin type (PHS) NOS inhibitors. Although the type I anti-pterin, PHS-32, which does not affect basal dimeric NOS activity, also had no effect on either reductase activity, the type II anti-pterin, PHS-72, which inhibits basal NOS activity, inhibited both reductase activities and the NADPH diaphorase histochemical stain. Pterin-free NOS monomers catalysed both cytochrome c and tetrazolium salt reduction. Our data suggest that both NOS reductase activities are independent of tetrahydrobiopterin. However, occupation of an exosite near the pterin site in NOS by type II anti-pterins may interfere with the electron flow within the active centre, suggesting that steric perturbation of the pterin binding pocket or reductase interaction contribute to the mechanism of inhibition by this class of NOS inhibitors.

Biopterins↗
PubMed1993

Induction of pterin synthesis is not required for cytokine-stimulated tryptophan metabolism.

Activation of the immune system which occurs in inflammatory disease leads to parallel increases in pterin synthesis and increased production of neuroactive L-tryptophan metabolites. Several model systems were studied to determine whether pterins, which are cofactors for hydroxylation reactions, could be required in the oxidative kynurenine pathway of L-tryptophan degradation. Treatment of mice with interferon-gamma increased L-tryptophan metabolism without any corresponding change in tissue biopterin concentrations. Cytokine-treated human fibroblasts, macrophages and glioblastoma cells all showed increases in kynurenine production, which were completely independent of pterin synthesis. When pterin synthesis de novo was blocked, either by an inhibitor of GTP cyclohydrolase or because of a genetic deficiency of one of the enzymes of the pathway of pterin biosynthesis, cytokine-stimulated increases in tryptophan metabolism were unaffected. Furthermore, increasing intracellular tetrahydrobiopterin concentrations by treating cells with sepia-pterin also had no effect on markers of tryptophan metabolism. Therefore, both normal and cytokine-stimulated L-tryptophan metabolism appears to be completely independent of pterin biosynthesis.

Animals↗
PubMed2001

Reconstitution of pterin-free inducible nitric-oxide synthase.

Inducible nitric-oxide synthase (NOS) was expressed and purified in the absence of 6(R)-tetrahydro-l-biopterin (H(4)B). Pterin-free NOS exhibits a Soret band (416-420 nm) characteristic of predominantly low spin heme and does not catalyze the formation of nitric oxide (. NO) (Rusche, K. M., Spiering, M. M., and Marletta, M. A. (1998) Biochemistry 37, 15503-15512). Reconstitution of pterin-free NOS with H(4)B was monitored by a shift in the Soret band to 396-400 nm, the recovery of.NO-forming activity, and the measurement of H(4)B bound to the enzyme. As assessed by these properties, H(4)B binding was not rapid and required the presence of a reduced thiol. Spectral changes and recovery of activity were incomplete in the absence of reduced thiol. Full reconstitution of holoenzyme activity and stoichiometric H(4)B binding was achieved in the presence of 5 mm glutathione (GSH). Preincubation with GSH before the addition of H(4)B decreased, whereas lower concentrations of GSH extended, the time required for reconstitution. Six protected cysteine residues in pterin-free NOS were identified by labeling of NOS with cysteine-directed reagents before and after reduction with GSH. Heme and metal content of pterin-free and H(4)B-reconstituted NOS were also measured and were found to be independent of H(4)B content. Additionally, pterin-free NOS was reconstituted with 6-methylpterin analogs, including redox-stable deazapterins. Reconstitution with the redox-stable pterin analogs was neither time- nor thiol-dependent. Apparent binding constants were determined for the 6-methyl- (50 microm) and 6-ethoxymethyl (200 microm) deazapterins. The redox-stable pterin analogs appear to bind to NOS in a different manner than H(4)B.

Animals↗