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At least 109 records · Page 6Linked to original sources
PubMed2003

Cerebrospinal fluid pterins and folates in Aicardi-Goutières syndrome: a new phenotype.

OBJECTIVE: To describe three unrelated children with a distinctive variant of Aicardi-Goutières syndrome (AGS) characterized by microcephaly, severe mental and motor retardation, dyskinesia or spasticity, and occasional seizures. RESULTS: Neuroimaging showed bilateral calcification of basal ganglia and white matter. CSF glucose, protein, cell count, and interferon alpha were normal. Abnormal CSF findings included extremely high neopterin (293 to 814 nmol/L; normal 12 to 30 nmol/L) and biopterin (226 to 416 nmol/L; normal 15 to 40 nmol/L) combined with lowered 5-methyltetrahydrofolate (23 to 48 nmol/L; normal 64 to 182 nmol/L) concentrations in two patients. The absence of pleocytosis and normal CSF interferon alpha was a characteristic finding compared to the classic AGS syndrome. Genetic and enzymatic tests excluded disorders of tetrahydrobiopterin metabolism, including mutation analysis of GTP cyclohydrolase feed-back regulatory protein. CSF investigations in three patients with classic AGS also showed increased pterins and partially lowered folate levels. CONCLUSIONS: Intrathecal overproduction of pterins is the first biochemical abnormality identified in patients with AGS variants. Long-term substitution with folinic acid (2-4 mg/kg/day) resulted in substantial clinical recovery with normalization of CSF folates and pterins in one patient and clinical improvement in another. The underlying defect remains unknown.

Basal Ganglia↗
PubMed2004

Stability of the heme environment of the nitric oxide synthase from Staphylococcus aureus in the absence of pterin cofactor.

We have used resonance Raman spectroscopy to probe the heme environment of a recently discovered NOS from the pathogenic bacterium Staphylococcus aureus, named SANOS. We detect two forms of the CO complex in the absence of L-arginine, with nu(Fe-CO) at 482 and 497 cm(-1) and nu(C-O) at 1949 and 1930 cm(-1), respectively. Similarly to mammalian NOS, the binding of L-arginine to SANOS caused the formation of a single CO complex with nu(Fe-CO) and nu(C-O) frequencies at 504 and 1,917 cm(-1), respectively, indicating that L-arginine induced an electrostatic/steric effect on the CO molecule. The addition of pterins to CO-bound SANOS modified the resonance Raman spectra only when they were added in combination with L-arginine. We found that (6R) 5,6,7,8 tetra-hydro-L-biopterin and tetrahydrofolate were not required for the stability of the reduced protein, which is 5-coordinate, and of the CO complex, which does not change with time to a form with a Soret band at 420 nm that is indicative of a change of the heme proximal coordination. Since SANOS is stable in the absence of added pterin, it suggests that the role of the pterin cofactor in the bacterial NOS may be limited to electron/proton transfer required for catalysis and may not involve maintaining the structural integrity of the protein as is the case for mammalian NOS.

Amino Acid Sequence↗
PubMed1985

The enzymatic conversion of dihydroneopterin triphosphate to tripolyphosphate and 6-pyruvoyl-tetrahydropterin, an intermediate in the biosynthesis of other pterins in Drosophila melanogaster.

The enzyme, previously called "sepiapterin synthase A," has been purified by approximately 700-fold from the heads of Drosophila melanogaster. This enzyme catalyzes the Mg2+-dependent conversion of 2-amino-4-oxo-6-(D-erythro-1',2',3'-trihydroxypropyl)-7,8-dihydrop teridine triphosphate (dihydroneopterin triphosphate or H2-NTP) to two products, one of which we have identified as tripolyphosphate. The other product is a phosphate-free, unstable compound which is an intermediate in the biosynthesis of several other naturally occurring pterins in Drosophila. This product is stable enough under anaerobic conditions to allow it to be characterized as 6-pyruvoyl-5,6,7,8-tetrahydropterin (6-pyruvoyl-H4-pterin). The 3-carbon side chain was identified as a pyruvoyl group on the basis of the susceptibility of the enzymatic product to reduction with tritiated sodium borohydride and the determination of the amounts and the sites of incorporation of tritium resulting from this reduction. From these observations, we suggest that this enzyme be renamed "6-pyruvoyl-H4-pterin synthase."

Alcohol Oxidoreductases↗
PubMed1980

Excretion of pterins in phenylketonuria and phenylketonuria variants.

Total urinary biopterin (B), neopterin (Ne) and monapterin (M) were measured in 25 healthy newborns, children and adults, in 49 patients with phenylketonuria (PKU) assumed to be deficient in phenylalanine-4-hydroxylase (PH), in 7 patients with dihydrobiopterin synthetase (DHBS) deficiency and in 4 patients with dihydropteridine reductase (DHPR) deficiency. Excretion of Ne based on creatinine (Ne/C) was 6.6 times higher in healthy newborns than in adults, suggesting a slow maturation of DHBS activity. Newborns excreted more Ne than B and adults more B than Ne (32 and 72% B of the sum of B + Ne, respectively). In all cases, excretion of M was 4-15% of that of Ne. PH deficient patients excreted more B and Ne than healthy controls and again, newborns more than older children. In individual patients, excretion of pterins correlated with phenylalanine (Phe) concentration in plasma; plasma Phe of different patients did not correlate well with excretion of pterins. In PKU variants with deficiency of tetrahydrobiopterin (BH4), extreme pterin patterns were observed: in DHBS- and DHPR-deficient patients, less than 3.5 and more than 81% B were found, respectively. All 30 samples from these patients investigated could be distinguished from those of PH-deficient patients and controls by a two-dimensional plot of % B versus B/C. Thus it seems likely that PKU variants due to BH4 deficiency could be detected early and differentiated by measurement of urinary B, Ne and C. This was exemplified already in one case. - In urine of patients with DHBS deficiency, high concentrations of 3'-hydroxysepiapterin were found in addition to Ne.

Adolescent↗
PubMed1994

Changes in folate and pterin metabolism after disruption of the Leishmania H locus short chain dehydrogenase gene.

The short chain dehydrogenase gene ltdh, which is derived from the H locus of Leishmania, confers high level resistance to the dihydrofolate reductase inhibitor methotrexate via a novel mechanism. Resistance is correlated with LTDH overproduction. High level resistance of ltdh transfectants was observed even in poor media where reduced folates are essential for the synthesis of thymidylate precursors. The ltdh transfectants were also capable of growing for several passages, at slightly reduced rates, in unsupplemented folate-deficient medium (fdDME-L), unlike the wild-type cells that could grow only in fdDME-L if supplemented with various folates or pterins. An homozygous ltdh mutant was obtained by gene targeting. This mutant became hypersensitive to methotrexate, but unlike wild-type cells, methotrexate toxicity could not be circumvented by the addition of thymidine. Although the homozygous mutant was capable of growing in fdDME-L supplemented with folate derivatives, it lost its ability to thrive in fdDME-L supplemented with pterins. Our results support the model in which LTDH is a key enzyme responsible for the conversion of a pterin derivative into an essential cofactor. This essential cofactor can also be converted into reduced folates at sufficient levels for growth when LTDH is overproduced, rendering dihydrofolate reductase dispensable. The novelty and uniqueness of LTDH opens the possibility of developing parasite-specific inhibitors.

Animals↗
PubMed2001

Electrochemistry of pterin cofactors and inhibitors of nitric oxide synthase.

Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthase (NOS), but its function is not fully understood. Specifically, it is unclear whether BH4 participates directly in electron transfer. We investigated the redox properties of BH4 and several other pteridines with cyclic voltammetry and Osteryoung square wave voltammetry. BH4 was oxidized at a potential of +0.27 V vs normal hydrogen electrode (NHE); the corresponding reductive signal after the reversal of the scan direction was very small. Instead, reduction occurred at a potential of -0.16 V vs NHE; there was no corresponding oxidative signal. These two transitions were interdependent, indicating that the reductive wave at -0.16 V represented the regeneration of BH4 from its product of oxidation at +0.27 V. Similar voltammograms were obtained with tetrahydroneopterin and 6,7-dimethyltetrahydropterin, both of which can substitute for BH4 in NOS catalysis. Completely different voltammograms were obtained with 7,8-dihydrobiopterin, sepiapterin, 2'-deoxysepiapterin, and autoxidized BH4. These 7,8-dihydropterins, which do not sustain NOS catalysis, were oxidized at much higher potentials (+0.82-1.04 V vs NHE), and appreciable reduction did not occur between +1.2 and -0.8 V, in line with the concept of a redox role for BH4 in NOS catalysis. However, the electrochemical properties of the potent pterin-site NOS inhibitor 4-amino-BH4 resembled those of BH4, whereas the active pterin cofactor 5-methyl-BH4 was not re-reduced after oxidation. We conclude that the 2-electron redox cycling of the pterin cofactor between BH4 and quinonoid dihydrobiopterin is not essential for NO synthesis. The data are consistent with 1-electron redox cycling between BH4 and the trihydrobiopterin radical BH3(*).

Antioxidants↗
PubMed2003

Studies on the regulatory properties of the pterin cofactor and dopamine bound at the active site of human phenylalanine hydroxylase.

The catalytic activity of phenylalanine hydroxylase (PAH, phenylalanine 4-monooxygenase EC 1.14.16.1) is regulated by three main mechanisms, i.e. substrate (l-phenylalanine, L-Phe) activation, pterin cofactor inhibition and phosphorylation of a single serine (Ser16) residue. To address the molecular basis for the inhibition by the natural cofactor (6R)-l-erythro-5,6,7,8-tetrahydrobiopterin, its effects on the recombinant tetrameric human enzyme (wt-hPAH) was studied using three different conformational probes, i.e. the limited proteolysis by trypsin, the reversible global conformational transition (hysteresis) triggered by L-Phe binding, as measured in real time by surface plasmon resonance analysis, and the rate of phosphorylation of Ser16 by cAMP-dependent protein kinase. Comparison of the inhibitory properties of the natural cofactor with the available three-dimensional crystal structure information on the ligand-free, the binary and the ternary complexes, have provided important clues concerning the molecular mechanism for the negative modulatory effects. In the binary complex, the binding of the cofactor at the active site results in the formation of stabilizing hydrogen bonds between the dihydroxypropyl side-chain and the carbonyl oxygen of Ser23 in the autoregulatory sequence. L-Phe binding triggers local as well as global conformational changes of the protomer resulting in a displacement of the cofactor bound at the active site by 2.6 A (mean distance) in the direction of the iron and Glu286 which causes a loss of the stabilizing hydrogen bonds present in the binary complex and thereby a complete reversal of the pterin cofactor as a negative effector. The negative modulatory properties of the inhibitor dopamine, bound by bidentate coordination to the active site iron, is explained by a similar molecular mechanism including its reversal by substrate binding. Although the pterin cofactor and the substrate bind at distinctly different sites, the local conformational changes imposed by their binding at the active site have a mutual effect on their respective binding affinities.

Binding Sites↗
PubMed1998

Pterins in human hair follicle cells and in the synchronized murine hair cycle.

Human dermal papilla cells (HDPC) express mRNA for the key enzymes for de novo synthesis/recycling and regulation of the pterin (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (6BH4). HDPC had significantly higher enzyme activities and 6BH4 levels in a comparative study with dermal fibroblasts, epidermal melanocytes, and keratinocytes under in vitro conditions. In addition, a significantly more rapid uptake of 14C-L-phenylalanine was demonstrated in HDPC compared with fibroblasts, whereas the differences in turnover to L-tyrosine were insignificant, suggesting a pooling of L-phenylalanine in HDPC. These results suggested that HDPC driven 6BH4 synthesis could be of major functional importance in the hair cycle. In order to follow this hypothesis in vivo, expression of enzyme activities and levels of the produced cofactor during the synchronized hair cycle were determined employing the murine model C57BL/6. These data revealed a significantly increased de novo synthesis for 6BH4 via GTP-cyclohydrolase I concomitant with high levels of 6BH4, and the induction of phenylalanine hydroxylase activities during the telogen/early anagen stage (days 0-1). Pterin levels and enzyme activities fall on day 3 and plateau during the rest of the entire cycle. In addition, thioredoxin reductase and glutathione reductase activities were measured, where the latter enzyme remained constant but thioredoxin reductase activities showed a biphasic behavior. The first peak coincided with the induction of 6BH4 de novo synthesis at the beginning of the hair cycle. The second peak was observed at mid-anagen, when melanogenesis takes place. Taken together, our results show the presence of autocrine pterin synthesis/recycling in human hair follicle cells under in vitro conditions, and a possible role for 6BH4 in the synchronized murine hair cycle.

Animals↗
PubMed1990

Dictyopterin, 6-(D-threo-1,2-dihydroxypropyl)-pterin, a new natural isomer of L-biopterin. Isolation from vegetative cells of Dictyostelium discoideum and identification.

A major pterin was isolated by reverse-phase high-performance liquid chromatography from cellular extract of vegetative cells of Dictyostelium discoideum after perchloric deproteinization and oxidation with acidic iodine. This compound was characterized by its chromatographic behavior, its absorption and fluorescence properties, by its oxidation product with alkaline permanganate, by secondary ion mass spectrometry and by circular dichroism. The final identification was obtained by comparison with authentic materials. It is concluded that the major pterin of D. discoideum is the compound 6-(D-threo-1,2-dihydroxypropyl)-pterin. The name dictyopterin is proposed for this new natural isomer of L-biopterin.

Biopterins↗
PubMed1996

Dimethylsulfide:acceptor oxidoreductase from Rhodobacter sulfidophilus. The purified enzyme contains b-type haem and a pterin molybdenum cofactor.

Dimethylsulfide:receptor oxidoreductase was purified from the purple non-sulfur phototrophic bacterium Rhodobacter sulfidophilus. The native form of the enzyme had a molecular mass of 152 kDa and was composed of three distinct subunits of 94, 38 and 32 kDa. Dimethylsulfide:acceptor oxidoreductase did not oxidise other thioethers which were tested. The enzyme was able to reduce a variety of N-oxides using reduced methylviologen as electron donor but it reduced dimethylsulfoxide at a very low rate. The resting form of dimethylsulfide:acceptor oxidoreductase exhibited a spectrum which was characteristic of a reduced cytochrome with absorbance maxima at 562 nm, 533 nm and 428 nm. Pyridine haemochrome analysis established that the cytochrome contained a b-type haem and a content of 0.65 mol protohaem/mol enzyme was determined. After oxidation of the haem with ferricyanide, the absorbance spectrum of the reduced cytochrome was restored by reduction with dimethylsulfide. Metal analysis revealed that dimethylsulfide:acceptor oxidoreductase contained 0.5 mol Mo and 3.5 mol Fe/mol enzyme. Heat treatment of the enzyme released material with fluorescence excitation and emission spectra which were characteristic of form B of the pterin component of the pterin molybdenum cofactor. From this analysis it is concluded that dimethylsulfide:acceptor oxidoreductase is a molybdenum oxotransferase which may also contain a iron-sulfur cluster. It is suggested that the haem and pterin molybdenum cofactor are associated with the 94-kDa subunit.

Chromatography↗
PubMed1998

Structure of nitric oxide synthase oxygenase dimer with pterin and substrate.

Crystal structures of the murine cytokine-inducible nitric oxide synthase oxygenase dimer with active-center water molecules, the substrate L-arginine (L-Arg), or product analog thiocitrulline reveal how dimerization, cofactor tetrahydrobiopterin, and L-Arg binding complete the catalytic center for synthesis of the essential biological signal and cytotoxin nitric oxide. Pterin binding refolds the central interface region, recruits new structural elements, creates a 30 angstrom deep active-center channel, and causes a 35 degrees helical tilt to expose a heme edge and the adjacent residue tryptophan-366 for likely reductase domain interactions and caveolin inhibition. Heme propionate interactions with pterin and L-Arg suggest that pterin has electronic influences on heme-bound oxygen. L-Arginine binds to glutamic acid-371 and stacks with heme in an otherwise hydrophobic pocket to aid activation of heme-bound oxygen by direct proton donation and thereby differentiate the two chemical steps of nitric oxide synthesis.

Animals↗
PubMed1986

Pterins in patients with Rett syndrome.

We have found normal concentrations of neopterin, monapterin, isoxanthopterin, biopterin and pterin in the urine of 10 patients with Rett syndrome, and normal values for total biopterin and neopterin in the blood of 4 subjects. Thus, there is no biochemical evidence of a generalized tetrahydrobiopterin deficiency in this syndrome. Since we had no opportunity so far to study cerebrospinal fluid, a defect in the metabolism of pterins in the central nervous system is not yet fully excluded.

Adolescent↗
PubMed2004

Photooxidation of pterin in aqueous solutions: biological and biomedical implications.

Studies of the photochemical reactivity of pterin (= 2-aminopteridin-4(3H)-one; PT) in acidic (pH 5.0-6.0) and alkaline (pH 10.2-10.8) aqueous solutions have been performed. The photochemical reactions were followed by UV/VIS spectrophotometry, thin layer chromatography (TLC), high-performance liquid chromatography (HPLC), and an enzymatic method for H2O2 determination. PT is not light-sensitive in the absence of molecular oxygen, but it undergoes photooxidation in the presence of O2, yielding several nonpteridinic products. The quantum yields for PT disappearance were found to be 8.2 (+/-0.6) x 10(-4) and 1.2 (+/-0.2) x 10(-3) in acidic and alkaline media, respectively. H2O2 was detected and quantified in irradiated solutions of PT; and its importance from a biomedical point of view is discussed. The rate constant of the chemical reaction between singlet oxygen ((1)O2) and PT was determined to be 2.5 (+/-0.2) x 10(5) l mol(-1) s(-1) in alkaline medium, and the role of (1)O2 in the photooxidation of pterin was evaluated.

Oxidation-Reduction↗
PubMed1999

The structural basis of the recognition of phenylalanine and pterin cofactors by phenylalanine hydroxylase: implications for the catalytic mechanism.

Phenylalanine hydroxylase (PAH) is a tetrahydrobiopterin and non-heme iron-dependent enzyme that hydroxylates L-Phe to l-Tyr using molecular oxygen as additional substrate. A dysfunction of this enzyme leads to phenylketonuria (PKU). The conformation and distances to the catalytic iron of both L-Phe and the cofactor analogue L-erythro-7,8-dihydrobiopterin (BH2) simultaneously bound to recombinant human PAH have been estimated by (1)H NMR. The resulting bound conformers of both ligands have been fitted into the crystal structure of the catalytic domain by molecular docking. In the docked structure L-Phe binds to the enzyme through interactions with Arg270, Ser349 and Trp326. The mode of coordination of Glu330 to the iron moiety seems to determine the amino acid substrate specificity in PAH and in the homologous enzyme tyrosine hydroxylase. The pterin ring of BH2 pi-stacks with Phe254, and the N3 and the amine group at C2 hydrogen bond with the carboxylic group of Glu286. The ring also establishes specific contacts with His264 and Leu249. The distance between the O4 atom of BH2 and the iron (2.6(+/-0.3) A) is compatible with coordination, a finding that is important for the understanding of the mechanism of the enzyme. The hydroxyl groups in the side-chain at C6 hydrogen bond with the carbonyl group of Ala322 and the hydroxyl group of Ser251, an interaction that seems to have implications for the regulation of the enzyme by substrate and cofactor. Some frequent mutations causing PKU are located at residues involved in substrate and cofactor binding. The sites for hydroxylation, C4 in L-Phe and C4a in the pterin are located at a distance of 4.2 and 4.3 A from the iron moiety, respectively, and at 6.3 A from each other. These distances are adequate for the intercalation of iron-coordinated molecular oxygen, in agreement with a mechanistic role of the iron moiety both in the binding and activation of dioxygen and in the hydroxylation reaction.

Boron Compounds↗
PubMed1993

Inter-relationships between pterins and cytokines produced during allogeneic immune reactions and possible use as early markers of immune activation.

The pterins neopterin and xanthopterin have been measured together with the cytokines IFN-gamma, TNF-alpha and TNF-beta in the supernatants of 20 allogeneic mixed lymphocyte reactions. We have calculated rank correlation coefficients between these analytes and the immune response. Our findings confirm that neopterin is a sensitive early marker of immune activation and show that another pterin, xanthopterin could be used likewise. Cytokine production was also proportional to immune activation but none could be used consistently as early markers of immune activation.

Biomarkers↗
PubMed1976

Correlation of guanosine triphosphate cyclohydrolase activity and the synthesis of pterins in Drosophila melanogaster.

The enzyme guanosine triphosphate cyclohydrolase (GTP cyclohydrolase), which in bacteria is known to be the first enzyme in the biosynthetic pathway for the synthesis of pteridines, has been discovered in extracts of Drosophila melanogaster. Most of the enzyme (80%) is located in the head of the adult fly. An analysis of enzyme activity during development in Drosophila has revealed the presence of a relatively small peak of activity at pupariation and a much larger peak that appears at about the time of eclosion. Enzyme activity declines radidly as the fly ages. Analysis for the production of the typical pteridine pigments of Drosophila have indicated that the small peak of GTP cyclohydrolase activity evident at pupariation coincides with the appearance of isoxanthopterin, sepiapterin, and pterin, and the larger peak at eclosion roughly corresponds to the accumulation of drospterin as well as to the appearence in larger amounts of pterin and sepiaterin. These observations strongly suggest that in Drosophila, like bacteria, GTP cyclohydrolase is involved in the biosynthesis of pteridines. Analyses of a variety of zeste mutants of Drosophila melanogaster have shown that these mutants all contain GTP cyclohydrolase equal approximately to the amount found in the wild-type fly. These observations do not support the suggestions made by Rasmusson et al. (1973) that zeste is the strucural locus for GTP cyclohydrolase.

Aminohydrolases↗
PubMed1981

Pterin metabolism in normal subjects and hyperphenylalaninaemic patients.

The application of high performance liquid chromatography to the estimation of urinary pterins is illustrated by results from normal subjects and from patients with phenylketonuria, dihydropteridine reductase deficiency and biopterin synthetase deficiency. In normal subjects following a phenylalanine load the is a temporary increase in pterin elimination, the pattern being different to that seen in chronic hyperphenylalaninaemia.

Adult↗
PubMed2002

Order of substrate binding in bacterial phenylalanine hydroxylase and its mechanistic implication for pterin-dependent oxygenases.

Phenylalanine hydroxylase (PAH) is a pterin-dependent non-heme metalloenzyme that catalyzes the oxidation of phenylalanine to tyrosine, which is the rate-limiting step in the catabolism of Phe. Chromobacterium violaceum phenylalanine hydroxylase (cPAH) has been prepared and its steady-state mechanism has been investigated. The enzyme requires iron for maximal activity. Initial rate measurements, done in the presence of the 6,7-dimethyl-5,6,7,8-tetrahydropterin (DMPH(4)) cofactor, yielded an average apparent k(cat) of 36+/-1 s(-1). The apparent K(M) values measured for the substrates DMPH(4), L-Phe, and O(2) are 44+/-7, 59+/-10, and 76+/-7 microM, respectively. Steady-state kinetic analyses using double-reciprocal plots revealed line patterns consistent with a sequential ter-bi mechanism in which L-Phe is the middle substrate in the order of binding. The occurrence of a line intersection on the double-reciprocal plot abscissa when either pterin or O(2) is saturated suggests that, prior to O(2) binding, DMPH(4) and L-Phe are in associative pre-equilibrium with cPAH. Together with an inhibition study using the oxidized cofactor, 7,8-dimethyl-6,7-dihydropterin, it is conclusive that the mechanism is fully ordered, with DMPH(4) binding the active site first, L-Phe second, and O(2) last. This represents the first conclusive steady-state mechanism for a PAH enzyme.

Binding Sites↗