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At least 739 records · Page 41Linked to original sources

PubMed1991

Genetic and biochemical characterization of little isoxanthopterin (lix), a gene controlling dihydropterin oxidase activity in Drosophila melanogaster.

Dihydropterin oxidase catalyses the oxidation of 7,8-dihydropteridines into their fully oxidized products, and is involved in the biosynthesis of isoxanthopterin. Fifteen Drosophila melanogaster mutants, selected for their low pterin and isoxanthopterin content, were assayed for dihydropterin oxidase activity. The activity was around 100% in most mutants tested, slightly reduced in red, g and dke, and undetectable in lix. In flies carrying various doses of the lix+ allele, a correlation was found between enzyme activity and the number of lix+ copies in the genome. The results suggest that lix is the structural gene for the dihydropterin oxidase enzyme. Isoxanthopterin was quantitated in strains carrying deficiencies for the region in which lix has been mapped by recombination. This allowed us to assign the lix locus to the 7D10-7F1-2 segment of the X chromosome.

Animals↗

PubMed1988

Report on a new patient with combined deficiencies of sulphite oxidase and xanthine dehydrogenase due to molybdenum cofactor deficiency.

A newborn infant exhibiting seizures and spastic tetraparesis at the age of 1 week was shown to excrete excessive quantities of sulphite, taurine, S-sulphocysteine and thiosulphate, characteristic of sulphite oxidase deficiency. In addition, increased renal excretion of xanthine and hypoxanthine combined with a low serum and urinary uric acid was consistent with xanthine dehydrogenase deficiency. Both deficiencies could be established at the enzyme level. The primary defect giving rise to the combined abnormalities is the absence of a molybdenum cofactor, a molybdenum-containing pterin being an essential component of both enzymes. The patient developed a severe neurological syndrome, brain atrophy and lens dislocation and died at the age of 22 months. Attempts at treatment, such as oral administration of ammonium molybdate, sodium sulphate, D-penicillamine, 2-mercaptoethane sulphonic acid, pyridoxine and thiamine did not influence the clinical course.

Abnormalities, Multiple↗

PubMed1984

Combined tetrahydrobiopterin-phenylalanine loading test in the detection of partially defective biopterin synthesis.

Deficiency in the synthesis of biopterin causes neonatal hyperphenylalaninemia. We report a 10-year-old girl of normal appearance with a partial defect in biopterin synthesis, normal intelligence and normal serum phenylalanine levels (95 mumol/l) (1.6 mg/dl). During her 1st year of life serum phenylalanine levels were 250 mumol/l (4 mg/dl) and phenylalanine loading performed at 6 months and 1 year of age was not followed by an increase in serum tyrosine. At 9 years of age she had developed a severely abnormal EEG with focal spike activity but no observable clinical abnormalities. Determination of urinary pterins showed abnormal low levels of biopterin and high levels of neopterin. Phenylalanine loading combined with oral administration of tetrahydrobiopterin (BH4) was followed by a normal increase in serum tyrosine and a normal decrease in serum phenylalanine. Considering the importance of BH4 for the synthesis of dopamine, catecholamines, and serotonin we suggest that these cases should be followed carefully. If neurological symptoms appear, e.g., epilepsy, it may be worthwhile to consider treatment with BH4 and neurotransmitter precursors.

Adolescent↗

PubMed1983

Dihydrobiopterin biosynthesis deficiency.

For the last 2 years, a program has been developed to screen all hyperphenylalaninemic babies for tetrahydrobiopterin deficiency, by measurement of pterins in urine. High neopterin and low biopterin levels were found in the urine of a 1-month-old girl. Further investigations confirmed an impaired conversion of neopterin to biopterin. No neurological signs were noted, but, in regard to the laboratory data, neurotransmitter replacement therapy was instituted at 2.5 months of age. The most remarkable feature was a rapid increase in the dietetic phenylalanine tolerance, despite the proof that the child was not able to clear a challenging dose of phenylalanine and the record of unchanged pathologically low excretion of biopterin during a 2 month period.

Biopterins↗

PubMed1992

Identification of two tungstate-sensitive molybdenum cofactor mutants, chl2 and chl7, of Arabidopsis thaliana.

The characterization of mutants that are resistant to the herbicide chlorate has greatly increased our understanding of the structure and function of the genes required for the assimilation of nitrate. Hundreds of chlorate-resistant mutants have been identified in plants, and almost all have been found to be defective in nitrate reduction due to mutations in either nitrate reductase (NR) structural genes or genes required for the synthesis of the NR cofactor molybdenum-pterin (MoCo). The cholorate-resistant mutant of Arabidopsis thaliana, chl2, is also impaired in nitrate reduction, but the defect responsible for this phenotype has yet to be explained. chl2 plants have low levels of NR activity, yet the map position of the chl2 mutation is clearly distinct from that of the two NR structural genes that have been identified in Arabidopsis. In addition, chl2 plants are not thought to be defective in MoCo, as they have near wild-type levels of xanthine dehydrogenase activity, which has been used as a measure of MoCo in other organisms. These results suggest that chl2 may be a NR regulatory mutant. We have examined chl2 plants and have found that they have as much NR (NIA2) mRNA as wild type a variable but often reduced level of NR protein, and one-eighth the NR activity of wild-type plants. It is difficult to explain these results by a simple regulatory model; therefore, we reexamined the MoCo levels in chl2 plants using a sensitive, specific assay for MoCo: complementation of Neurospora MoCo mutant extracts.(ABSTRACT TRUNCATED AT 250 WORDS)

Blotting, Northern↗

PubMed1989

The human tyrosine hydroxylase gene.

1. Tyrosine hydroxylase (TH) is a rate-limiting enzyme for catecholamine biosynthesis, and it is a pterin-requiring monooxygenase. Both cDNAs and genomic DNA of human TH have been cloned and the nucleotide sequence has been determined. 2. Four similar but distinct mRNAs encode human TH. The results of Southern blot analysis and the nucleotide sequence of the human TH genomic DAN indicate that the four types of human TH mRNA are produced through alternative splicing from a single gene. 3. The human TH gene was split into 4 exons and 13 introns. The 12-bp insertion sequence is encoded by the 3'-terminal portion of the first exon. The 81-bp insertion sequence corresponds to the second exon. Two kinds of alternative splicing are involved: the alternative use of two donor sites in the first exon and the inclusion/exclusion of the second exon. 4. The four types (type 1-4) were expressed in COS cells, and all had enzymatic activities. The type 1 enzyme had the highest homospecific activity (activity per enzyme protein), the values for the other enzymes ranging from 30 to 40%. The Km values of the four types for L-tyrosine and 6-methyl-5,6,7,8-tetrahydropterin were similar.

Base Sequence↗

PubMed1978

Characteristics of the activation by dithiothreitol and Fe(2+) of tryptophan hydroxylase from the rat brain.

The preincubation of tryptophan hydroxylase extracted from various areas of the central nervous system of the rat with 30 mM dithiothreitol and 50 muM ferrous ammonium sulfate under nitrogen atmosphere resulted in a persistent increase of its activity. Studies on the enzyme characteristics indicated that this activation was associated with a doubling in its Vmax and a shift (from 7.6 to 7.2) of the optimal pH for its activity. In contrast, the molecular weight and the apparent affinities of tryptophan hydroxylase for its pterin cofactor and for tryptophan were not significantly altered by the preincubation with dithiothreitol and ferrous ammonium sulfate. Since this treatment did not prevent the stimulatory effects of various compounds (phosphatidylserine, ATP and MG(2+), Ca(2+)) on tryptophan hydroxylase activity, this might be a good procedure to activate this enzyme with only minor changes in its regulatory properties.

Animals↗

PubMed1981

Biopterin. VII. Inhibition of synthesis of reduced biopterins and its bearing on the function of cerebral tryptophan-5-hydroxylase in vivo.

Repeated intraventricular injections of 2,4-diamino-6-hydroxypyrimidine (DAO-Pyr), inhibitor of D-erythro-q-dihydroneopterin triphosphate synthetase, inhibited q-BH2 synthesis from GTP, markedly increased accumulation of 2-amino-4-hydroxy-5 (or -6)-formamido-6-triphosphoribosylaminopyrimidine (FPyd-P3) and brought about a 60% decrease in the in vivo of reduced biopterin (BH2 and BH4) pool in the brain. Nevertheless, there was no effect on the rate of hydroxylation of L-tryptophan or on the 5-hydroxytryptamine level in rat brain. These data emphasized the significance of the rate of hydrogen transfer and the limitation of the concept of "unsaturation" (i.e., the absolute amount of the carrier pterin molecule) for the synthesis of neurotransmitters in vivo.

Animals↗

PubMed1991

Identification of a mammalian growth factor as a ribofolate peptide.

Thymocyte growth peptide (TGP) promotes DNA synthesis of immature thymocytes. TGP has been purified from sheep, human and calf thymus and recently characterized as an N-terminally blocked nonapeptide. Evidence is presented here that the blocking moiety consists of a formylpteroyl group bound to the N-terminal glutamyl residue of the nonapeptide. The pterin part of the TGP molecule has a ribityl substituent in analogy with riboflavin, which explains the pronounced hydrophilic property of TGP in contrast to unsubstituted and unconjugated folates. The compound can be classified as a ribofolate peptide, a novel class of growth factor. Zn2+ counteracts degradation of the molecule and is required for full biological activity; mass spectrometric data confirm that native TGP contains zinc.

Amino Acid Sequence↗

PubMed1982

Changes in the circadian rhythmicity of hydroxyindole-O-methyl transferase (HIOMT) activity in the synthesis of 5-methoxyindoles in the pineal gland of 28 day old male Wistar rats exposed to white, red and green light.

Hydroxyindole-O-methyl transferase activity for the synthesis of 5-methoxyindoles was investigated in the pineal gland of 28 day old male Wistar rats after exposure to white, red and green light for 12 hours daily. It could be demonstrated that, in comparison to white light, red light causes a shift of HIOMT activity for the synthesis of melatonin/5-methoxytryptophol towards an earlier period being highest between 12 and 16 hours. The synthesis of 5-methoxytryptamine and of 5-methoxytryptophan is shifted to 16 hours, while the synthesis of 5-methoxyindole-3-acetic acid, which normally peaks at 16 hours, is increased at this same hour. Green light shifts HIOMT activity for the synthesis of melatonin/5-method being highest between 12 and 16 hours. The synthesis of 5-methoxytryptamine and of 5-methoxytryptophan is shifted to 16 hours, while the synthesis of 5-methoxyindole-3-acetic acid, which normally peaks at 16 hours, is increased at this same hour. Green light shifts HIOMT activity for the synthesis of melatonin/5-method being highest between 12 and 16 hours. The synthesis of 5-methoxytryptamine and of 5-methoxytryptophan is shifted to 16 hours, while the synthesis of 5-methoxyindole-3-acetic acid, which normally peaks at 16 hours, is increased at this same hour. Green light shifts HIOMT activity for the synthesis of melatonin/5-methoxytryptophol to a later period, showing a peak at 24 hours. The synthesis of 5-methoxytryptamine is significantly increased at 24 hours. An increase is also observed in the synthesis of 5-methoxyindole-3-acetic acid at 12 and at 4 hours, times at which this synthesis is also maximal using white light, whereas the synthesis of 5-methoxytryptophan is generally decreased. A possible relationship between the present results and those obtained after exposure to different wavelengths of light on N-acetyltransferase activity, the effect of pterins on HIOMT activity and the effect of different wavelengths on gonadal growth are discussed.

5-Methoxytryptamine↗

PubMed1981

Changes in the circadian rhythmicity of N- and O-acetyltransferase activities in the pineal gland of 38 day old male wistar rats when examined under white, red and green light.

N-acetyltransferase activity was quantified in the pineal gland of 38 day-old male Wistar rats under different experimental conditions. Under daily white light/dark photoperiods (12 L : 12 D), N-acetyltransferase activity showed a peak of activity at midnight for the synthesis of both N-acetylserotonin and melatonin. Using red light instead of white light a shift of the enzyme activity involved in the production of both compounds towards the preceding light period was observed. Using green light instead of white light the enzyme activity shifted to later periods. Under white light/dark conditions pineal O-acetyltransferase activity when quantified was maximal during the early hours of the night. With periodic red light this maximal activity was extended over a longer period including late hours of the preceding day and later hours of the night. Periodic illumination with green light caused a peak of activity at midnight and an increase of activity at then end of the dark period. A possible relationship between previous results obtained on the influence of pterins on HIOMT activity and the effects of light on reproduction is discussed.

Acetyltransferases↗

PubMed1987

Assignment of human tryptophan hydroxylase locus to chromosome 11: gene duplication and translocation in evolution of aromatic amino acid hydroxylases.

A cDNA clone for rabbit tryptophan hydroxylase was used as a probe to identify human tryptophan hydroxylase gene fragments in a panel of hamster-human somatic cell hybrids and determine its chromosomal location in man. A single locus was identified for tryptophan hydroxylase on chromosome 11. Tryptophan hydroxylase is a member of the superfamily of pterin-dependent aromatic amino acid hydroxylases which includes tyrosine hydroxylase, located at 11p15.5-p15, and phenylalanine hydroxylase, located at 12q22-q24.1 in human. The locations of these genes and the evolutionary distance between their sequences suggest that at least three distinct genetic events have occurred during the evolution of the aromatic amino acid hydroxylase superfamily: two sequential gene duplications giving rise to the three distinct hydroxylase loci, and a translocation which separated the tryptophan and tyrosine hydroxylase loci on chromosome 11 from the phenylalanine hydroxylase locus on chromosome 12.

Animals↗

PubMed1985

Hyperphenylalaninaemia caused by defects in biopterin metabolism.

The hepatic phenylalanine hydroxylating system consists of three essential components, phenylalanine hydroxylase, dihydropteridine reductase and the non-protein coenzyme, tetrahydrobiopterin. The reductase and the pterin coenzyme are also essential components of the tyrosine and tryptophan hydroxylating systems. Recent studies have shown that there are three distinct forms of phenylketonuria or hyperphenylalaninaemia, each caused by the lack of one of these essential components. The variant forms of the disease that are caused by the lack of dihydropteridine reductase or tetrahydrobiopterin are characterized by severe neurological deterioration, impaired functioning of tyrosine and tryptophan hydroxylases and the resultant deficiency of tyrosine- and tryptophan-derived monoamine neurotransmitters in brain.

Amino Acid Metabolism, Inborn Errors↗

PubMed1986

A model for hyperphenylalaninaemia due to tetrahydrobiopterin deficiency.

A model for tetrahydrobiopterin deficiency in mice is described. Elevated levels of phenylalanine produced in the model were shown to be dramatically reduced after injection of tetrahydrobiopterin. A comparison of several reduced pterins for their efficacy in the system is described. The unnatural S isomer of tetrahydrobiopterin was shown to be active in the system.

Animals↗

PubMed1993

Correlation of interleukin-2 receptor and neopterin secretion in rheumatoid arthritis.

In rheumatoid arthritis (RA) an immuno dysregulation alters the release of neopterin from human monocytes/macrophages, probably by activation of a feed-back regulation mechanism in pterin metabolism. With the overactivation of T-lymphocytes, the secretion of interleukin-2 and its receptor (IL-2R) is influenced. Investigation on 84 RA patients has shown that this immunoactivation is accompanied by an increased secretion of neopterin and soluble IL-2R in the serum, and that both parameters are very suitable for detection of inflammatory disease activity. The significant correlation between neopterin and IL-2R (r = 0.65; p < or = 0.001) in RA points out a possible connection in pathomechanisms of the immune system.

Adult↗

PubMed1992

The screening diagnosis of tetrahydrobiopterin deficient phenylketonuria.

Since 1990, 20 diagnostically confirmed phenylketonuria (PKU) patients have been screened with a tetrahydrobiopterin (BH4) loading test, in which plasma phenylalanine and urinary pterin metabolites were investigated, ind activity of dihydropteridine reductase (DHPR) was determined as well. The results showed that there was no statistical difference between the concentrations of plasma phenylalanine before and after BH4 (20mg/kg) administration in all patients, and values of urinary neopterin and biopterin were within the range of classic PKU. All patients but one had normal activity of DHPR in red cells. This suggests that incidence of BH4 deficiency in PKU patients amounts to five percent (1/20) which is almost the same as reported abroad.

Biopterins↗

PubMed1998

Purification and characterization of GTP cyclohydrolase I from Streptomyces tubercidicus, a producer of tubercidin.

GTP cyclohydrolase I catalyzing the first reaction in the biosynthesis of pterin moiety of folic acid in bacteria, was purified from Streptomyces tubercidicus by at least 203-fold with a yield of 32% to apparent homogeneity, using ammonium sulfate fractionation, DEAE-cellulose, Sepharose CL-6B, and hydroxylapatite column chromatography. The molecular weight of the native enzyme was estimated to be 230,000 daltons by gel permeation chromatography. The purified enzyme gave a single band on sodium dodesyl sulfate-polyacrylamide gel electrophoresis and its molecular weight was apparently 58,000 daltons. These results indicate that the enzyme consists of four subunits with the same molecular weight. The K(m) and Vmax values for GTP of the purified enzyme were determined to be 80 microM and 90 nmol/min (mg protein), respectively. The optimum pH and temperature for the enzyme reaction were pH 7.5-8.5 and 40-42 degrees C, respectively. Coenzyme or metal ion was not required for the enzyme activity. The enzyme activity was inhibited by most divalent cations, while it was slightly activated by potassium ion. In case of nucleotides, CTP, GMP, GDP, and UTP inhibited enzyme activity, among which GDP exhibited the strongest inhibitory effect.

Anti-Bacterial Agents↗

PubMed2005

Molybdenum cofactor biosynthesis and deficiency.

The molybdenum cofactor (Moco) forms the active site of all molybdenum (Mo) enzymes, except nitrogenase. Mo enzymes catalyze important redox reactions in global metabolic cycles. Moco consists of Mo covalently bound to one or two dithiolates attached to a unique tricyclic pterin moiety commonly referred to as molybdopterin (MPT). Moco is synthesized by an ancient and conserved biosynthetic pathway that can be divided into four steps, according to the biosynthetic intermediates precursor Z (cyclic pyranopterin monophosphate), MPT and adenylated MPT. In a fifth step modifications such as attachment of nucleotides, sulfuration or bond formation between Mo and the protein result in different catalytic Mo centers. A defect in any of the steps of Moco biosynthesis results in the pleiotropic loss of all Mo enzyme activities. Human Moco deficiency is a hereditary metabolic disorder characterized by severe neurodegeneration resulting in early childhood death. Recently, a first substitution therapy was established.

Animals↗