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At least 523 records · Page 29Linked to original sources
PubMed1999

X-ray crystallographic analysis of the structural basis for the interactions of pokeweed antiviral protein with its active site inhibitor and ribosomal RNA substrate analogs.

The pokeweed antiviral protein (PAP) belongs to a family of ribosome-inactivating proteins (RIP), which depurinate ribosomal RNA through their site-specific N-glycosidase activity. We report low temperature, three-dimensional structures of PAP co-crystallized with adenyl-guanosine (ApG) and adenyl-cytosine-cytosine (ApCpC). Crystal structures of 2.0-2.1 A resolution revealed that both ApG or ApCpC nucleotides are cleaved by PAP, leaving only the adenine base clearly visible in the active site pocket of PAP. ApCpC does not resemble any known natural substrate for any ribosome-inactivating proteins and its cleavage by PAP provides unprecedented evidence for a broad spectrum N-glycosidase activity of PAP toward adenine-containing single stranded RNA. We also report the analysis of a 2.1 A crystal structure of PAP complexed with the RIP inhibitor pteoric acid. The pterin ring is strongly bound in the active site, forming four hydrogen bonds with active site residues and one hydrogen bond with the coordinated water molecule. The second 180 degrees rotation conformation of pterin ring can form only three hydrogen bonds in the active site and is less energetically favorable. The benzoate moiety is parallel to the protein surface of PAP and forms only one hydrogen bond with the guanido group of Arg135.

Binding Sites↗
PubMed1994

Multiple states of the molybdenum centre of dimethylsulphoxide reductase from Rhodobacter capsulatus revealed by EPR spectroscopy.

The dimethylsulphoxide reductase of Rhodobacter capsulatus contains a pterin molybdenum cofactor molecule as its only prosthetic group. Kinetic studies were consistent with re-oxidation of the enzyme being rate limiting in the turnover of dimethylsulphoxide in the presence of the benzyl viologen radical. EPR spectra of molybdenum(V) were generated by reducing the highly purified enzyme under a variety of conditions, and with careful control it was possible to generate at least five clearly distinct EPR signals. These could be simulated, indicating that each corresponds to a single chemical species. Structures of the signal-giving species are discussed in light of the EPR parameters and of information from the literature. Three of the signals show coupling of molybdenum to an exchangeable proton and, in the corresponding species, the metal is presumed to bear a hydroxyl ligand. One signal with gav 1.96 shows a very strong similarity to a signal for the desulpho form of xanthine oxidase, while two others with gav values of 1.98 show a distinct similarity to signals from nitrate reductase of Escherichia coli. These data indicate an unusual flexibility in the active site of dimethylsulphoxide reductase, as well as emphasising structural similarities between molybdenum enzymes bearing different forms of the pterin cofactor. Interchange among the different species must involve either a change of coordination geometry, a ligand exchange, or both. The latter may involve replacement of an amino acid residue co-ordinating molybdenum via O or N, for a cysteine co-ordinating via S. Since the two signals with gav 1.96 were obtained only under specific conditions of reduction of the enzyme by dithionite, it is postulated that their generation may be triggered by reduction of the pteridine of the molybdenum cofactor from a dihydro state to the tetrahydro state.

Binding Sites↗
PubMed1978

Inactivation of the chemoattractant folic acid by cellular slime molds and identification of the reaction product.

Enzymes inactivating the chemoattractants folic acid and pterin were detected in extracellular, intracellular, and particulate fractions obtained from Dictyostelium discoideum strains NC4 and AX-2 and Polysphondylium violaceum. The products of the inactivation reaction were analyzed by thin-layer chromatography and UV spectroscopy. Results obtained indicate that folic acid and pterin were deaminated to 2-deamino folic acid and lumazine, respectively.

Aminohydrolases↗
PubMed1987

In vitro system for molybdopterin biosynthesis.

A high-Mr fraction present in chl+ and chlA1 strains of Escherichia coli synthesizes molybdopterin (MPT) from the low-Mr fraction of several MPT-deficient mutants. Using this in vitro complementation as an assay, we have partially characterized the high-Mr fraction as a protein, termed MPT converting factor, of Mr 45,000, distinguishable from the Mo cofactor carrier protein of similar Mr by its absolute requirement for the low-Mr fraction of a non-chlA1 mutant in the nit-1 reconstitution assay. MPT converting factor was rapidly inactivated in the absence of a reduced sulfhydryl compound. Anaerobic incubation of MPT converting factor with trypsin destroyed its activity. High-performance liquid chromatographic analysis of alkaline KMnO4 oxidation products demonstrated that the factor did not contain any bound pterin. Since mutants lacking MPT converting factor are not auxotrophs for folate or riboflavin, the factor appears to be distinct from known pteridine biosynthetic enzymes in E. coli. We have partially purified and characterized the low-Mr fractions as probable MPT precursors. Several distinct precursors were separable by high-performance liquid chromatography. Like MPT activity, precursor activity was oxygen sensitive. Precursor activity was not correlated with levels of L-threo-neopterin, a major pterin of unknown function in E. coli. Precursor activity was correlated with levels of a new 6-alkylpterin, compound Z, produced by acidic iodine oxidation. Compound Z has the properties expected of an oxidized MPT precursor.

Chromatography, High Pressure Liquid↗
PubMed1990

Methanogenesis involving a novel carrier of C1 compounds in Methanogenium tationis.

The pathway of CO2 reduction to methane in Methanogenium tationis and Methanogenium thermophilicum is similar to that observed in other methanogens. In M. tationis a novel pterin, tatiopterin, is present. This pterin appears to be a structural and functional analog of methanopterin and sarcinapterin. Folate could not substitute for tatiopterin.

Carbon Dioxide↗
PubMed1992

Atypical (mild) forms of dihydropteridine reductase deficiency: neurochemical evaluation and mutation detection.

We investigated two patients with an atypical (mild) form of dihydropteridine reductase (DHPR) deficiency. Both responded to the loading test with tetrahydrobiopterin; their plasma phenylalanine levels were lowered from 278 mumol/L to 85 and 48 mumol/L and from 460 mumol/L to 97 and 36 mumol/L after 4 and 8 h, respectively. In one of the patients, a combined loading test with phenylalanine followed by tetrahydrobiopterin was also carried out and showed a profile typical for DHPR deficiency. The phenylalanine hydroxylation rate was calculated to be 43 and 87%, 4 and 8 h after cofactor administration, respectively. Diagnosis was confirmed by the absence of DHPR activity in the patient's erythrocytes. In cultured fibroblasts, residual activity of 4 and 10%, respectively, was found. Excretion of urinary pterins was essentially normal, and the biopterin to neopterin ratio in cerebrospinal fluid was increased. Although in both patients cerebrospinal fluid homovanillic acid was found to be normal, and 5-hydroxyindoleacetic acid was substantially reduced, there was no sign of neurologic alterations until the age of 2 y. However, one of the patients recently developed deceleration of head growth, whereas psychomotor development continued to be normal for age. Using the chemical cleavage method on the amplified cDNA, mismatches of T to G at nucleotide 659 and of G to A at nucleotide 475, respectively, were identified. These results also demonstrate that screening for tetrahydrobiopterin deficiency by urinary pterin analysis alone can miss some newborns with mild DHPR deficiency and that all children with tetrahydrobiopterin defects need full neurochemical evaluation together with analysis of the enzyme activity.

Amino Acid Metabolism, Inborn Errors↗
PubMed2001

Carboxy-PTIO increases the tetrahydrobiopterin level in mouse brain microvascular endothelial cells.

The aim of the present study was to characterize the increase in tetrahydrobiopterin (BH4), which is a cofactor for nitric oxide synthase (NOS), by carboxy-PTIO, a scavenger of nitric oxide (NO), in vascular endothelial cells. BH4 level was determined by oxidation under acidic conditions as biopterin. Addition of lipopolysaccharide (LPS) to endothelial cells increased mRNA levels of inducible NOS (iNOS) and GTP-cyclohydrolase I (GTPCH), which is a rate-limiting enzyme for BH4 synthesis, and the biopterin level. NOS inhibitors, NO-donors and L-arginine, a substrate of NOS, did not affect the increase in the biopterin level induced by LPS, suggesting that BH4 synthesis is unlikely to be modulated by NO produced by iNOS during LPS treatment. However, carboxy-PTIO increased the biopterin level in the absence and the presence of LPS. Carboxy-PTIO did not affect the expression of GTPCH mRNA level. Moreover, 2,4-diamino-6-hydroxypyrimidine, an inhibitor of GTPCH, inhibited only about 30% of the carboxy-PTIO-induced increase in the biopterin level. Whereas, N-acetylserotonin, an inhibitor of sepiapterin reductase, strongly inhibited the increase in biopterin level. Carboxy-PTIO inhibited the accumulation of pterin, a decomposition product of BH4 in endothelial cells. These findings suggest that carboxy-PTIO accumulates BH4 under basal and LPS-treated conditions in vascular endothelial cells due to both inhibition of the decomposition of BH4 to pterin and activation of the salvage pathway of BH4 synthesis via sepiapterin reductase.

Alcohol Oxidoreductases↗
PubMedDate not supplied

Negligible ability of oxygen and peroxide ion activation by Al(III) ion is essential for Al(III)-induced neurodegeneration.

The electron densities of the atoms in Fe(II)- or Al(III)-tyrosine hydroxylase (THO) containing oxygen and pterin were calculated by the DFT (Density-functional theory) method. The results obtained are consistent with our previous proposal that oxygen activation in THO proceeds through the formation of an intermediate derived from Fe(II), oxygen, and pterin. Electron donation from substrate to the oxygen molecule is important to cleave the O-O bond, and to give the hydroxylated product. Based on these results, it was concluded that hydroxylation of the aromatic ring does not proceed in the Al(III)-containing THO, and a relationship exists between Al(III) ion and neurodegeneration.

Aluminum↗
PubMed1992

[Effects of caffeine on shuttle, operating behaviors, and brain metabolism in rats].

Effects of caffeine (30, 60, and 120 mg.kg-1, ip) on shuttling and operating behaviors in 80 rats were studied. Effects of caffeine (60, 120 mg.kg-1, ip) on contents of dinucleotides and pterins in 6 brain areas of 18 rats were investigated by HPLC with fluorescent detector. The results showed that the dose of caffeine that induced augment of shuttle behavior was lower than that induced operating behavior. Caffeine 120 mg.kg-1 inhibited both shuttling and operating behavior, decreased FAD content in caudate nucleus; caffeine 60 mg.kg-1 increased FAD in cerebellum and brain stem. Caffeine 60, 120 mg.kg-1 increased brain NADH contents, decreased pterin contents, and increased biopterin contents in some brain areas.

Animals↗
PubMed2006

6-pyruvoyltetrahydropterin synthase deficiency two-case report.

6-Pyruvoyltetrahydropterin Synthase (PTPS) deficiency is the most common cause of hyperphenylalaninemia due to tetrahydrobiopterin deficiency. The presenting symptoms of PTPS deficiency are mental retardation, convulsions, disturbance of tone and posture, drowsiness, irritability, abnormal movements, hypersalivation, and swallowing difficulties(1-3). The authors reported the first two cases of PTPS deficiency in Thailand. Both cases were male infants who showed phenylalanine levels of 25.23 mg/dl and 23.4 mg/dl respectively. The urinary pterins analysis showed low biopterin and high neopterin. The percentage of urinary biopterin was also found to be very low. The mutation analysis of the first case revealed a point mutation of exon 4, a homozygous C to T transition at nucleotide 200 in codon 67 (T67M), and the second case showed a compound heterozygous of exon 4, C to A transition at nucleotide 200, and exon 5, C to T transition at nucleotide 259 of the PTS gene confirming that they had PTPS deficiency. Treatment was started with neurotransmitters and a low phenylalanine diet. Family carriers were detected by means of urinary pterins determination and mutation analysis.

Humans↗
PubMed1987

Activation of rat caudate tyrosine hydroxylase phosphatase by tetrahydropterins.

Tyrosine hydroxylase phosphatase activity in rat caudate nucleus was separated into three peaks by chromatography on DEAE-cellulose. [32P]Tyrosine hydroxylase phosphorylated by cyclic AMP-dependent protein kinase was dephosphorylated only by the major peak eluting at 0.3 M NaCl, while tyrosine hydroxylase phosphorylated by Ca2+-calmodulin-dependent protein kinase was also dephosphorylated by two calcium-inhibited phosphatases. The Vmax of the enzyme in the major DEAE peak was increased by 10 microM tetrahydrobiopterin (BH4) from 0.78 to 5.0 fmol min-1 mg-1 while the Km was only slightly affected, increasing from 45 to 62 pM. The activation could not be reversed by dilution. On Sephadex G-200, the enzyme was found to consist of two major forms with molecular masses of 420 and 100 kDa. In contrast to the activation of liver phosphatases by freezing with beta-mercaptoethanol, activation by tetrahydrobiopterin was not associated with a shift in the molecular weight of the phosphatase to lower molecular weight forms. Other reduced pterins, including tetrahydroneopterin, 6-methyltetrahydropterin, and 5-methyltetrahydrofolate, also activated the enzyme, while oxidized pterins had no effect. GTP, the metabolic precursor of tetrahydrobiopterin, was a potent inhibitor of the phosphatase reaction, inhibiting by 65% at a concentration of 1 microM. These findings suggest a close regulatory interrelationship between the tetrahydrobiopterin synthetic pathway and catecholamine biosynthesis.

Animals↗
PubMed1987

Entrance of tetrahydropterin derivatives in brain after peripheral administration: effect on biogenic amine metabolism.

The ability of various structural analogs of tetrahydrobiopterin to enter the rat brain and remain in the reduced form after i.p. administration was tested because tetrahydrobiopterin itself enters poorly. The total content of various pterins in different brain areas was measured by high-pressure liquid chromatography-fluorescence detection, whereas high-pressure liquid chromatography-electrochemical detection was used to measure the content of reduced pterins. The effect of injection of certain tetrahydropterins on brain content of biogenic amines and their major metabolites was also monitored. In general, when the position 6 side-chain of tetrahydrobiopterin was made shorter and smaller in size, entrance into the brain from the periphery was markedly enhanced. Increasing the lipophilicity or size of the position 6 side-chain did not allow for better entry into brain and, in some cases, hindered entry. Under the conditions tested, none of the tetrahydropterins influenced the brain content of biogenic amines or their major metabolites; higher brain concentrations of tetrahydropterins are probably necessary to modify central nervous system biogenic amine metabolism. Other types of structural modifications or experimental approaches may be necessary to achieve higher brain concentrations of active cofactors, which may be required for the successful treatment of certain human diseases with tetrahydropterins.

Animals↗
PubMed1983

Study of tetrahydrobiopterin and 6-methyltetrahydropterin on alcohol dependence in mice.

The literature establishes a potential link between the function of tetrahydroisoquinolines in the biological actions of alcohol and the reduced pterin cofactor needed for synthesis of certain neurotransmitters. The effect of the administration of 6-methyltetrahydropterin and tetrahydrobiopterin upon alcohol withdrawal in mice was tested. Dependence was produced by ip administration of alcohol, supplemented by alcohol delivered by a subcutaneously implanted silastic tube. Administration of the reduced pterins at relatively high doses did not reduce the magnitude of the alcohol withdrawal syndrome.

Alcoholism↗
PubMed1982

Use of tetrahydropterins in the treatment of hyperphenylalaninemia due to defective synthesis of tetrahydrobiopterin: evidence that peripherally administered tetrahydropterins enter the brain.

Substantial amounts of tetrahydrobiopterin and 6-methyltetrahydropterin can be detected in CSF when these pterins are given peripherally to patients with hyperphenylalaninemia due to defective biopterin synthesis. Results of this study suggest that administration of either of these pterins in proper doses may prove to be a treatment not only for the impaired peripheral phenylalanine metabolism, but also for the neurologic disorders that are characteristic of the variant forms of hyperphenylalaninemia due to defective tetrahydrobiopterin synthesis or metabolism.

Biopterins↗
PubMed1993

Identification of molybdopterin as the organic component of the tungsten cofactor in four enzymes from hyperthermophilic Archaea.

The hyperthermophilic Archaea represent some of the most ancient organisms on earth. A study of enzymatic cofactors in these organisms could provide basic information on the origins of related cofactors in man and other more recently evolved organisms. To this end, the nature of the tungsten cofactor in aldehyde ferredoxin oxidoreductases from Pyrococcus furiosus and ES-4 and in formaldehyde ferredoxin oxidoreductases from P. furiosus and Thermococcus litoralis has been investigated. All four proteins contain molybdopterin, previously characterized as the organic component of the molybdenum cofactor in a large number of molybdoenzymes. Molybdopterin was identified by conversion to the dicarboxamidomethyl derivative by alkylation of the vicinal sulfhydryl groups on the pterin side chain and by conversion to the oxidized fluorescent derivative, Form A. The pterin of the tungsten cofactor in the four enzymes was examined for the presence of appended GMP, CMP, AMP, or IMP previously observed in molybdenum cofactors of some molybdoenzymes. No evidence for the presence of a molybdopterin dinucleotide or other modified form of molybdopterin was obtained. These results further document the essential nature of molybdopterin for the function of molybdenum and tungsten enzymes in diverse life forms.

Aldehyde Oxidoreductases↗
PubMedDate not supplied

Tetrahydrobiopterin and inherited hyperphenylalaninemias.

Tetrahydrobiopterin deficiency, a variant of hyperphenylalaninemia, may be caused by deficiency of one of the following enzymes: guanosine triphosphate cyclohydrolase 1,6-pyruvoyltetrahydropterin synthase, dihydropteridin reductase and pterin-4a-carbinolamine dehydratase. The first two enzymes are involved in the biosynthesis of tetrahydrobiopterin, the last two in its regeneration. Although these diseases are rare, early detection by selective screening is essential for the treatment and outcome. Tetrahydrobiopterin deficiencies are very heterogenous ranging from mild forms requiring only marginal if any treatment to severe forms which are in some cases very difficult to treat. All variants of tetrahydrobiopterin deficiency can be differentiated from the classical phenylketonuria (PKU) by measurement of pterin metabolites in patients' urine, tetrahydrobiopterin loading test, and by dihydropteridine reductase activity in erythrocytes from the Guthrie card.

Biopterins↗
PubMed2005

6-pyruvoyl-tetrahydropterin synthase deficiency with mild hyperphenylalaninemia.

Severe 6-pyruvoyl-tetrahydrobiopterin synthase deficiency is a tetrahydrobiopterin deficiency disorder that presents in infancy with developmental delay, seizures, and abnormal movements associated with hyperphenylalaninemia usually detectable by neonatal phenylketonuria screening programs. We describe an 8-year-old girl with delay, seizures, and dystonia with mild hyperphenylalaninemia detected in late childhood. The diagnosis of 6-pyruvoyl-tetrahydrobiopterin synthase deficiency was made by analysis of pterins in urine, pterins and neurotransmitters in cerebrospinal fluid, and enzyme assay. The patient improved clinically taking oral tetrahydrobiopterin, levodopa/carbidopa, and 5-hydroxytryptophan. This treatable condition may not always be detected by routine population screening for hyperphenylalaninemia.

5-Hydroxytryptophan↗
PubMed1993

Products of the tyrosine-dependent oxidation of tetrahydrobiopterin by rat liver phenylalanine hydroxylase.

Phenylalanine hydroxylase, a tetrahydrobiopterin (BH4)-dependent oxygenase, catalyzes the conversion of phenylalanine to tyrosine. During this physiological reaction, the oxidation of BH4 is tightly coupled to the hydroxylation of the amino acid substrate with a stoichiometry of 1 mol of BH4 oxidized for every mole of tyrosine formed. In the presence of an activator and certain analogues of either the amino acid or the pterin coenzyme, the enzyme also catalyzes a partially uncoupled reaction in which the amount of tetrahydropterin oxidized exceeds the amount of amino acid hydroxylated. With tyrosine as the amino acid analogue, the reaction is completely uncoupled, i.e., the enzyme functions as a tetrahydropterin oxidase with no net hydroxylation of the amino acid. We have investigated whether the normal pterin intermediate, a 4a-hydroxytetrahydropterin, is formed during the completely uncoupled reaction and whether oxygen is reduced exclusively to the level of water, as in the tightly coupled reaction, or whether some reduction to hydrogen peroxide occurs. We present direct evidence that both the normal hydroxytetrahydropterin intermediate and hydrogen peroxide are formed. The amount of hydrogen peroxide formed, however, is not stoichiometric with the amount of oxygen reduced, an indication that there are at least two pathways for this reduction, one leading to the formation of water and one to hydrogen peroxide. We also postulate that hydrogen peroxide and the hydroxytetrahydropterin are both derived from alternate routes of breakdown of a common precursor, the corresponding 4a-hydroperoxytetrahydropterin. By contrast, in the normal tightly coupled reaction, we suggest that this peroxy compound participates in the hydroxylation of the amino acid substrate.

Animals↗