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PubMed1986

Molybdopterin cofactor from Methanobacterium formicicum formate dehydrogenase.

The molybdopterin cofactor from the formate dehydrogenase of Methanobacterium formicicum was studied. The cofactor was released by guanidine denaturation of homogeneous enzyme, which also released greater than 80% of the molybdenum present in the enzyme. The anoxically isolated cofactor was nonfluorescent, but after exposure to air it fluoresced with spectra similar to those of described molybdopterin cofactors. Aerobic release from acid-denatured formate dehydrogenase in the presence of I2 and potassium iodide produced a mixture of fluorescent products. Alkaline permanganate oxidation of the mixture yielded pterin-6-carboxylic acid as the only detectable fluorescent product. The results showed that the cofactor from formate dehydrogenase contained a pterin nucleus with a 6-alkyl side chain of unknown structure. Covalently bound phosphate was also present. The isolated cofactor was unable to complement the cofactor-deficient nitrate reductase of the Neurospora crassa nit-1 mutant.

Aldehyde Oxidoreductases↗
PubMed1997

D-erythro-neopterin biosynthesis in the methanogenic archaea Methanococcus thermophila and Methanobacterium thermoautotrophicum deltaH.

The steps in the biosynthetic transformation of GTP to 7,8-dihydro-D-erythro-neopterin (H2neopterin), the precursor to the modified folates found in the methanogenic archaea, has been elucidated for the first time in two members of the domain Archaea. In Methanococcus thermophila and Methanobacterium thermoautotrophicum deltaH, it has been demonstrated that H2neopterin 2':3'-cyclic phosphate is an intermediate in this conversion. In addition, the formation of the pterin ring of the H2neopterin 2':3'-cyclic phosphate is catalyzed not by a single enzyme, as is known to occur with GTP cyclohydrolase I in the Eucarya and Bacteria, but rather by two or more enzymes. A 2,4,5-triamino-4(3H)-pyrimidinone-containing molecule, most likely 2,5-diamino-6-ribosylamino-4(3H)-pyrimidinone 5'-triphosphate, has been identified as an intermediate in the formation of the H2neopterin 2':3'-cyclic phosphate. Synthetic H2neopterin 2':3'-cyclic phosphate was found to be readily hydrolyzed by cell extracts of M. thermophila via the H2neopterin 3'-phosphate to H2neopterin, a known precursor to the pterin portion of methanopterin.

Biopterins↗
PubMed1991

Tetrahydrobiopterin loading test in hyperphenylalaninemia.

Some cases of primary hyperphenylalaninemia are not caused by the lack of phenylalanine hydroxylase, but by the lack of its cofactor tetrahydrobiopterin. These patients are not clinically responsive to a phenylalanine-restricted diet, but need specific substitution therapy. Thus, it became necessary to examine all newborns screened as positive with the Guthrie test for tetrahydrobiopterin deficiency. Methods based on urinary pterin or on specific enzyme activity measurements are limited in their availability, and the simplest method, based on the lowering of serum phenylalanine after loading with cofactor, was discouraged by the finding that some dihydropteridine reductase-deficient patients were unresponsive. The preliminary observation that this limitation could be overcome by increasing the dose of the administered cofactor prompted us to reevaluate the potential of the tetrahydrobiopterin loading test in hyperphenylalaninemia. Fifteen patients, eight with ultimate diagnosis of phenylketonuria, three with 6-pyruvoyl tetrahydropterin synthase-, and four with dihydropteridine reductase-deficiency, have been examined by administering synthetic tetrahydrobiopterin both orally, at doses of 7.5 and 20 mg/kg, and i.v., at a dose of 2 mg/kg. All the tetrahydrobiopterin-deficient patients, unlike those with phenylketonuria, responded to the oral dose of 20 mg/kg cofactor by lowering their serum phenylalanine concentration markedly below baseline to an extent easily detectable by Guthrie cards. This method allows for a simple screening method when enzyme or pterin studies are not available.

Administration, Oral↗
PubMed2001

[Perspectives on tetrahydrobiopterin research].

Tetrahydrobiopterin ((6R)-L-erythro-tetrahydrobiopterin, BH4) is de novo synthesized from GTP. Enzymes involved in its synthesis are the rate limiting enzyme GTP cyclohydrolase I, 6-pyruvoyl tetrahydropterin synthase (PTPS) and sepiapterin reductase. Abnormalities in the metabolism of BH4 have been demonstrated in some diseases affecting the central nervous systems such as atypical phenylketonuria, hereditary progressive dystonia (Segawa's disease). Furthermore, BH4 has been shown to be involved in vascular protection. It is suggested that the dysfunction of endothelial BH4 leads to atherosclerosis. Recently we established BH4-deficient mice by disrupting the PTPS gene to investigate the effects of BH4 depletion on the animals and the involvement of BH4 in regulating biological functions including neural systems. Investigation utilizing this model animal can contribute to the development of new therapeutic strategies toward various diseases involving neurological and vascular systems. Pterin derivatives other than biopterin may also be involved in the regulation of a variety of biological functions. We found that ciliated protozoan Tetrahymena pyriformis synthesizes tetrahydromonapterin, isomer of BH4, and its levels alter according to the progress of the cell cycle. How pterin derivatives are related to the human physiology and diseases is an interesting subject of investigation.

Animals↗
PubMed2001

Diagnosis of dopa-responsive dystonia and other tetrahydrobiopterin disorders by the study of biopterin metabolism in fibroblasts.

BACKGROUND: Dopa-responsive dystonia (DRD) and tetrahydrobiopterin (BH4) defects are inherited disorders characterized by monoamine neurotransmitter deficiency with decreased activity of one of the BH4-metabolizing enzymes. The aim of the study was to determine the utility of cultured skin fibroblasts for the diagnosis of these diseases. METHODS: Neopterin and biopterin production and GTP cyclohydrolase I (GTPCH) activity were measured in cytokine-stimulated fibroblasts; 6-pyruvoyltetrahydropterin synthase (PTPS), sepiapterin reductase (SR), and dihydropteridine reductase (DHPR) activities were measured in unstimulated fibroblasts. We examined 8 patients with DRD, 3 with autosomal recessive GTPCH deficiency, 7 with PTPS deficiency, 3 with DHPR deficiency, and 49 controls (35 fibroblast and 14 amniocyte samples). RESULTS: Fibroblasts from patients with DRD and autosomal recessive GTPCH deficiency showed reduced GTPCH activity (15.4% and 30.7% of normal activity, respectively) compared with controls (P < 0.001). Neopterin production was very low and biopterin production was reduced in both disorders. PTPS- and DHPR-deficient cells showed no enzyme activities; in PTPS deficiency the pattern of pterin production was typical (neopterin, 334-734 pmol/mg; controls, 18-98 pmol/mg; biopterin, 0 pmol/mg; controls, 154-303 pmol/mg). Reference values of all enzyme activities and pterin production were measured in fibroblasts and also in amniocytes for prenatal diagnosis. CONCLUSIONS: Cultured skin fibroblasts are a useful tool in the diagnosis of BH4 deficiencies. Intracellular neopterin and biopterin concentrations and GTPCH activity in cytokine-stimulated fibroblasts are particularly helpful in diagnosing patients with DRD.

Alcohol Oxidoreductases↗
PubMed1975

Studies on the phenylalanine hydroxylase system in liver slices.

A method was developed to study the unsupplemented phenylalanine hydroxylase system in rat liver slices. All of the components of the system--tetrahydrobiopterin, dihydropteridine reductase, and the hydroxylase itself--are present under conditions which should be representative of the actual physiological state of the animal. The properties of the system in liver slices have been compared to those of the purified enzyme in vitro. The three pterins, tetrahydrobiopterin, 6,7-dimethyltetrahydropterin, and 6-methyltetrahydropterin, all stimulate the hydroxylation of phenylalanine when added to the liver slice medium in the presence of a chemical reducing agent. The relative velocities found at 1 mM phenylalanine and saturating pterin concentrations are: tetrahydrobiopterin, 1; 6,7-dimethyltetrahydropterin, 2.5; 6-methyltetrahydropterin, 13. This ratio of activities is similar to that found for the purified, native phenylalanine hydroxylase and indicates that the enzyme in vivo is predominantly in the native form. Rats pretreated with 6-methyltetrahydropterin showed enhanced phenylalanine hydroxylase activity in liver slices demonstrating for the first time that an exogenous tetrahydropterin can interact with the phenylalanine hydroxylase system in vivo. This finding opens up the possibility of treating phenylketonurics who still possess some residual phenylalanine hydroxylase activity with a tetrahydropterin like 6-methyltetrahydropterin which can give a large increase in rate over that seen with the natural cofactor, tetrahydrobiopterin.

Animals↗
PubMedDate not supplied

[Tolerance of 5,10-methenyltetrahydrofolate to ultraviolet radiation].

Aeration of aqueous solutions of 5,10-methenyltetrahydrofolic acid (MTHF) during exposure to ultraviolet irradiation (lambda 300-390 nm, 240 W/m2, 30 min) slowed down photolysis in comparison with deaerated solutions. The rate of photolysis in the presence of oxygen depended on buffer composition. It did not exceed 6% of the starting amount of MTHF. Photolysis of MTHF included opening of the imidazoline ring, dehydrogenation of the tetrahydropterin portion, and elimination of the p-aminobenzoylglutamate moiety. 6,7-Dimethyltetrahydropterin was used as a model compound to show that protonation of the reduced pterin heterocycle increased its tolerance to oxidation, and UV irradiation did not accelerate this process. The stabilizing effect of protonation of the pterin portion and the presence of the positively charged imidazoline moiety are assumed to hamper MTHF oxidation and photolysis. It is assumed that these factors favored the choice of MTHF molecules as photosensors in light-sensitive proteins in the course of evolution.

Oxidation-Reduction↗
PubMedDate not supplied

[Time course of the content of folates and free amino acids in leaves of Pisum sativum L. after irradiation with ultraviolet C].

The effect of irradiation with UV-C on the time course of the content of total folates and free amino acids in leaves of pea (Pisum sativum L.) cultivar Neistoshchimyi was studied. It was shown that photolysis of folates is a rapid response to exposure to ultraviolet, as a result of which the plant produces a stable compound, pterin-6-carboxylic acid, with a relative fluorescence quantum yield approximately 2.0 at 20 degrees C (total value, 0.58). Presumably, this compound may be involved in the pterin-mediated photosensitization of singlet oxygen production. The kinetics of changes in the composition of free amino acids after exposure to UV-C has been studied. Exposure to UV-C for 0.5 and 1min induced utilization of free amino acids, suggesting activation of the synthesis of hormones and alkaloids that may facilitate resistance to the stressor. Greater doses as a result of exposure to radiation for 10 and 40 min decreased the content of free hydrophobic amino acids. This phenomenon could be due to the formation of covalent cross-links in membranes, which decrease the accessibility of hydrophobic amino acids. It is concluded that the changes in the qualitative and quantitative composition of free amino acids in leaves of irradiated plants were due to glycolysis.

Amino Acids↗
PubMed1991

The mechanisms of inactivation of sulfite oxidase by periodate and arsenite.

The inactivation of sulfite oxidase, a molybdoenzyme containing the Mo cofactor, by arsenite and periodate was investigated. In contrast to ferricyanide (Gardlik, S., and Rajagopalan, K.V. (1991) J. Biol. Chem. 266, 4889-4895), neither of these reagents causes oxidation of the pterin ring of the Mo cofactor. Instead, inactivation by these reagents appears to involve attack on sulfhydryl groups at the active site of the enzyme. The inactivation of sulfite oxidase by arsenite was shown to be dependent on the presence of O2 and on the enzymatic oxidation of arsenite to arsenate. The inactivation was preventable by the presence of sulfite, or by the use of cytochrome c as the electron acceptor instead of O2. It is concluded that inactivation by arsenite is the result of arsenite displacement of Mo during enzymatic oxidation of arsenite to arsenate, when Mo transiently breaks its bond to protein or molybdopterin sulfhydryl(s) in order to provide a site for transfer of electrons to O2. Data indicate that arsenite is properly oriented to displace Mo only once every 20,800 turnovers, thus accounting for the slow rate of inactivation by this reagent. Inactivation of sulfite oxidase by periodate is believed to occur as the result of direct attack of periodate on the thiolate ligands of Mo, either those of the protein and/or molybdopterin, leading to Mo loss. Treatment of enzyme with even low levels of periodate resulted in loss of Mo and both sulfite:cytochrome c and sulfite:O2 activities. Molybdopterin of periodate-inactivated enzyme retained the ability to reconstitute nitrate reductase apoprotein in nit-1 extracts and the ability to reduce dichlorophenolindophenol, indicating that the pterin ring had not been oxidized.

Animals↗
PubMed1991

Identification of a molybdopterin-containing molybdenum cofactor in xanthine dehydrogenase from Pseudomonas aeruginosa.

Xanthine dehydrogenase has been purified from Pseudomonas aeruginosa cultured on a rich medium and induced with hypoxanthine. The enzyme was shown to contain FAD, iron sulfur centers and a molybdenum cofactor as prosthetic groups. Analysis of the molybdenum cofactor in this enzyme has revealed that the cofactor contains molybdopterin (MPT) rather than molybdopterin guanine dinucleotide or molybdopterin cytosine dinucleotide which have previously been identified in a number of molybdoenzymes of bacterial origin. The pterin cofactor in P.aeruginosa xanthine dehydrogenase was alkylated and the resulting product was identified as dicarboxamidomethyl molybdopterin. In addition, the pterin released from the enzyme by denaturation with guanidine-HCl was found to chromatograph on Sephadex G-15 with an apparent molecular weight of 350. These results document the first example of a bacterial enzyme with a molybdenum cofactor comprising molybdopterin and the metal only.

Animals↗
PubMed1990

Simultaneous determination of GTP cyclohydrolase activity and biopterin content in pheochromocytoma PC12h cells.

A method to measure the GTP cyclohydrolase and biopterin (BP) content at the same time in the sonicate of pheochromocytoma PC12h cells was described. The cells cultured in a 5-cm dish were sonicated with 0.4 to 0.5 ml of 50 mM Tris-HCl, pH 7.8, and a 50 microliters aliquot was used for one assay. After the GTP cyclohydrolase reaction, dihydroneopterin triphosphate, the reaction product, was oxidized and dephosphorylated to form neopterin (NP); and the pterins in the reaction mixture were then analyzed by high-performance liquid chromatography (HPLC). Mainly three peaks of pterins were detected in the eluate from the HPLC column: they were NP, BP, and 2-amino-4-hydroxypteridine (AHP). The amount of NP was a measure of the enzyme activity. On the other hand, a significant part of the biopterin contained in the enzyme sample was converted to AHP during the GTP cyclohydrolase reaction. Therefore, the sum amount of BP plus AHP was a measure of total BP content in the enzyme sample (sonicate of PC12h cells). The method is convenient and useful to study the actions and action mechanisms of various biologically active substances on the BP level of pheochromocytoma cells in culture.

Animals↗
PubMed1979

The activity of 2,4,5-triamino-6-hydroxypyrimidine in the phenylalanine hydroxylase system.

The pyrimidine moiety of a pterin, 2,4,5-triamino-6-hydroxypyrimidine, has been found to be active in the phenylalanine-hydroxylating system. The phenylalanine-dependent, phenylalanine hydroxylase-catalyzed reaction in the presence of the pyrimidine is largely, but not completely, uncoupled; the ratio of DPNH oxidized to tyrosine formed is about 20 to 1. In addition to the pyrimidine having activity with phenylalanine hydroxylase, a product of the pyrimidine is also a substrate for dihydropteridine reductase. The activity of the pyrimidine with the hydroxylase indicates that neither carbon atoms 6 or 7 of the pterin ring is involved in activation of oxygen during the hydroxylase-catalyzed reaction.

Animals↗
PubMed1990

The state of reduction of molybdopterin in xanthine oxidase and sulfite oxidase.

Methods have been devised to examine the spectral properties and state of reduction of the pterin ring of molybdopterin (MPT) in milk xanthine oxidase and the Mo-containing domain of rat liver sulfite oxidase. The absorption spectrum of the native pterin was visualized by difference spectroscopy of each protein, denatured anaerobically in 6 M guanidine hydrochloride (GdnHCl), versus a sample containing the respective apoprotein and other necessary components. The state of reduction of MPT was also probed using 2,6-dichlorobenzenoneindophenol (DCIP) to measure reducing equivalents/MPT, after anaerobic denaturation of the protein in GdnHCl in the presence or absence of Hg2+. In the case of xanthine oxidase the data indicate that the terminal sulfide ligand of Mo causes the reduction of a native dihydro form of MPT to the tetrahydro level. This reduction does not occur if Hg2+ is added prior to denaturation of the protein. Based on its observed behavior, the native MPT in the Mo cofactor of xanthine oxidase is postulated to exist as a quinonoid dihydropterin. Quantitation of DCIP reduction by MPT of Mo fragment of sulfite oxidase showed a two-electron oxidation of MPT, even when the Mo fragment was denatured in the presence of Hg2+ to prevent internal reduction reactions due to sulfhydryls or sulfide. Difference spectra of DCIP-treated versus untreated Mo fragment showed that MPT had been fully oxidized. These data indicate that the native MPT in sulfite oxidase must be a dihydro isomer different from that in xanthine oxidase.

Animals↗
PubMed1985

Ethanol-induced changes in tyrosine hydroxylase activity in adrenal glands of mice selectively bred for differences in sensitivity to ethanol.

In the present study catecholaminergic systems in the adrenal glands of mice selectively bred for differences in sensitivity to ethanol, the long-sleep (LS) and short-sleep (SS) mice, have been examined. Tyrosine hydroxylase (TH) activity and catecholamine levels were measured in the adrenal glands at various times after a single injection of ethanol (4.0 g/kg i.p.). Basal levels of TH activity, epinephrine and norepinephrine are significantly higher in the adrenal glands of LS mice by 87, 20, and 26%, respectively. Ten minutes after ethanol administration, LS mouse adrenal gland TH activity is decreased by 33% whereas SS mouse adrenal gland TH activity is increased by 68%. At 25 and 125 min after ethanol, SS mouse adrenal gland TH activity is no longer increased, but the decrease in TH activity persists in adrenals of LS mice. The corresponding adrenal gland catecholamine levels are unchanged in the LS and SS mice at all times measured except at 125 min in LS mice when both epinephrine (24%) and norepinephrine (31%) are decreased. The increase in SS adrenal gland TH activity at 10 min after ethanol administration is associated with an increase in the affinity of the enzyme for the pterin cofactor (decreased Km). Conversely, the decrease in TH activity at 10 min after ethanol in LS mice is associated with an increase in Km for the pterin cofactor. The Vmax is unchanged by ethanol treatment in either line. Prior administration of chlorisondamine (15 mg/kg i.p.) has no effect on either the ethanol-induced changes in adrenal gland TH activity at 10 min or the sleep time of LS mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1985

A new mechanism for regulation of tyrosine 3-monooxygenase by end product and cyclic AMP-dependent protein kinase.

Tyrosine 3-monooxygenase activity of the crude extract from rat striatum had a sharp pH optimum at pH 5.4 and showed almost no activity at or above pH 7. When the crude extract was partially purified by pH precipitation and chromatography on DEAE-cellulose, the enzyme showed a high activity in the pH range of 5.8 to 7.4. Incubation of the partially purified enzyme with catecholamines such as dopamine, norepinephrine, and epinephrine resulted in a remarkable decrease in the enzyme activity, as assayed at a neutral pH. This suppression of the enzyme activity by catecholamines differed from the well-known feedback inhibition which is competitive with respect to the pterin cofactor; the former occurred at a very much lower concentration of catecholamines even in the presence of a near-saturating concentration of a pterin cofactor, and the former was a time-dependent reaction. The enzyme, the activity of which had been suppressed by the incubation with dopamine, was remarkably activated by the incubation with the catalytic subunit of cyclic AMP-dependent protein kinase in the presence of an ATP-generating system. These results suggest that the activity of tyrosine 3-monooxygenase may be suppressed by its end products in a normal state and it may be stimulated by cyclic AMP-dependent protein kinase as occasion demands.

Animals↗
PubMed1985

The C-6 proton of tetrahydrobiopterin is acquired from water, not NADPH, during de novo biosynthesis.

Tetrahydrobiopterin, the cofactor for the aromatic amino acid hydroxylases, is synthesized in mammals from GTP via a pathway involving both dihydropterin and tetrahydropterin intermediates. In this work, we have investigated the mechanism of conversion of the product formed from GTP, 7,8-dihydroneopterin triphosphate, into the tetrahydropterin intermediates. Tetrahydrobiopterin can be oxidized under conditions which yield pterin or pterin 6-carboxylate without exchange of the C-6 and C-7 protons. Using these techniques, a gas chromatography/mass spectrometry method was developed to determine that in the biosynthesis of tetrahydrobiopterin de novo, in preparations of bovine adrenal medulla, the C-6 proton of tetrahydrobiopterin is derived from water and not from NADPH. In contrast, the C-6 proton of tetrahydrobiopterin produced from sepiapterin (6-lactoyl-7,8-dihydropterin) comes from NADPH. The results are consistent with evidence for the formation of the first tetrahydropterin intermediate by a tautomerization without any requirement for NADPH.

Animals↗
PubMed1988

Molybdopterin--problems and perspectives.

Structural studies on several derivatives of molybdopterin, the organic component of the molybdenum cofactor common to virtually all molybdoenzymes, have provided definitive evidence for the presence of a reduced pterin ring with a 6-alkyl side-chain containing an enedithiol and a phosphomonoester in active molybdopterin. The cryptic nature of the cofactor makes structure - function studies on the protein-bound prosthetic group extremely difficult. In this review some of the relevant properties of the pterin ring are presented, and the possible roles of molybdopterin in catalysis are discussed.

Coenzymes↗
PubMed1987

The oxidation product of molybdenum cofactor from milk xanthine oxidase.

In extracts of acid treated molybdenum cofactor containing xanthine oxidase, fluorescence is maximally developed upon a three hours incubation. Analysis by means of reversed phase HPLC revealed the presence of several fluorescent compounds, the main one being a blue fluorescent compound with an emission maximum of 465 nm when maximal excited at 395 nm at a neutral pH. Definite proof is presented that this compound is the oxidation product of the molybdenum cofactor. The remaining fluorescent products are shown to be pterin-derivatives, yielding predominantly pterin-6-carboxylic acid upon permanganate oxidation. Purified oxidation product of molybdenum cofactor however, didn's yield a fluorescent derivative at all upon treatment with permanganate.

Animals↗