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At least 163 records · Page 9Linked to original sources
PubMed2000

Crystal structure of Mycobacterium tuberculosis 7,8-dihydropteroate synthase in complex with pterin monophosphate: new insight into the enzymatic mechanism and sulfa-drug action.

The enzyme 7,8-dihydropteroate synthase (DHPS) catalyzes the condensation of para-aminobenzoic acid (pABA) with 6-hydroxymethyl-7, 8-dihydropterin-pyrophosphate to form 7,8-dihydropteroate and pyrophosphate. DHPS is essential for the de novo synthesis of folate in prokaryotes, lower eukaryotes, and in plants, but is absent in mammals. Inhibition of this enzyme's activity by sulfonamide and sulfone drugs depletes the folate pool, resulting in growth inhibition and cell death. Here, we report the 1.7 A resolution crystal structure of the binary complex of 6-hydroxymethylpterin monophosphate (PtP) with DHPS from Mycobacterium tuberculosis (Mtb), a pathogen responsible for the death of millions of human beings each year. Comparison to other DHPS structures reveals that the M. tuberculosis DHPS structure is in a unique conformation in which loop 1 closes over the active site. The Mtb DHPS structure hints at a mechanism in which both loops 1 and 2 play important roles in catalysis by shielding the active site from bulk solvent and allowing pyrophosphoryl transfer to occur. A binding mode for pABA, sulfonamides and sulfones is suggested based on: (i) the new conformation of the closed loop 1; (ii) the distribution of dapsone and sulfonamide resistance mutations; (iii) the observed direction of the bond between the 6-methyl carbon atom and the bridging oxygen atom to the alpha-phosphate group in the Mtb DHPS:PtP binary complex; and (iv) the conformation of loop 2 in the Escherichia coli DHPS structure. Finally, the Mtb DHPS structure reveals a highly conserved pterin binding pocket that may be exploited for the design of novel antimycobacterial agents.

Amino Acid Sequence↗
PubMed1987

[Pterins: pigments, cofactors and signal connections in cell interactions].

Pteridines were originally described as pigments of insects and lower vertebrates. The electron-donating function of tetrahydrobiopterin for aromatic amino acid hydroxylation and thus, for neurotransmitter biosynthesis adduced the participation of unconjugated pterins in cellular metabolism. There has been increasing evidence moreover that they are signal molecules for intercellular recognition in primitive eucaryotes, as well as modifiers of signal polypeptides in higher vertebrates.

Animals↗
PubMed1992

Plasma and urinary levels of biopterin, neopterin, and related pterins and plasma levels of folate in infantile autism.

Tetrahydrobiopterin is essential for brain cells to make monoamine neurotransmitters. It has been reported that the concentrations of tetrahydrobiopterin in plasma and urine are low in certain mental disorders and that oral supplements are beneficial. A group of Japanese investigators have been conducting clinical trials of the effect of administration of tetrahydrobiopterin to autistic children and reported that it is beneficial with no significant side effects. We, therefore, initiated a study to assess plasma and urinary levels of tetrahydrobiopterin in infantile autism to see if they are reduced. Besides tetrahydrobiopterin, we also determined plasma and urinary levels of neopterin and monapterin in these individuals in order to evaluate the status of dihydroneopterin triphosphate, a key biosynthetic precursor of tetrahydrobiopterin. Sixteen autistic children and 12 healthy controls were included in this study. Results indicated that the plasma and urinary levels of tetrahydrobiopterin are not statistically different between the two groups and, therefore, no simple explanation for the beneficial effects of administration of tetrahydrobiopterin on autistic children can be offered at the present time. In contrast, plasma and urinary levels of neopterin were depressed (.01 less than p less than .05) and plasma monapterin was also significantly depressed (p less than .01) in autistic subjects compared with controls. Levels of other pterins, including folate, were not statistically different between the two groups. The basis for this depression in neopterin and monapterin is unknown. It does not seem likely that this depression could be attributed to a difference in age or T-lymphocyte/macrophage activity. However, further studies are needed to investigate these possibilities.

Adolescent↗
PubMed1998

Mutations in the pterin-4alpha-carbinolamine dehydratase (PCBD) gene cause a benign form of hyperphenylalaninemia.

Four patients with primapterinuria, postulated to be due to pterin-4alpha-carbinolamine dehydratase (PCD) deficiency, were diagnosed by biochemical and DNA analysis. All four patients presented in the neonatal period with hyperphenylalaninemia, and elevated neopterin and decreased biopterin levels in the urine. These symptoms are common to 6-pyruvoyltetrahydropterin synthase deficiency and thus there is a danger of misdiagnosis. In addition, all four patients had elevated urinary excretion of primapterin (7-biopterin), the only persistent biochemical abnormality. Analysis of fibroblast DNA from the patients identified the following mutations in the PCBD gene: one patient homozygous for the missense mutation E96K and one homozygous for the nonsense mutation Q97X, both in exon 4; one compound heterozygote with the mutations E96K and Q97X; and one patient with two different homozygous mutations: E26X in exon 2 and R87Q in exon 4. In two families, the parents were investigated and found to be obligate heterozygotes for particular mutations. One sibling was found to be unaffected. These results further substantiate the idea that primapterinuria is associated with mutations in the PCBD gene.

Amino Acid Metabolism, Inborn Errors↗
PubMed1992

Structural requirements for the modulatory effect of 6-substituted pterins on interleukin 2 receptor binding.

(6R)-5,6,7,8-Tetrahydrobiopterin is produced by stimulated human T lymphocytes, and is known to affect various aspects of interleukin-2-directed T cell proliferation. Using an increased apparent affinity of interleukin 2 receptor to interleukin 2 as a measure of activity, this study explores whether other 6-substituted pterins might have the same effect, and what structural features are necessary for activity. Of the compounds tested, only the T-lymphocyte-derived (6R)-5,6,7,8-tetrahydrobiopterin was active. The diastereomeric (6S)-5,6,7,8-tetrahydrobiopterin was inactive, as were 7,8-dihydrobiopterin, sepiapterin, 5,6,7,8-tetrahydroneopterin, 6,7-dimethyl-5,6,7,8-tetrahydropterin and 6-hydroxymethylpterin. 7,8-Dihydroneopterin and neopterin were also found to be inactive. It follows that neither of these compounds participates in the feedback modulation of IL-2 receptor affinity, although both of them can be detected upon IFN-gamma stimulation of human monocytes/macrophages. A computer-based molecular modelling study of (6R)-5,6,7,8-tetrahydrobiopterin and (6R)-5,6,7,8-tetrahydroneopterin revealed substantial differences in overall shape between the two molecules, with certain features figuring prominently in the low-energy conformers of (6R)-5,6,7,8-tetrahydrobiopterin.

Biopterins↗
PubMed2004

Calcium pterin as an antitumor agent.

A series of in vivo studies are reported that provide evidence for an immunologically mediated mechanism for the antitumor response from a calcium pterin (CaPterin) suspension. Strong antitumor efficacy was demonstrated in fully immunocompetent female C3H/HeN-MTV+ mice (retired breeders) presenting spontaneous mammary gland adenocarcinomas. Comparison of results obtained by testing CaPterin in either nude or SCID mice (severely compromised immunodeficient) implanted with MDA-MB-231 human cancer cells showed a significant antitumor response in the nudes and no response in the SCIDs. This comparison argues for B-cell immunological involvement in the mechanism of CaPterin antitumor activity since nude mice possess B-cell capability while SCID mice do not. This comparison also indicates that there is no measurable direct cancer cell toxicity from the CaPterin. Results showing no CaPterin antitumor efficacy against EMT6 tumor cells implanted in Balb/c mice also suggest an antitumor mechanism involving B-cells, since transforming growth factor beta (TGF-beta), produced by EMT6 cells, is known to cause B-cell apoptosis. Taken together, these results, along with those of other researchers, indicate that CaPterin's antitumor mechanism involves antibody-dependent cellular cytotoxicity (ADCC) mediated, for example, by natural killer (NK) cells, interlukin-2, and CaPterin.

Adenocarcinoma↗
PubMed1998

Neuroprotective effects of pterin-6-aldehyde in gerbil global brain ischemia: comparison with those of alpha-phenyl-N-tert-butyl nitrone.

The superoxide (O2.-) scavenging activity and the neuroprotective effects of pterin-6-aldehyde (P6A), a xanthine oxidase inhibitor, were examined and compared with those of alpha-phenyl-N-tert-butyl nitrone (PBN), a spin trapping agent. The scavenging activity of P6A was more potent than that of PBN by 150-fold in neutrophil/phorbol myristate acetate O2.- generating system. P6A attenuated the neuronal damage with a much smaller dose and a greater efficiency than PBN in global brain ischemia in gerbils. These findings suggest that P6A is a more potent neuroprotective agent than PBN and has possible therapeutic effects against various diseases in which O2.- is involved.

Animals↗
PubMed1986

Estimation of tetrahydrobiopterin and other pterins in cerebrospinal fluid using reversed-phase high-performance liquid chromatography with electrochemical and fluorescence detection.

We describe an isocratic, reversed-phase high-performance liquid chromatographic method for the simultaneous measurement of fully oxidised, dihydro- and tetrahydropterins in cerebrospinal fluid. Tetrahydrobiopterin is detected electrochemically using an ESA Coulochem detector in the redox mode. Dihydropterins are detected by fluorescence following post-column electrochemical oxidation, and fully oxidised pterins by their natural fluorescence. Apart from addition of antioxidants, no sample preparation is required. Comparison is made with methods requiring chemical oxidation for detection of tetrahydrobiopterin. Some results on children with neurological disease are presented.

Antioxidants↗
PubMed1999

Formation of a pterin radical in the reaction of the heme domain of inducible nitric oxide synthase with oxygen.

The heme domain (iNOS(heme)) of inducible nitric oxide synthase (NOS) was expressed in Escherichia coli and purified to homogeneity. Rapid freeze-quench (RFQ) EPR was used to monitor the reaction of the reduced iNOS(heme) with oxygen in the presence and absence of substrate. In these reactions, heme oxidation occurs at a rate of approximately 15 s(-)(1) at 4 degrees C. A transient species with a g = 2.0 EPR signal is also observed under these conditions. The spectral properties of the g = 2.0 signal are those of an anisotropic organic radical with S = (1)/(2). Comparison of the EPR spectra obtained when iNOS(heme) is reconstituted with N5-(14)N- and (15)N-substituted tetrahydrobiopterin (H(4)B) shows a hyperfine interaction with the pterin N5 nitrogen and identifies the radical as the one-electron oxidized form (H(3)B.) of the bound H(4)B. Substitution of D(2)O for H(2)O reveals the presence of hyperfine-coupled exchangeable protons in the H(4)B radical. This radical forms at a rate of 15-20 s(-)(1), with a slower decay rate that varies (0.12-0.7 s(-)(1)) depending on the substrate. At 127 ms, H(3)B. accumulates to a maximum of 80% of the total iNOS(heme) concentration in the presence of arginine but only to approximately 2.8% in the presence of NHA. Double-mixing RFQ experiments, where NHA is added after the formation of H(3)B., show that NHA does not react rapidly with H(3)B. and suggest that NHA instead prevents the formation of the H(4)B radical. These data constitute the first direct evidence for an NOS-bound H(3)B. and are most consistent with a role for H(4)B in electron transfer in the NOS reaction.

Arginine↗
PubMed1996

Control of 6-(D-threo-1',2'-dihydroxypropyl) pterin (dictyopterin) synthesis during aggregation of Dictyostelium discoideum. Involvement of the G-protein-linked signalling pathway in the regulation of GTP cyclohydrolase I activity.

6-(D-threo-1',2'-Dihydroxypropylpterin (dictyopterin) has been identified in extracts of growing Dictyostelium dicoideum cells [Klein, Thiery and Tatischeff (1990) Eur. J. Biochem. 187, 665-669]. We demonstrate that it originates from GTP by de novo biosynthesis and that the first committed step is catalysed by GTP cyclohydrolase I, yielding dihydroneopterin triphosphate [neopterin is 6-(D-erythro-1',2',3'-trihydroxypropyl) pterin]. The GTP cyclohydrolase I activity is found in the cytosolic fraction and in a membrane-associated form. The level of a 0.9 kb mRNA coding for GTP cyclohydrolase I decreases to about 10% of its initial value within 2 h after Dictyostelium cells start development induced by starvation. In the cytosolic fraction, the specific activities of GTP cyclohydrolase I, as well as the concentrations of (6R/S)-5,6,7,8-tetrahydrodictyopterin (H4dictyopterin), follow this decline of the mRNA level. In the particulate fraction, however, the specific activities of GTP cyclohydrolase I and, in consequence, H4dictyopterin synthesis, transiently increase and reach a maximum after 4-5 h of development. The time-course of H4dictyopterin concentrations in the starvation medium closely correlates with its production in the membrane fraction. The activity of membrane-associated GTP cyclohydrolase I can be increased by pre-incubation of the cell lysate with guanosine 5'-[gamma-thio]triphosphate and Mg2+. This GTP analogue does not serve as a substrate and has no direct effect on the enzyme activity, indicating that a G-protein-linked signalling pathway is involved in the regulation of GTP cyclohydrolase I activity and thus in H4dictyopterin production during early development of D. discoideum.

Alcohol Oxidoreductases↗
PubMed2000

Abnormalities in urinary pterin levels in Rett syndrome.

The pterins, neopterin and biopterin, occur naturally in body fluids including urine. Increased neopterin levels are associated with activation of the cellular immune system and reduced biopterins are essential for biosynthesis of the monoamine neurotransmitters. The present study measured urinary neopterin and biopterin by high-performance liquid chromatography in 40 subjects with Rett syndrome, eight of their healthy sisters and 29 female control volunteers (age range 2-54 years). The results confirm earlier preliminary findings that urinary neopterin levels are raised in a proportion of young girls with Rett syndrome but not in the older women. In contrast urinary biopterin levels are not different from controls in the youngest children but remain low while control values increase with age. These findings may indicate immune activation during the regression phase of Rett syndrome but also raise the possibility that an inherited fault in tetrahydrobiopterin metabolism increases the risk of developing the disorder.

Adolescent↗
PubMed2002

Folate synthesis in plants: the first step of the pterin branch is mediated by a unique bimodular GTP cyclohydrolase I.

GTP cyclohydrolase I (GCHI) mediates the first and committing step of the pterin branch of the folate-synthesis pathway. In microorganisms and mammals, GCHI is a homodecamer of approximately 26-kDa subunits. Genomic approaches identified tomato and Arabidopsis cDNAs specifying approximately 50-kDa proteins containing two GCHI-like domains in tandem and indicated that such bimodular proteins occur in other plants. Neither domain of these proteins has a full set of the residues involved in substrate binding and catalysis in other GCHIs. The tomato and Arabidopsis cDNAs nevertheless encode functional enzymes, as shown by complementation of a yeast fol2 mutant and by assaying GCHI activity in extracts of complemented yeast cells. Neither domain expressed separately had GCHI activity. Recombinant tomato GCHI formed dihydroneopterin triphosphate as reaction product, as do other GCHIs, but unlike these enzymes it did not show cooperative behavior and was inhibited by its substrate. Denaturing gel electrophoresis verified that the bimodular GCHI polypeptide is not cleaved in vivo into its component domains, and size-exclusion chromatography indicated that the active enzyme is a dimer. The deduced tomato and Arabidopsis GCHI polypeptides lack overt targeting sequences and thus are presumably cytosolic, in contrast to other plant folate-synthesis enzymes, which are mitochondrial proteins with typical signal peptides. GCHI mRNA and protein are strongly in expressed unripe tomato fruits, implying that fruit folate is made in situ rather than imported. As ripening advances, GCHI expression declines sharply, and folate content drops, suggesting that folate synthesis fails to keep pace with turnover.

Amino Acid Sequence↗
PubMed1995

Age structure and reproductive composition of summer Musca autumnalis (Diptera: Muscidae) populations estimated by pterin concentrations.

Pterins in face flies, Musca autumnalis DeGeer, were measured spectrofluorimetrically to estimate the chronological ages of adults in natural summer populations. The age distributions showed a systematic undersampling of young males. Exponential, Gompertz, and Weibull models were fitted to the age distributions. A 1-parameter exponential model suggested mean daily survival rates of 0.83 for female face flies, and a mean life expectation of 5.5 d. But the Weibull model best fit the age distributions, providing mean life expectations of 10.1 and 11 d for males and females, respectively. Ovarian dynamics were examined with respect to chronological age and delays were detected in vitellogenesis and oviposition. Face fly populations seemed to reproduce at less than the maximum rate allowed by prevailing temperatures, at which it was estimated that an average female would undergo 2.2 ovarian cycles and have a lifetime fecundity of 28.5 female progeny.

Aging↗
PubMed1986

Cloning, expression and sequencing the molybdenum-pterin binding protein (mop) gene of Clostridium pasteurianum in Escherichia coli.

mop is the structural gene for the molybdenum-pterin binding protein, which is the major molybdenum binding protein in Clostridium pastuerianum. The mop gene was detected by immunoscreening genomic libraries of C. pastuerianum and identified by determining the nucleotide sequence of the cloned insert of clostridial DNA. The deduced amino acid sequence of an open reading frame proved to be identical to the first twelve residues of purified Mop. The DNA sequence flanking the mop gene contains promoter-like consensus sequences which are probably responsible for the expression of Mop in Escherichia coli. The deduced amino acid composition shows that the protein is hydrophobic, lacks aromatic and cysteine residues and has a calculated molecular weight of 7,038. The N-terminal amino acid sequence of Mop has sequence homology with DNA binding proteins. The pattern and type of residues in the N-terminal region suggest it forms the helix-turn-helix structure observed in DNA binding proteins. We propose that Mop may be a regulatory protein binding the anabolic source of molybdenum.

Amino Acid Sequence↗
PubMed2005

Hydrogen bond removal of pterin derivative whose structure is similar to nucleic acid bases.

Pterin, an analog of guanine, is an electron transfer compound in biological systems. Among the analogs, 6-formylpterin (6FP) has been demonstrated to have many marked physiological and pharmacological activities and it is, therefore, worthwhile to elucidate whole mechanism of its activities. Unfortunately, however, 6FP is hardly soluble in water and organic solvents. Like nucleic acid bases, 6FP makes intermolecular hydrogen bonds and forms stacking structure causing such drawback nature. This has made mechanistic studies on 6FP activities extremely difficult. In this study, we carried out derivatization for 6FP and succeeded in increasing water solubility with maintaining its physiological activities.

Antineoplastic Agents↗
PubMed2000

The molybdenum cofactor biosynthetic protein Cnx1 complements molybdate-repairable mutants, transfers molybdenum to the metal binding pterin, and is associated with the cytoskeleton.

Molybdenum (Mo) plays an essential role in the active site of all eukaryotic Mo-containing enzymes. In plants, Mo enzymes are important for nitrate assimilation, phytohormone synthesis, and purine catabolism. Mo is bound to a unique metal binding pterin (molybdopterin [MPT]), thereby forming the active Mo cofactor (Moco), which is highly conserved in eukaryotes, eubacteria, and archaebacteria. Here, we describe the function of the two-domain protein Cnx1 from Arabidopsis in the final step of Moco biosynthesis. Cnx1 is constitutively expressed in all organs and in plants grown on different nitrogen sources. Mo-repairable cnxA mutants from Nicotiana plumbaginifolia accumulate MPT and show altered Cnx1 expression. Transformation of cnxA mutants and the corresponding Arabidopsis chl-6 mutant with cnx1 cDNA resulted in functional reconstitution of their Moco deficiency. We also identified a point mutation in the Cnx1 E domain of Arabidopsis chl-6 that causes the molybdate-repairable phenotype. Recombinant Cnx1 protein is capable of synthesizing Moco. The G domain binds and activates MPT, whereas the E domain is essential for activating Mo. In addition, Cnx1 binds to the cytoskeleton in the same way that its mammalian homolog gephyrin does in neuronal cells, which suggests a hypothetical model for anchoring the Moco-synthetic machinery by Cnx1 in plant cells.

Amino Acid Sequence↗
PubMed1993

Characterization of Rhodobacter capsulatus genes encoding a molybdenum transport system and putative molybdenum-pterin-binding proteins.

The alternative, heterometal-free nitrogenase of Rhodobacter capsulatus is repressed by traces of molybdenum in the medium. Strains carrying mutations located downstream of nifB copy II were able to express the alternative nitrogenase even in the presence of high molybdate concentrations. DNA sequence analysis of a 5.5-kb fragment of this region revealed six open reading frames, designated modABCD, mopA, and mopB. The gene products of modB and modC are homologous to ChlJ and ChlD of Escherichia coli and represent an integral membrane protein and an ATP-binding protein typical of high-affinity transport systems, respectively. ModA and ModD exhibited no homology to known proteins, but a leader peptide characteristic of proteins cleaved during export to the periplasm is present in ModA, indicating that ModA might be a periplasmic molybdate-binding protein. The MopA and MopB proteins showed a high degree of amino acid sequence homology to each other. Both proteins contained a tandem repeat of a domain encompassing 70 amino acid residues, which had significant sequence similarity to low-molecular-weight molybdenum-pterin-binding proteins from Clostridium pasteurianum. Compared with that for the parental nifHDK deletion strain, the molybdenum concentrations necessary to repress the alternative nitrogenase were increased 4-fold in a modD mutant and 500-fold in modA, modB, and modC mutants. No significant inhibition of the heterometal-free nitrogenase by molybdate was observed for mopA mopB double mutants. The uptake of molybdenum by mod and mop mutants was estimated by measuring the activity of the conventional molybdenum-containing nitrogenase. Molybdenum transport was not affected in a mopA mopB double mutant, whereas strains carrying lesions in the binding-protein-dependent transport system were impaired in molybdenum uptake.

Amino Acid Sequence↗