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Molecular Pharmacology Nov 1977
Topics: Ammonia-Lyases; Animals; Binding, Competitive; Cytosol; Folic Acid; Hydroxymethylbilane Synthase; In Vitro Techniques; Lead; Liver; Porphobilinogen Synthase; Protein Binding; Proteins; Pteridines; Rats; gamma-Glutamyl Hydrolase
PubMed: 593266
DOI: No ID Found -
Journal of Inherited Metabolic Disease 1985In most patients with deficiency of tetrahydrobiopterin (BH4) continuous administration of BH4 or of a synthetic analogue such as 6-methyltetrahydropterin (6-MPH4)...
In most patients with deficiency of tetrahydrobiopterin (BH4) continuous administration of BH4 or of a synthetic analogue such as 6-methyltetrahydropterin (6-MPH4) lowers plasma phenylalanine concentrations to the therapeutic range. The effective dose of BH4 varies from 1 to 2 mg kg-1 daily in patients with defective biopterin synthesis, to 5 mg kg-1 or more in patients with dihydropteridine reductase (DHPR) deficiency. The cost of 2 mg kg-1 day-1 of BH4 is comparable to the cost of a low phenylalanine diet. Higher doses of pterins given orally (20 mg kg-1) raise the levels of tetrahydropterin in cerebrospinal fluid (CSF) to normal in patients with defective biopterin synthesis in whom initial concentration of biopterin species are low. In some, but not all, such patients pterin therapy also raises CSF amine metabolite concentrations and ameliorates symptoms. High dose therapy does not appear to be effective in raising CSF pterin levels in patients with DHPR deficiency who already accumulate dihydrobiopterin (BH2) in CSF. Central folate deficiency is an additional cause of neurological deterioration in patients with DHPR deficiency who require supplementation with folate as folinic acid. It is suggested that the accumulation of BH2 in such patients competitively interferes with folate metabolism.
Topics: Amino Acid Metabolism, Inborn Errors; Biogenic Amines; Biopterins; Brain; Folic Acid; Folic Acid Deficiency; Humans; Infant; Phenylalanine; Phenylketonurias; Pteridines
PubMed: 3930840
DOI: 10.1007/BF01800658 -
Proceedings of the National Academy of... Feb 2008Pteridine reductase (PTR1) is essential for salvage of pterins by parasitic trypanosomatids and is a target for the development of improved therapies. To identify...
Pteridine reductase (PTR1) is essential for salvage of pterins by parasitic trypanosomatids and is a target for the development of improved therapies. To identify inhibitors of Leishmania major and Trypanosoma cruzi PTR1, we combined a rapid-screening strategy using a folate-based library with structure-based design. Assays were carried out against folate-dependent enzymes including PTR1, dihydrofolate reductase (DHFR), and thymidylate synthase. Affinity profiling determined selectivity and specificity of a series of quinoxaline and 2,4-diaminopteridine derivatives, and nine compounds showed greater activity against parasite enzymes compared with human enzymes. Compound 6a displayed a K(i) of 100 nM toward LmPTR1, and the crystal structure of the LmPTR1:NADPH:6a ternary complex revealed a substrate-like binding mode distinct from that previously observed for similar compounds. A second round of design, synthesis, and assay produced a compound (6b) with a significantly improved K(i) (37 nM) against LmPTR1, and the structure of this complex was also determined. Biological evaluation of selected inhibitors was performed against the extracellular forms of T. cruzi and L. major, both wild-type and overexpressing PTR1 lines, as a model for PTR1-driven antifolate drug resistance and the intracellular form of T. cruzi. An additive profile was observed when PTR1 inhibitors were used in combination with known DHFR inhibitors, and a reduction in toxicity of treatment was observed with respect to administration of a DHFR inhibitor alone. The successful combination of antifolates targeting two enzymes indicates high potential for such an approach in the development of previously undescribed antiparasitic drugs.
Topics: Animals; Antiprotozoal Agents; Crystallography, X-Ray; Drug Design; Drug Evaluation, Preclinical; Enzyme Inhibitors; Folic Acid; Isonipecotic Acids; Leishmania major; Oxidoreductases; Parasitic Sensitivity Tests; Protozoan Proteins; Pteridines; Tetrahydrofolate Dehydrogenase; Thymidylate Synthase; Trypanocidal Agents; Trypanosoma cruzi
PubMed: 18245389
DOI: 10.1073/pnas.0704384105 -
Organic & Biomolecular Chemistry Jan 2013Four new acylated pteridine alkaloids, duramidines A-D, two new acylated thymidine alkaloids, leptoclinidines A and B, two new...
Four new acylated pteridine alkaloids, duramidines A-D, two new acylated thymidine alkaloids, leptoclinidines A and B, two new 1-acylglyceryl-3-(O-carboxyhydroxymethylcholine) alkaloids, durabetaines A and B, three new 1,3-dimethyl-5-methylsulfanylimidazole alkaloids, leptoclinidamines D-F, and the known alkaloids leptoclinidamines B and C and 6-bromo-1H-indolo-3-yl-oxoacetic acid methyl ester were isolated from the Australian ascidian Leptoclinides durus. The duramidines are the first pteridine alkaloids, possessing a three carbon side chain esterified at C-1' with a 4-hydroxy-2'-methoxycinnamic acid, and are either hydroxylated or sulfated at C-2'. The leptoclinidines are the first 3'-indole-3-carboxylic acid ester derivatives of thymidine to be reported in the literature. The durabetaines are the first glyceryl-3-(O-carboxyhydroxymethylcholine) alkaloids to be reported from an animal source and are also the only known derivatives from this class to be acylated with aromatic carboxylic acids. MS and NMR data analysis established the structures of the new compounds. All compounds were shown to be inactive when tested for cytotoxic activity against prostate (LNCaP) and breast (MDA-MB-231) cancer cell lines and antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus.
Topics: Alkaloids; Animals; Australia; Betaine; Choline; Dimethyl Sulfoxide; Imidazoles; Magnetic Resonance Spectroscopy; Molecular Conformation; Pteridines; Thymidine; Tryptamines; Urochordata
PubMed: 23160826
DOI: 10.1039/c2ob26879e -
Archiv Der Pharmazie Dec 2022The present article is devoted to searching for biologically active agents among novel thio-containing pteridines. Synthetic protocols based on the condensation of...
The present article is devoted to searching for biologically active agents among novel thio-containing pteridines. Synthetic protocols based on the condensation of 5,6-diamino-2-thioxo-2,3-dihydropyrimidin-4(1H)-ones with dicarbonyl compounds were elaborated and used for the synthesis of target products. The directions for further modification of the obtained thio-containing pteridines were substantiated and realized. The spectral properties of the obtained compounds were studied and described. The results of the in silico study revealed that the predicted affinity of the obtained compounds to the dihydrofolate reductase (DHFR) active site is comparable with the affinity of methotrexate, despite the differences in the nature of the ligand-enzyme interactions. The in vitro study of DHFR-inhibiting activity revealed that the most active compounds 3.9 and 4.2 have lg IC values of -5.889 and -5.233, respectively, significantly inferior to methotrexate (lg IC = -7.605). Additionally, the synthesized compounds were studied for their antiradical activity as a possible mechanism of pharmacological effects. Among the obtained pteridines, compounds 5.1 (lg EC = -4.82) and 5.3 (lg EC = -4.92) have antiradical activity higher than the reference compound ascorbic acid (lg EC = -4.81). The conducted structure-activity relationship analysis provided valuable data for the further search for biologically active agents among thio-containing pteridines and related compounds.
Topics: Pteridines; Folic Acid Antagonists; Methotrexate; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase
PubMed: 36166689
DOI: 10.1002/ardp.202200252 -
Archives of Biochemistry and Biophysics Nov 1958
Topics: Eukaryota; Pteridines; Pterins
PubMed: 13595906
DOI: 10.1016/0003-9861(58)90317-5 -
Biochimica Et Biophysica Acta Mar 2002A gene (slr1166) putatively encoding pteridine glycosyltransferase was disrupted with a kanamycin resistance cassette in Synechocystis sp. PCC 6803, which produces... (Comparative Study)
Comparative Study
A gene (slr1166) putatively encoding pteridine glycosyltransferase was disrupted with a kanamycin resistance cassette in Synechocystis sp. PCC 6803, which produces cyanopterin. The deduced polypeptide from slr1166 consisted of 354 amino acid residues sharing 45% sequence identity with UDP-glucose:tetrahydrobiopterin alpha-glucosyltransferase (BGluT) isolated previously from Synechococcus sp. PCC 7942. The knockout mutant was unable to produce cyanopterin but only 6-hydroxymethylpterin-beta-galactoside, verifying that slr1166 encodes a pteridine glycosyltransferase, which is responsible for transfer of the second sugar glucuronic acid in cyanopterin synthesis. The mutant was affected in its intracellular pteridine content and growth rate, which were 74% and 80%, respectively, of wild type, demonstrating that the second sugar residue is still required for quantitative maintenance of cyanopterin. This supports the previous suggestion that glycosylation may contribute to high cellular concentration of pteridine compounds.
Topics: Amino Acid Sequence; Bacterial Proteins; Cyanobacteria; Disaccharides; Genes, Bacterial; Glucosyltransferases; Glucuronic Acid; Glycosyltransferases; Kanamycin Resistance; Molecular Sequence Data; Pteridines; Pterins
PubMed: 11985899
DOI: 10.1016/s0304-4165(02)00156-3 -
Medical and Veterinary Entomology Mar 2013To assess the potential application of pteridine fluorescence in determining the age of adult Boettcherisca peregrina (Diptera: Sarcophagidae) Robineau-Desvoidy and...
To assess the potential application of pteridine fluorescence in determining the age of adult Boettcherisca peregrina (Diptera: Sarcophagidae) Robineau-Desvoidy and further for the postmortem interval, the age-dependent changes of pteridine fluorescence were investigated for the adults maintained at five constant temperatures. From the results, significant linear relationships were found between pteridine fluorescence and the age of the adults maintained at 16, 20, 24, 28 or 32 °C (P < 0.001, r(2) > 0.85). In addition, the relationships between the rate of pteridine accumulation and temperature were well described using linear equations for adult females and males. Then for each cohort of the flies at the ambient temperature, a calendar was constructed and used to determine the ages of females and males, respectively, in which was recorded in reverse time order the amount of pteridine accumulated per hour by the flies and their expected pteridine level when they emerged at the specified time. A significant linear relationship between estimated ages and chronological ages was observed for female or male adults, with the mean errors of the estimated ages of ±1.82 days for females and ±1.58 days for males. It is suggested that pteridine fluorescence analysis has a potential value in determining the age of adult B. peregrina.
Topics: Aging; Animals; Entomology; Female; Fluorescence; Forensic Sciences; Male; Pteridines; Sarcophagidae; Temperature
PubMed: 22845466
DOI: 10.1111/j.1365-2915.2012.01021.x -
Comparative Biochemistry and... 19821. The crab-eating monkey (Macaca fascicularis) has been studied for enzymes which react in the biosynthesis of pteridine cofactor of phenylalanine hydroxylase: 2....
1. The crab-eating monkey (Macaca fascicularis) has been studied for enzymes which react in the biosynthesis of pteridine cofactor of phenylalanine hydroxylase: 2. Rather high activity of sepiapterin reductase (EC 1.1.1.153)(0.130 mumol) and measurable activity of dihydrofolate reductase (EC 1.5.1.3)(0.039 mumol), (in amount of substrate reduced/hr/mg protein at 37 degrees C) were found in the crude extract from the liver. 3. Sepiapterin reductase was observed, in blood, only in the erythrocytes while dihydrofolate reductase was observed both in erythrocytes and leucocytes. 4. Activity of pteridine cofactor of phenylalanine hydroxylase was detected in the extract of the liver. 5. Sepiapterin reductase was partially purified from the liver, and was studied in the mol. wt, coenzyme-requirement, pH optimum, KmS and inhibitors.
Topics: Alcohol Oxidoreductases; Animals; In Vitro Techniques; Kinetics; Liver; Macaca; Macaca fascicularis; Male; Phenylalanine Hydroxylase; Proteins; Pteridines; Subcellular Fractions; Tetrahydrofolate Dehydrogenase
PubMed: 7037283
DOI: 10.1016/0305-0491(82)90172-9 -
The Journal of Pharmacology and... Oct 1963
Topics: Adrenalectomy; Animals; Anions; Body Fluids; Chlorides; Diuretics; Dogs; Hydrochlorothiazide; Pharmacology; Potassium; Pteridines; Pterins; Rats; Research; Sodium; Triamterene; Urine
PubMed: 14076513
DOI: No ID Found