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International Journal of Molecular... Oct 2023Red coloration is considered an economically important trait in some fish species, including spotted scat, a marine aquaculture fish. Erythrophores are gradually covered...
Red coloration is considered an economically important trait in some fish species, including spotted scat, a marine aquaculture fish. Erythrophores are gradually covered by melanophores from the embryonic stage. Despite studies of black spot formation and melanophore coloration in the species, little is known about erythrophore development, which is responsible for red coloration. 1-phenyl 2-thiourea (PTU) is a tyrosinase inhibitor commonly used to inhibit melanogenesis and contribute to the visualization of embryonic development. In this study, spotted scat embryos were treated with 0.003% PTU from 0 to 72 h post fertilization (hpf) to inhibit melanin. Erythrophores were clearly observed during the embryonic stage from 14 to 72 hpf, showing an initial increase (14 to 36 hpf), followed by a gradual decrease (36 to 72 hpf). The number and size of erythrophores at 36 hpf were larger than those at 24 and 72 hpf. At 36 hpf, LC-MS and absorbance spectrophotometry revealed that the carotenoid content was eight times higher than the pteridine content, and β-carotene and lutein were the main pigments related to red coloration in spotted scat larvae. Compared with their expression in the normal hatching group, , , and related to retinol metabolism and and related to steroid hormone biosynthesis and steroid biosynthesis were significantly up-regulated in the PTU group, and associated with phototransduction was significantly down-regulated. By qRT-PCR, the expression levels of genes involved in carotenoid metabolism (, , , , , and ), pteridine synthesis (), and chromatophore differentiation ( and ) were significantly higher at 36 hpf than at 24 hpf and 72 hpf, except for . These gene expression profiles were consistent with the developmental changes of erythrophores. These findings provide insights into pigment cell differentiation and gene function in the regulation of red coloration and contribute to selective breeding programs for ornamental aquatic animals.
Topics: Animals; Larva; Fishes; Gene Expression Profiling; Carotenoids; Pteridines; Steroids
PubMed: 37895036
DOI: 10.3390/ijms242015356 -
The Journal of Biological Chemistry May 1997Trypanosomatid protozoans depend upon exogenous sources of pteridines (pterins or folates) for growth. A broad spectrum pteridine reductase (PTR1) was recently...
Trypanosomatid protozoans depend upon exogenous sources of pteridines (pterins or folates) for growth. A broad spectrum pteridine reductase (PTR1) was recently identified in Leishmania major, whose sequence places it in the short chain alcohol dehydrogenase protein family although its enzymatic activities resemble dihydrofolate reductases. The properties of PTR1 suggested a role in essential pteridine salvage as well as in antifolate resistance. To prove this, we have characterized further the properties and relative roles of PTR1 and dihydrofolate reductase-thymidylate synthase in Leishmania pteridine metabolism, using purified enzymes and knockout mutants. Recombinant L. major and Leishmania tarentolae, and native L. major PTR1s, were tetramers of 30-kDa subunits and showed similar catalytic properties with pterins and folates (pH dependence, substrate inhibition with H2pteridines). Unlike PTR1, dihydrofolate reductase-thymidylate synthase showed weak activity with folate and no activity with pterins. Correspondingly, studies of ptr1(-) and dhfr-ts- mutants implicated only PTR1 in the ability of L. major to grow on a wide array of pterins. PTR1 exhibited 2000-fold less sensitivity to inhibition by methotrexate than dihydrofolate reductase-thymidylate synthase, suggesting several mechanisms by which PTR1 may compromise antifolate inhibition in wild-type Leishmania and lines bearing PTR1 amplifications. We incorporate these results into a comprehensive model of pteridine metabolism and discuss its implications in chemotherapy of this important human pathogen.
Topics: Animals; Biopterins; Blotting, Western; Chromatography, Gel; Folic Acid; Folic Acid Antagonists; Humans; Hydrogen-Ion Concentration; Kinetics; Leishmania major; Methotrexate; Models, Chemical; Multienzyme Complexes; NADP; Oxidoreductases; Pteridines; Tetrahydrofolate Dehydrogenase; Thymidylate Synthase
PubMed: 9153248
DOI: 10.1074/jbc.272.21.13883 -
Journal of Medicinal Chemistry Sep 2014Novel substituted pteridine-derived inhibitors of monocarboxylate transporter 1 (MCT1), an emerging target for cancer therapy, are reported. The activity of these...
Novel substituted pteridine-derived inhibitors of monocarboxylate transporter 1 (MCT1), an emerging target for cancer therapy, are reported. The activity of these compounds as inhibitors of lactate transport was confirmed using a (14)C-lactate transport assay, and their potency against MCT1-expressing human tumor cells was established using MTT assays. The four most potent compounds showed substantial anticancer activity (EC50 37-150 nM) vs MCT1-expressing human Raji lymphoma cells.
Topics: Animals; Antineoplastic Agents; Biological Transport; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Humans; Lactic Acid; MCF-7 Cells; Mice; Models, Chemical; Molecular Structure; Monocarboxylic Acid Transporters; Pteridines; Structure-Activity Relationship; Symporters
PubMed: 25068893
DOI: 10.1021/jm500640x -
The Journal of Biological Chemistry Apr 2004The molybdenum cofactor (Moco), a highly conserved pterin compound coordinating molybdenum (Mo), is required for the activity of all Mo-dependent enzymes with the...
The molybdenum cofactor (Moco), a highly conserved pterin compound coordinating molybdenum (Mo), is required for the activity of all Mo-dependent enzymes with the exception of nitrogenase. Moco is synthesized by a unique and evolutionary old multi-step pathway with two intermediates identified so far, the sulfur-free and metal-free pterin derivative precursor Z and molybdopterin, a pterin with an enedithiolate function essential for Mo ligation. The latter pterin component is believed to form a tetrahydropyranopterin similar to the one found for Moco in the crystal structure of Mo as well as tungsten (W) enzymes. Here we report the spectroscopic characterization and structure elucidation of precursor Z purified from Escherichia coli overproducing MoaA and MoaC, two proteins essential for bacterial precursor Z synthesis. We have shown that purified precursor Z is as active as precursor Z present in E. coli cell extracts, demonstrating that no modifications during the purification procedure have occurred. High resolution electrospray ionization mass spectrometry afforded a [M + H]+ ion compatible with a molecular formula of C10H15N5O8P. Consequently 1H NMR spectroscopy not allowed structural characterization of the molecule but confirmed that this intermediate undergoes direct oxidation to the previously well characterized non-productive follow-up product compound Z. The 1H chemical shift and coupling constant data are incompatible with previous structural proposals and indicate that precursor Z already is a tetrahydropyranopterin system and carries a geminal diol function in the C1' position.
Topics: Coenzymes; Escherichia coli; Metalloproteins; Molybdenum; Molybdenum Cofactors; Nuclear Magnetic Resonance, Biomolecular; Protein Conformation; Pteridines; Sulfur
PubMed: 14761975
DOI: 10.1074/jbc.M311815200 -
Genes & Development Feb 2021Molybdenum cofactor (Moco) is synthesized endogenously in humans and is essential for human development. Supplementation of Moco or its precursors has been explored as a... (Review)
Review
Molybdenum cofactor (Moco) is synthesized endogenously in humans and is essential for human development. Supplementation of Moco or its precursors has been explored as a therapy to treat Moco-deficient patients but with significant limitations. By using the nematode as a model, Warnhoff and colleagues (pp. 212-217) describe the beneficial impact of protein-bound Moco supplementation to treat Moco deficiency. If such an effect is conserved, this advance from basic research in worms may have significant clinical implications as a novel therapy for molybdenum cofactor deficiency.
Topics: Animals; Caenorhabditis elegans; Coenzymes; Humans; Metal Metabolism, Inborn Errors; Metalloproteins; Molybdenum Cofactors; Pteridines
PubMed: 33526584
DOI: 10.1101/gad.348176.120 -
Nucleic Acids Research May 1981Queuine, a modified form of 7-deazaguanine present in certain transfer RNAs, is shown to occur in Drosophila melanogaster adults in a free form and its concentration...
Queuine, a modified form of 7-deazaguanine present in certain transfer RNAs, is shown to occur in Drosophila melanogaster adults in a free form and its concentration varies as a function of age, nutrition and genotype. In several, but not all mutant strains, the concentrations of queuine and the Q(+) (queuine-containing) form of tRNATyr are correlated. The bioassay employs L-M cells which respond to the presence of queuine by an increase in their Q(+)tRNAAsp that is accompanied by a decrease in the Q(-)tRNAAsp isoacceptors. The increase in Q(+)tRNATyr in Drosophila that occurs on a yeast diet is accompanied by an increase in queuine. Similarly the increase of Q(+)tRNAs with age also is accompanied by an increase in free queuine. In two mutants, brown and sepia, these correlations were either diminished or failed to occur. Indeed, the extract of both mutants inhibited the response of the L-M cells to authentic queuine. When the pteridines that occur at abnormally high levels in sepia were used at 1 x 10(-6)M, the inhibition of the L-M cell assay occurred in the order biopterin greater than pterin greater than sepiapterin. These pteridines were also inhibitory for the purified guanine:tRNA transglycosylase from rabbit but the relative effectiveness then was pterin greater than biopterin greater than sepiapterin. Pterin was competitive with guanine in the enzyme reaction with Ki = 0.9 x 10(-7)M. Also when an extract of sepia was chromatographed on Sephadex G-50, the pteridine-containing fractions only were inhibitory toward the L-M cell assay or the enzyme assay. These results indicate that free queuine occurs in Drosophila but also that certain pteridines may interfere with the incorporation of queuine into RNA.
Topics: Animals; Drosophila melanogaster; Genotype; Guanine; Kinetics; Mutation; Pentosyltransferases; Pteridines; RNA, Transfer; Transferases
PubMed: 6789305
DOI: 10.1093/nar/9.10.2351 -
ACS Chemical Biology Mar 2020While recognized as a therapeutic target, the spliceosome may offer a robust vector to improve established therapeutics against other protein targets. Here, we describe...
While recognized as a therapeutic target, the spliceosome may offer a robust vector to improve established therapeutics against other protein targets. Here, we describe how modulating the spliceosome using small molecule splice modulators (SPLMs) can prime a cell for sensitivity to a target-specific drug. Using the cell cycle regulators aurora kinase and polo-like kinase as models, this study demonstrates how the combination of SPLM treatment in conjunction with kinase inhibition offers synergy for antitumor activity using reduced, sublethal levels of SPLM and kinase inhibitors. This concept of splice-modulated drug attenuation suggests a possible approach to enhance therapeutic agents that have shown limited applicability due to high toxicity or low efficacy.
Topics: Antineoplastic Agents; Aurora Kinases; Benzamides; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Heterocyclic Compounds, 3-Ring; Humans; Macrolides; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; Pyrazoles; Pyrimidines; Structure-Activity Relationship; Substrate Specificity; Polo-Like Kinase 1
PubMed: 32004428
DOI: 10.1021/acschembio.9b00833 -
Nature Microbiology Nov 2020Escherichia coli is an important model organism in microbiology and a prominent member of the human microbiota. Environmental isolates readily colonize the...
Escherichia coli is an important model organism in microbiology and a prominent member of the human microbiota. Environmental isolates readily colonize the gastrointestinal tract of humans and other animals, and they can serve diverse probiotic, commensal and pathogenic roles in the host. Although certain strains have been associated with the severity of inflammatory bowel disease (IBD), the diverse immunomodulatory phenotypes remain largely unknown at the molecular level. Here, we decode a previously unknown E. coli metabolic pathway that produces a family of hybrid pterin-phenylpyruvate conjugates, which we named the colipterins. The metabolites are upregulated by subinhibitory levels of the antifolate sulfamethoxazole, which is used to treat infections including in patients with IBD. The genes folX/M and aspC/tyrB involved in monapterin biosynthesis and aromatic amino acid transamination, respectively, were required to initiate the colipterin pathway. We show that the colipterins are antioxidants, harbour diverse immunological activities in primary human tissues, activate anti-inflammatory interleukin-10 and improve colitis symptoms in a colitis mouse model. Our study defines an antifolate stress response in E. coli and links its associated metabolites to a major immunological marker of IBD.
Topics: Animals; Antioxidants; Cells, Cultured; Colitis; Disease Models, Animal; Escherichia coli; Escherichia coli Proteins; Gastrointestinal Microbiome; Humans; Immunomodulation; Interleukin-10; Metabolic Networks and Pathways; Mice; Oxidation-Reduction; Pteridines; Stress, Physiological; Sulfamethoxazole
PubMed: 32719505
DOI: 10.1038/s41564-020-0763-4 -
Journal of Pharmacological Sciences Mar 2003Although insulin-resistant states have been associated with endothelial dysfunction due to increased vascular oxidative stress, the underlying mechanisms are pooly... (Review)
Review
Although insulin-resistant states have been associated with endothelial dysfunction due to increased vascular oxidative stress, the underlying mechanisms are pooly understood. Recent experimental evidence suggests that tetrahydrobiopterin (BH(4)), the natural and essential cofactor of NO synthases (NOS), plays a crucial role not only in increasing the rate of NO generation by NOS but also in controlling the formation of superoxide anion (O(2)(-)) in endothelial cells. Because insulin resistance has been suggested to be a significant contributing factor in the development of abnormal pteridine metabolism and endothelial dysfunction, we investigated pteridine content and NO/O(2)(-) production with the use of isolated thoracic aortas obtained from fructose-induced insulin-resistant rats. Under insulin-resistant conditions where BH(4) levels are suboptimal, the production of O(2)(-) by NOS leads to endothelial dysfunction. Furthermore, oral supplementation of BH(4) restores endothelial function and relieved oxidative tissue damage, at least in part, through activation of endothelial NOS (eNOS) in the aorta of insulin-resistant rats. These results indicate that insulin resistance may be a pathogenic factor for endothelial dysfunction through impaired eNOS activity and increased oxidative breakdown of NO due to enhanced formation of O(2)(-), which are caused by relative deficiency of BH(4) in vascular endothelial cells.
Topics: Administration, Oral; Animals; Antioxidants; Biopterins; Cardiovascular Diseases; Endothelium, Vascular; Humans; Insulin; Insulin Resistance; Muscle Relaxation; Nitric Oxide Synthase; Oxidative Stress; Pteridines
PubMed: 12686740
DOI: 10.1254/jphs.91.187 -
FEMS Microbiology Reviews Dec 1998This work gives an overview of the recent achievements which have contributed to the understanding of the structure and function of molybdenum and tungsten enzymes.... (Comparative Study)
Comparative Study Review
This work gives an overview of the recent achievements which have contributed to the understanding of the structure and function of molybdenum and tungsten enzymes. Known structures of molybdo-pterin cofactor-containing enzymes will be described briefly and the structural differences between representatives of the same and different families will be analyzed. This comparison will show that the molybdo-pterin cofactor-containing enzymes represent a very heterogeneous group with differences in overall enzyme structure, cofactor composition and stoichiometry, as well as differences in the immediate molybdenum environment. Two recently discovered molybdo-pterin cofactor-containing enzymes will be described with regard to molecular and EPR spectroscopic properties, pyrogallol-phloroglucinol transhydroxylase from Pelobacter acidigallici and acetylene hydratase from Pelobacter acetylenicus. On the basis of its amino acid sequence, transhydroxylase can be classified as a member of the dimethylsulfoxide reductase family, whereas classification of the tungsten/molybdenum-containing acetylene hydratase has to await the determination of its amino acid sequence.
Topics: Bacteria, Anaerobic; Coenzymes; Humans; Hydro-Lyases; Metalloproteins; Mixed Function Oxygenases; Molybdenum; Molybdenum Cofactors; Oxidoreductases; Oxidoreductases Acting on Sulfur Group Donors; Pteridines; Tungsten; Xanthine Oxidase
PubMed: 9990727
DOI: 10.1111/j.1574-6976.1998.tb00384.x