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Molecules (Basel, Switzerland) Mar 2021In this report, we employed the solid-phase synthetic approach to prepare variously substituted dihydropteridinones, tetrahydropyrrolopteridinones, and...
In this report, we employed the solid-phase synthetic approach to prepare variously substituted dihydropteridinones, tetrahydropyrrolopteridinones, and pyrimidodiazepinones, using a versatile building block-4,6-dichloro-5-nitropyrimidine. All these compounds are pharmacologically significant scaffolds of the great importance of medicinal chemists. The fast and efficient synthetic methodology is highly desirable for defining their structure-activity relationship (SAR) and optimizing pharmacokinetic properties. Our research efforts utilize simple synthetic methods to generate a library of analogues for future SAR studies. The efficiency of our approach was exemplified in various pteridinones as well as pyrimidodiazepinones.
Topics: Pharmaceutical Preparations; Polymers; Pteridines; Structure-Activity Relationship
PubMed: 33799340
DOI: 10.3390/molecules26061603 -
IUBMB Life Apr 2013Certain pterins having a hydroxyalkyl side chain at C-6 have been found as glycosidic forms in certain prokaryotes, such as 2'-O-(α-D-glucopyranosyl)biopterin from... (Review)
Review
Certain pterins having a hydroxyalkyl side chain at C-6 have been found as glycosidic forms in certain prokaryotes, such as 2'-O-(α-D-glucopyranosyl)biopterin from various kinds of cyanobacteria, and limipterin from a green sulfur photosynthetic bacterium. Synthetic studies on glycosides of biopterin and related pterins have been made in view of the structural proof as well as for closer examination of their biological activities and functions. The syntheses of these natural pterin glycosides have effectively been achieved, mostly through appropriately protected N(2) -(N,N-dimethylaminomethylene)-3-[2-(4-nitrophenyl)ethyl]pterin derivatives as glycosyl acceptors, and are reviewed here.
Topics: Biopterins; Glycosides; Glycosylation; Molecular Structure; Pteridines; Pterins
PubMed: 23436386
DOI: 10.1002/iub.1137 -
Scientific Reports Mar 2018Sulfite oxidase is a mononuclear molybdenum enzyme that oxidises sulfite to sulfate in many organisms, including man. Three different reaction mechanisms have been...
Sulfite oxidase is a mononuclear molybdenum enzyme that oxidises sulfite to sulfate in many organisms, including man. Three different reaction mechanisms have been suggested, based on experimental and computational studies. Here, we study all three with combined quantum mechanical (QM) and molecular mechanical (QM/MM) methods, including calculations with large basis sets, very large QM regions (803 atoms) and QM/MM free-energy perturbations. Our results show that the enzyme is set up to follow a mechanism in which the sulfur atom of the sulfite substrate reacts directly with the equatorial oxo ligand of the Mo ion, forming a Mo-bound sulfate product, which dissociates in the second step. The first step is rate limiting, with a barrier of 39-49 kJ/mol. The low barrier is obtained by an intricate hydrogen-bond network around the substrate, which is preserved during the reaction. This network favours the deprotonated substrate and disfavours the other two reaction mechanisms. We have studied the reaction with both an oxidised and a reduced form of the molybdopterin ligand and quantum-refinement calculations indicate that it is in the normal reduced tetrahydro form in this protein.
Topics: Animals; Chickens; Coenzymes; Hydrogen Bonding; Mechanical Phenomena; Metalloproteins; Models, Molecular; Molecular Dynamics Simulation; Molybdenum; Molybdenum Cofactors; Pteridines; Quantum Theory; Sulfite Oxidase; Sulfites
PubMed: 29549261
DOI: 10.1038/s41598-018-22751-6 -
The FEBS Journal Jun 2013The xylene ring of riboflavin (vitamin B2 ) is assembled from two molecules of 3,4-dihydroxy-2-butanone 4-phosphate by a mechanistically complex process that is jointly... (Review)
Review
The xylene ring of riboflavin (vitamin B2 ) is assembled from two molecules of 3,4-dihydroxy-2-butanone 4-phosphate by a mechanistically complex process that is jointly catalyzed by lumazine synthase and riboflavin synthase. In Bacillaceae, these enzymes form a structurally unique complex comprising an icosahedral shell of 60 lumazine synthase subunits and a core of three riboflavin synthase subunits, whereas many other bacteria have empty lumazine synthase capsids, fungi, Archaea and some eubacteria have pentameric lumazine synthases, and the riboflavin synthases of Archaea are paralogs of lumazine synthase. The structures of the molecular ensembles have been studied in considerable detail by X-ray crystallography, X-ray small-angle scattering and electron microscopy. However, certain mechanistic aspects remain unknown. Surprisingly, the quaternary structure of the icosahedral β subunit capsids undergoes drastic changes, resulting in formation of large, quasi-spherical capsids; this process is modulated by sequence mutations. The occurrence of large shells consisting of 180 or more lumazine synthase subunits has recently generated interest for protein engineering topics, particularly the construction of encapsulation systems.
Topics: Archaea; Bacteria; Escherichia coli Proteins; Fungi; Multienzyme Complexes; Plants; Pteridines; Riboflavin; Riboflavin Synthase; Schizosaccharomyces
PubMed: 23551830
DOI: 10.1111/febs.12255 -
Bioscience Reports Jan 2020Molybdenum insertases (Mo-insertases) catalyze the final step of molybdenum cofactor (Moco) biosynthesis, an evolutionary old and highly conserved multi-step pathway. In...
Molybdenum insertases (Mo-insertases) catalyze the final step of molybdenum cofactor (Moco) biosynthesis, an evolutionary old and highly conserved multi-step pathway. In the first step of the pathway, GTP serves as substrate for the formation of cyclic pyranopterin monophosphate, which is subsequently converted into molybdopterin (MPT) in the second pathway step. In the following synthesis steps, MPT is adenylated yielding MPT-AMP that is subsequently used as substrate for enzyme catalyzed molybdate insertion. Molybdate insertion and MPT-AMP hydrolysis are catalyzed by the Mo-insertase E-domain. Earlier work reported a highly conserved aspartate residue to be essential for Mo-insertase functionality. In this work, we confirmed the mechanistic relevance of this residue for the Arabidopsis thaliana Mo-insertase Cnx1E. We found that the conservative substitution of Cnx1E residue Asp274 by Glu (D274E) leads to an arrest of MPT-AMP hydrolysis and hence to the accumulation of MPT-AMP. We further showed that the MPT-AMP accumulation goes in hand with the accumulation of molybdate. By crystallization and structure determination of the Cnx1E variant D274E, we identified the potential reason for the missing hydrolysis activity in the disorder of the region spanning amino acids 269 to 274. We reasoned that this is caused by the inability of a glutamate in position 274 to coordinate the octahedral Mg2+-water complex in the Cnx1E active site.
Topics: Adenosine Monophosphate; Amino Acid Sequence; Amino Acids; Arabidopsis; Arabidopsis Proteins; Catalysis; Catalytic Domain; Coenzymes; Hydrolysis; Metalloproteins; Molybdenum; Molybdenum Cofactors; Organophosphorus Compounds; Pteridines; Pterins
PubMed: 31860061
DOI: 10.1042/BSR20191806 -
Journal of Medicinal Chemistry Jul 2022The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present a systematic, multidisciplinary...
The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present a systematic, multidisciplinary approach to the development of selective antiparasitic compounds. Computational fragment-based design of novel pteridine derivatives along with iterations of crystallographic structure determination allowed for the derivation of a structure-activity relationship for multitarget inhibition. The approach yielded compounds showing apparent picomolar inhibition of pteridine reductase 1 (PTR1), nanomolar inhibition of PTR1, and selective submicromolar inhibition of parasite dihydrofolate reductase (DHFR) versus human DHFR. Moreover, by combining design for polypharmacology with a property-based on-parasite optimization, we found three compounds that exhibited micromolar EC values against while retaining their target inhibition. Our results provide a basis for the further development of pteridine-based compounds, and we expect our multitarget approach to be generally applicable to the design and optimization of anti-infective agents.
Topics: Leishmania major; Oxidoreductases; Pteridines; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase; Trypanosoma brucei brucei
PubMed: 35675511
DOI: 10.1021/acs.jmedchem.2c00232 -
Genes & Development Feb 2021The molybdenum cofactor (Moco) is a 520-Da prosthetic group that is synthesized in all domains of life. In animals, four oxidases (among them sulfite oxidase) use Moco...
The molybdenum cofactor (Moco) is a 520-Da prosthetic group that is synthesized in all domains of life. In animals, four oxidases (among them sulfite oxidase) use Moco as a prosthetic group. Moco is essential in animals; humans with mutations in genes that encode Moco biosynthetic enzymes display lethal neurological and developmental defects. Moco supplementation seems a logical therapy; however, the instability of Moco has precluded biochemical and cell biological studies of Moco transport and bioavailability. The nematode can take up Moco from its bacterial diet and transport it to cells and tissues that express Moco-requiring enzymes, suggesting a system for Moco uptake and distribution. Here we show that protein-bound Moco is the stable, bioavailable species of Moco taken up by from its diet and is an effective dietary supplement, rescuing a model of Moco deficiency. We demonstrate that diverse Moco:protein complexes are stable and bioavailable, suggesting a new strategy for the production and delivery of therapeutically active Moco to treat human Moco deficiency.
Topics: Animals; Bacteria; Biological Transport; Caenorhabditis elegans; Coenzymes; Humans; Metal Metabolism, Inborn Errors; Metalloproteins; Molybdenum Cofactors; Protein Binding; Pteridines
PubMed: 33446569
DOI: 10.1101/gad.345579.120 -
Bioscience Reports Nov 2020The molybdenum cofactor (Moco) is a redox active prosthetic group found in the active site of Moco-dependent enzymes (Mo-enzymes). As Moco and its intermediates are...
The molybdenum cofactor (Moco) is a redox active prosthetic group found in the active site of Moco-dependent enzymes (Mo-enzymes). As Moco and its intermediates are highly sensitive towards oxidative damage, these are believed to be permanently protein bound during synthesis and upon maturation. As a major component of the plant Moco transfer and storage system, proteins have been identified that are capable of Moco binding and release but do not possess Moco-dependent enzymatic activities. The first protein found to possess these properties was the Moco carrier protein (MCP) from the green alga Chlamydomonas reinhardtii. Here, we describe the identification and biochemical characterisation of the Volvox carteri (V. carteri) MCP and, for the first time, employ a comparative analysis to elucidate the principles behind MCP Moco binding. Doing so identified a sequence region of low homology amongst the existing MCPs, which we showed to be essential for Moco binding to V. carteri MCP.
Topics: Carrier Proteins; Coenzymes; Metalloproteins; Models, Molecular; Molybdenum Cofactors; Plant Proteins; Protein Binding; Protein Conformation; Protein Interaction Domains and Motifs; Pteridines; Structure-Activity Relationship; Volvox
PubMed: 33084886
DOI: 10.1042/BSR20202351 -
Ecotoxicology and Environmental Safety Apr 2024Triphenyltin (TPT) is a typical persistent organic pollutant whose occurrence in coral reef ecosystems may threaten the survival of reef fishes. In this study, a...
Triphenyltin (TPT) is a typical persistent organic pollutant whose occurrence in coral reef ecosystems may threaten the survival of reef fishes. In this study, a brightly colored representative reef fish, Amphiprion ocellaris was used to explore the effects of TPT at environmental levels (1, 10, and 100 ng/L) on skin pigment synthesis. After the fish were exposed to TPT for 60 days, the skin became darker, owing to an increase in the relative area of black stripes, a decrease in orange color values while an increase in brown color values, and an increase in the number of melanocytes in the orange part of the skin tissues. To explore the mechanisms by which TPT induces darker body coloration, the enzymatic activity and gene expression levels of the members of melanocortin system that affect melanin synthesis were evaluated. Leptin levels and lepr expression were found to be increased after TPT exposure, which likely contributed to the increase found in pomc expression and α-melanocyte-stimulating hormone (α-MSH) levels. Then Tyr activity and mc1r, tyr, tyrp1, mitf, and dct were upregulated, ultimately increasing melanin levels. Importantly, RT-qPCR results were consistent with the transcriptome analysis of trends in lepr and pomc expression. Because the orange color values decreased, pterin levels and the pteridine metabolic pathway were also evaluated. The results showed that TPT induced BH levels and spr, xdh, and gch1 expression associated with pteridine synthesis decreased, ultimately decreasing the colored pterin content (sepiapterin). We conclude that TPT exposure interferes with the melanocortin system and pteridine metabolic pathway to increase melanin and decrease colored pterin levels, leading to darker body coloration in A. ocellaris. Given the importance of body coloration for the survival and reproduction of reef fishes, studies on the effects of pollutants (others alongside TPT) on body coloration are of high priority.
Topics: Animals; Melanocortins; Pro-Opiomelanocortin; Ecosystem; Melanins; Pteridines; Fishes; Perciformes; Pterins; Metabolic Networks and Pathways; Organotin Compounds
PubMed: 38461573
DOI: 10.1016/j.ecoenv.2024.116177 -
Nature Communications Jun 2019The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small...
The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08-2750 (Ro) binds directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrates in vivo inhibition of c-MYC and reduces disease burden in a murine AML leukemia model. Thus, we identify a small molecule that targets MSI's oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.
Topics: Animals; Apoptosis; Flavins; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Humans; Leukemia, Experimental; Leukemia, Myeloid, Acute; Male; Mice; Primary Cell Culture; Proto-Oncogene Proteins c-myc; Pteridines; RNA; RNA Recognition Motif; RNA, Small Interfering; RNA-Binding Proteins; Transcriptome; Tumor Cells, Cultured
PubMed: 31217428
DOI: 10.1038/s41467-019-10523-3