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International Journal of Molecular... Jul 2022Ligand modification by substituting chemical groups within the binding pocket is a popular strategy for kinase drug development. In this study, a series of...
Ligand modification by substituting chemical groups within the binding pocket is a popular strategy for kinase drug development. In this study, a series of pteridin-7(8)-one derivatives targeting wild-type FMS-like tyrosine kinase-3 (FLT3) and its D835Y mutant (FL3) were studied using a combination of molecular modeling techniques, such as docking, molecular dynamics (MD), binding energy calculation, and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies. We determined the protein-ligand binding affinity by employing molecular mechanics Poisson-Boltzmann/generalized Born surface area (MM-PB/GBSA), fast pulling ligand (FPL) simulation, linear interaction energy (LIE), umbrella sampling (US), and free energy perturbation (FEP) scoring functions. The structure-activity relationship (SAR) study was conducted using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), and the results were emphasized as a SAR scheme. In both the CoMFA and CoMSIA models, satisfactory correlation statistics were obtained between the observed and predicted inhibitory activity. The MD and SAR models were co-utilized to design several new compounds, and their inhibitory activities were anticipated using the CoMSIA model. The designed compounds with higher predicted pIC values than the most active compound were carried out for binding free energy evaluation to wild-type and mutant receptors using MM-PB/GBSA, LIE, and FEP methods.
Topics: Binding Sites; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Pteridines; Quantitative Structure-Activity Relationship; fms-Like Tyrosine Kinase 3
PubMed: 35887060
DOI: 10.3390/ijms23147696 -
Environmental Microbiology Jun 2020The biosynthesis of the molybdenum cofactor (Moco) is highly conserved among all kingdoms of life. In all molybdoenzymes containing Moco, the molybdenum atom is... (Review)
Review
The biosynthesis of the molybdenum cofactor (Moco) is highly conserved among all kingdoms of life. In all molybdoenzymes containing Moco, the molybdenum atom is coordinated to a dithiolene group present in the pterin-based 6-alkyl side chain of molybdopterin (MPT). In general, the biosynthesis of Moco can be divided into four steps in in bacteria: (i) the starting point is the formation of the cyclic pyranopterin monophosphate (cPMP) from 5'-GTP, (ii) in the second step the two sulfur atoms are inserted into cPMP leading to the formation of MPT, (iii) in the third step the molybdenum atom is inserted into MPT to form Moco and (iv) in the fourth step bis-Mo-MPT is formed and an additional modification of Moco is possible with the attachment of a nucleotide (CMP or GMP) to the phosphate group of MPT, forming the dinucleotide variants of Moco. This review presents an update on the well-characterized Moco biosynthesis in the model organism Escherichia coli including novel discoveries from the recent years.
Topics: Coenzymes; Escherichia coli; Metalloproteins; Molybdenum; Molybdenum Cofactors; Organophosphorus Compounds; Pteridines; Pterins
PubMed: 32239579
DOI: 10.1111/1462-2920.15003 -
Current Opinion in Psychiatry May 2015Since decades immunological aberrancies have been reported in schizophrenia patients. As schizophrenia represents a heterogenous disorder with a variety of clinical... (Review)
Review
PURPOSE OF REVIEW
Since decades immunological aberrancies have been reported in schizophrenia patients. As schizophrenia represents a heterogenous disorder with a variety of clinical manifestations, complex interactions between the immune system in the brain might have important etiological implications.
RECENT FINDINGS
Recent findings of altered expression of immune-related genes, changes of peripheral and central cytokines, antibodies and immune cells point toward dysbalanced immune response processes in schizophrenia.
SUMMARY
Based on immunogenetic factors, immune dysfunctions caused by infections, increased autoimmune reactivity and low-grade inflammatory processes in the periphery as well as in central nervous system may affect neurobiological circuits including changed neurotransmitter metabolisms contributing to pathophysiological alterations in schizophrenia. These immunological abnormalities might provide tools for better diagnostic characterization of this heterogenous disease and on the other side, they may also support the development of immune-related therapeutic strategies.
Topics: Autoimmunity; Brain; Cytokines; Humans; Inflammation; Neurotransmitter Agents; Phenylalanine Hydroxylase; Psychoneuroimmunology; Pteridines; Schizophrenia
PubMed: 25768084
DOI: 10.1097/YCO.0000000000000153 -
Journal of Biological Inorganic... Feb 2021Mo nitrogenase is the primary source of biologically fixed nitrogen, making this system highly interesting for developing new, energy efficient ways of ammonia...
Mo nitrogenase is the primary source of biologically fixed nitrogen, making this system highly interesting for developing new, energy efficient ways of ammonia production. Although heavily investigated, studies of the active site of this enzyme have generally been limited to spectroscopic methods that are compatible with the presence of water and relatively low protein concentrations. One method of overcoming this limitation is through lyophilization, which allows for measurements to be performed on solvent free, high concentration samples. This method also has the potential for allowing efficient protein storage and solvent exchange. To investigate the viability of this preparatory method with Mo nitrogenase, we employ a combination of electron paramagnetic resonance, Mo and Fe K-edge X-ray absorption spectroscopy, and acetylene reduction assays. Our results show that while some small distortions in the metallocofactors occur, oxidation and spin states are maintained through the lyophilization process and that reconstitution of either lyophilized protein component into buffer restores acetylene reducing activity.
Topics: Acetylene; Biocatalysis; Coenzymes; Electron Spin Resonance Spectroscopy; Enzyme Assays; Freeze Drying; Iron; Metalloproteins; Molybdenum; Molybdenum Cofactors; Nitrogenase; Pteridines; X-Ray Absorption Spectroscopy
PubMed: 33381859
DOI: 10.1007/s00775-020-01838-4 -
Molecules (Basel, Switzerland) Dec 2018All eukaryotic molybdenum (Mo) enzymes contain in their active site a Mo Cofactor (Moco), which is formed by a tricyclic pyranopterin with a dithiolene chelating the Mo... (Review)
Review
All eukaryotic molybdenum (Mo) enzymes contain in their active site a Mo Cofactor (Moco), which is formed by a tricyclic pyranopterin with a dithiolene chelating the Mo atom. Here, the eukaryotic Moco biosynthetic pathway and the eukaryotic Moco enzymes are overviewed, including nitrate reductase (NR), sulfite oxidase, xanthine oxidoreductase, aldehyde oxidase, and the last one discovered, the moonlighting enzyme mitochondrial Amidoxime Reducing Component (mARC). The mARC enzymes catalyze the reduction of hydroxylated compounds, mostly N-hydroxylated (NHC), but as well of nitrite to nitric oxide, a second messenger. mARC shows a broad spectrum of NHC as substrates, some are prodrugs containing an amidoxime structure, some are mutagens, such as 6-hydroxylaminepurine and some others, which most probably will be discovered soon. Interestingly, all known mARC need the reducing power supplied by different partners. For the NHC reduction, mARC uses cytochrome b5 and cytochrome b5 reductase, however for the nitrite reduction, plant mARC uses NR. Despite the functional importance of mARC enzymatic reactions, the structural mechanism of its Moco-mediated catalysis is starting to be revealed. We propose and compare the mARC catalytic mechanism of nitrite versus NHC reduction. By using the recently resolved structure of a prokaryotic MOSC enzyme, from the mARC protein family, we have modeled an in silico three-dimensional structure of a eukaryotic homologue.
Topics: Animals; Cardiac Myosins; Coenzymes; Enzymes; Eukaryotic Cells; Mammals; Metabolic Networks and Pathways; Metalloproteins; Molybdenum; Molybdenum Cofactors; Myosin Light Chains; Nitrate Reductase; Nitrites; Oxidoreductases; Pteridines
PubMed: 30545001
DOI: 10.3390/molecules23123287 -
Chemistry (Weinheim An Der Bergstrasse,... May 2023Unconjugated pterins are ubiquitous molecules that participate in countless enzymatic processes and are potentially involved in the photosensitization of singlet oxygen,...
Unconjugated pterins are ubiquitous molecules that participate in countless enzymatic processes and are potentially involved in the photosensitization of singlet oxygen, amino acids, and nucleotides. Following electronic excitation with UV-A light, some of these pterins degrade, producing hydrogen peroxide as the main side product. This process, which is known to take place in vivo, contributes to oxidative stress and melanocyte destruction in vitiligo. In this work, we present for the first time mechanistic insight into the formation of transient triplet species that simultaneously trigger Type I and Type II photosensitizing processes and the initiation of degradation processes. Our calculations reveal that photodegradation of 6-biopterin, which accumulates in the skin of vitiligo patients, leads to 6-formylpterin through a retro-aldol reaction, and subsequently to 6-carboxypterin through a water-mediated aldehyde oxidation. Additionally, we show that the changes in the photosensitizing potential of these systems with pH come from the modulation of their excited-state redox potentials.
Topics: Humans; Vitiligo; Photolysis; Photosensitizing Agents; Pterins; Oxidation-Reduction
PubMed: 36929221
DOI: 10.1002/chem.202300519 -
Journal of Insect Physiology Oct 2019Social insects are emerging models for studying aging and the longevity/fecundity trade-off. Research on the demography of colonies and populations are hampered by the...
Social insects are emerging models for studying aging and the longevity/fecundity trade-off. Research on the demography of colonies and populations are hampered by the lack of reliable age markers. Here we investigate the suitability of cuticular pigmentation and pteridine fluorescence for age grading individuals of the clonal ant Platythyrea punctata. We found that both traits varied with age. Cuticular color darkened with individual's age until 25-30 days after hatching. For pteridine fluorescence, we found that P. punctata workers show a decrease in head pteridine levels over time until 70-80 days of age. Together with other markers, such as age-based behavior, cuticular coloration and pteridine fluorescence may help to estimate the age structure of colonies.
Topics: Aging; Animals; Ants; Color; Fluorescence; Pteridines
PubMed: 31518554
DOI: 10.1016/j.jinsphys.2019.103943 -
IUBMB Life Jul 2022Flavoproteins are key players in numerous redox pathways in cells. Flavin cofactors FMN and FAD confer the required chemical reactivity to flavoenzymes. In most cases,...
Flavoproteins are key players in numerous redox pathways in cells. Flavin cofactors FMN and FAD confer the required chemical reactivity to flavoenzymes. In most cases, the interaction between the proteins and the flavins is noncovalent, yet stronger in comparison to other redox-active cofactors, such as NADH and NADPH. The association is considered static, but this view has started to change with the recent discovery of the dynamic association of flavins and flavoenzymes. Six cases from different organisms and various metabolic pathways are discussed here. The available mechanistic details span the range from rudimentary, as in the case of the ER-resident oxidoreductase Ero1, to comprehensive, as for the bacterial respiratory complex I. The same holds true in regard to the assumed functional role of the dynamic association presented here. More work is needed to clarify the structural and functional determinants of the known examples. Identification of new cases will help to appreciate the generality of the new principle of intracellular flavoenzyme regulation.
Topics: Dinitrocresols; Flavin Mononucleotide; Flavin-Adenine Dinucleotide; Flavins; Flavoproteins; Oxidation-Reduction
PubMed: 35015339
DOI: 10.1002/iub.2591 -
Nature Dec 2022Structural insights into a long-studied folate-transport protein provide evidence that might lead to entirely new targeted anticancer treatments, or boost the success of...
Structural insights into a long-studied folate-transport protein provide evidence that might lead to entirely new targeted anticancer treatments, or boost the success of immunotherapy approaches to tackling tumours.
Topics: Folic Acid
PubMed: 36418878
DOI: 10.1038/d41586-022-03767-5 -
Spectrochimica Acta. Part A, Molecular... May 2022The spectral and photophysical properties of two four-ring alloxazine derivatives, naphtho[2,3-g]pteridine-2,4(1H,3H)-dione (1a) and...
The spectral and photophysical properties of two four-ring alloxazine derivatives, naphtho[2,3-g]pteridine-2,4(1H,3H)-dione (1a) and 1,3-dimethylnaphtho[2,3-g]pteridine-2,4(1H,3H)-dione, (1b) were studied. The propensity of 1a for excited-state proton transfer reactions in the presence of acetic acid as a catalyst was also studied, showing no signature of the reaction occurring. In addition, quenching of 1a fluorescence by acetic acid was investigated. Singlet and triplet states and spectral data for 1a and 1b were calculated using density functional theory TD-DFT at B3LYP/6-31G(d) and UB3LYP levels. Finally, fluorescence lifetime imaging microscopy (FLIM) using 1a and 1b as fluorescence probes was applied to in vitro human red blood cells (RBCs) with and without tert-butyl hydroperoxide (TB) as an oxidising agent. To evaluate and compare the effects of 1a and 1b on the redox properties of RBCs, the fluorescence lifetime, amplitude and fractional intensities were calculated, and phasor plot analysis was performed. The results obtained show the appearance of a new proximal cluster in the phasor fingerprint of RBCs in the presence of 1b and a shorter fluorescence lifetime of RBCs in the presence of 1a.
Topics: Flavins; Fluorescent Dyes; Microscopy, Fluorescence; Oxidation-Reduction
PubMed: 35152097
DOI: 10.1016/j.saa.2022.120985