-
ENeuro Oct 2023The levels of purines, essential molecules to sustain eukaryotic cell homeostasis, are regulated by the coordination of the and salvage synthesis pathways. In the...
The levels of purines, essential molecules to sustain eukaryotic cell homeostasis, are regulated by the coordination of the and salvage synthesis pathways. In the embryonic central nervous system (CNS), the pathway is considered crucial to meet the requirements for the active proliferation of neural stem/progenitor cells (NSPCs). However, how these two pathways are balanced or separately used during CNS development remains poorly understood. In this study, we showed a dynamic shift in pathway utilization, with greater reliance on the pathway during embryonic stages and on the salvage pathway in postnatal-adult mouse brain. The pharmacological effects of various purine synthesis inhibitors and the expression profile of purine synthesis enzymes indicated that NSPCs in the embryonic cerebrum mainly use the pathway. Simultaneously, NSPCs in the cerebellum require both the and the salvage pathways. administration of inhibitors resulted in severe hypoplasia of the forebrain cortical region, indicating a gradient of purine demand along the anteroposterior axis of the embryonic brain, with cortical areas of the dorsal forebrain having higher purine requirements than ventral or posterior areas such as the striatum and thalamus. This histologic defect of the neocortex was accompanied by strong downregulation of the mechanistic target of rapamycin complex 1 (mTORC1)/ribosomal protein S6 kinase (S6K)/S6 signaling cascade, a crucial pathway for cell metabolism, growth, and survival. These findings indicate the importance of the spatiotemporal regulation of both purine pathways for mTORC1 signaling and proper brain development.
Topics: Mice; Animals; Purines; Homeostasis; Brain; Mechanistic Target of Rapamycin Complex 1
PubMed: 37770184
DOI: 10.1523/ENEURO.0159-23.2023 -
Journal of Biological Inorganic... Dec 2022New mono- and di-nuclear thio-purine and thio-purine nucleoside gold(I) complexes were synthesized, characterized, and evaluated in vitro for biological activities in...
New mono- and di-nuclear thio-purine and thio-purine nucleoside gold(I) complexes were synthesized, characterized, and evaluated in vitro for biological activities in comparison to related known purine complexes. By combining known anti-tumoral thio-purines with RPAu moieties as present in auranofin, complexes with enhanced effects and selectivities were obtained, which not only act as cytostatics, but also disrupt tumor-specific processes. Their IC values in cytotoxicity test with tumor cell lines ranged from three-digit nanomolar to single-digit micromolar, revealing a tentative structure-activity relationship (SAR). Both the residues R of the phosphane ligand and R at C2 of the pyrimidine ring had a significant impact on the cytotoxicity. In most cases, the introduction of a ribo-furanosyl group at N9 of the purine led to a distinctly more cytotoxic complex. Most complexes were more active against multi-drug-resistant tumor cells or such lacking functional p53 when compared to the respective untreated wild type cell lines. Some nucleoside complexes displayed an interesting dose-dependent dual mode of action regarding cell cycle arrest and DNA repair mechanism. Some phosphane(purine-6-thiolato)gold (I) complexes had a stronger inhibitory effect on the thioredoxin reductase (TrxR) and on the reactive oxygen species (ROS) generation in cancer cells than is typical of other gold complexes. They also led to DNA fragmentation and showed anti-angiogenic effects. Their stability under test conditions was demonstrated by Se NMR monitoring of an exemplary selenopurine complex.
Topics: Gold; Phosphines; Thioredoxin-Disulfide Reductase; Purines; Cell Line, Tumor; Antineoplastic Agents; Coordination Complexes
PubMed: 36244017
DOI: 10.1007/s00775-022-01968-x -
Bioengineered 2015The purine degradation pathway in humans ends with uric acid, which has low water solubility. When the production of uric acid is increased either by elevated purine... (Review)
Review
The purine degradation pathway in humans ends with uric acid, which has low water solubility. When the production of uric acid is increased either by elevated purine intake or by impaired kidney function, uric acid will accumulate in the blood (hyperuricemia). This increases the risk of gout, a disease described in humans for at least 1000 years. Many lower organisms, such as the yeast Arxula adeninivorans, possess the enzyme, urate oxidase that converts uric acid to 5-hydroxyisourate, thus preventing uric acid accumulation. We have examined the complete purine degradation pathway in A. adeninivorans and analyzed enzymes involved. Recombinant adenine deaminase, guanine deaminase, urate oxidase and endogenous xanthine oxidoreductase have been investigated as potential additives to degrade purines in the food. Here, we review the current model of the purine degradation pathway of A. adeninivorans and present an overview of proposed enzyme system with perspectives for its further development.
Topics: Food Additives; Fungal Proteins; Purines; Saccharomycetales; Urate Oxidase
PubMed: 25513995
DOI: 10.4161/21655979.2014.991667 -
Plant Physiology Jan 2020Nucleotide metabolism is an essential function in plants.
Nucleotide metabolism is an essential function in plants.
Topics: Models, Biological; Nucleotides; Plants; Purines; Pyrimidines
PubMed: 31641078
DOI: 10.1104/pp.19.00955 -
The Veterinary Clinics of North... Jan 2009The way in which veterinary scientists think about and approach the study of genetic disease has not changed, but the tools available to veterinary scientists have and... (Review)
Review
The way in which veterinary scientists think about and approach the study of genetic disease has not changed, but the tools available to veterinary scientists have and will continue to change, allowing us to study increasingly complex problems and to make more rapid advances in the context of simple problems. To put these advances in perspective, this article first gives a historical perspective on the approaches to studying genetic diseases, particularly in human beings, and then outlines the advances that have become possible with the availability of the dog genome sequence. The article then discusses two inherited defects that are associated with urolithiasis, in particular, those responsible for cystine and purine (uric acid and its salts) stone formation. Together, these two conditions illustrate the contemporary use of a broad range of genetic approaches.
Topics: Animals; Breeding; Cystine; Dog Diseases; Dogs; Female; Genetic Predisposition to Disease; Genome; Male; Purines; Urinary Calculi; Urolithiasis
PubMed: 19038654
DOI: 10.1016/j.cvsm.2008.09.006 -
Future Medicinal Chemistry Jul 2013Malaria is a leading cause of human death within the tropics. The gradual generation of drug resistance imposes an urgent need for the development of new and selective... (Review)
Review
Malaria is a leading cause of human death within the tropics. The gradual generation of drug resistance imposes an urgent need for the development of new and selective antimalarial agents. Kinetic isotope effects coupled to computational chemistry have provided the relevant details on geometry and charge of enzymatic transition states to facilitate the design of transition-state analogs. These features have been reproduced into chemically stable mimics through synthetic chemistry, generating inhibitors with dissociation constants in the pico- to femto-molar range. Transition-state analogs are expected to contribute to the control of malaria.
Topics: Adenylosuccinate Lyase; Antimalarials; Bacterial Proteins; Enzyme Inhibitors; Humans; Malaria; Pentosyltransferases; Plasmodium falciparum; Purines; Pyrrolidines; Tetrahydrofolate Dehydrogenase
PubMed: 23859211
DOI: 10.4155/fmc.13.51 -
PloS One 2012The antioxidant defense system, which is known to be dysregulated in schizophrenia, is closely linked to the dynamics of purine pathway. Thus, alterations in the...
BACKGROUND
The antioxidant defense system, which is known to be dysregulated in schizophrenia, is closely linked to the dynamics of purine pathway. Thus, alterations in the homeostatic balance in the purine pathway may be involved in the pathophysiology of schizophrenia.
METHODOLOGY/PRINCIPAL FINDINGS
Breakdown products in purine pathway were measured using high-pressure liquid chromatography coupled with a coulometric multi-electrode array system for 25 first-episode neuroleptic-naïve patients with schizophrenia at baseline and at 4-weeks following initiation of treatment with antipsychotic medication. Associations between these metabolites and clinical and neurological symptoms were examined at both time points. The ratio of uric acid and guanine measured at baseline predicted clinical improvement following four weeks of treatment with antipsychotic medication. Baseline levels of purine metabolites also predicted clinical and neurological symtpoms recorded at baseline; level of guanosine was associated with degree of clinical thought disturbance, and the ratio of xanthosine to guanosine at baseline predicted degree of impairment in the repetition and sequencing of actions.
CONCLUSIONS/SIGNIFICANCE
Findings suggest an association between optimal levels of purine byproducts and dynamics in clinical symptoms and adjustment, as well as in the integrity of sensory and motor processing. Taken together, alterations in purine catabolism may have clinical relevance in schizophrenia pathology.
Topics: Adolescent; Adult; Chromatography, High Pressure Liquid; Electrochemical Techniques; Electrodes; Female; Homeostasis; Humans; Male; Purines; Schizophrenia; Young Adult
PubMed: 22916123
DOI: 10.1371/journal.pone.0042165 -
Revista Medica de Chile Jul 2013Uric acid is the final metabolite of purine break down, such as ATP, ADP, AMP, adenosine, inosine and hypoxanthine. The metabolite has been used broadly as a renal... (Review)
Review
Uric acid is the final metabolite of purine break down, such as ATP, ADP, AMP, adenosine, inosine and hypoxanthine. The metabolite has been used broadly as a renal failure marker, as well as a risk factor for maternal and neonatal morbidity during pre-eclamptic pregnancies. High purine levels are observed in pre-eclamptic pregnancies, but the sources of these purines are unknown. However, there is evidence that pre-eclampsia (mainly severe pre-eclampsia) is associated with an increased release of cellular fragments (or microparticles) from the placenta to the maternal circulation. These in fact could be the substrate for purine metabolism. Considering this background, we propose that purines and uric acid are part of the same physiopathological phenomenon in pre-eclampsia (i.e., placental dysfunction) and could become biomarkers for placental dysfunction and postnatal adverse events.
Topics: Biomarkers; Female; Humans; Placenta; Pre-Eclampsia; Pregnancy; Purines; Uric Acid
PubMed: 24356738
DOI: 10.4067/S0034-98872013000700009 -
Current Medicinal Chemistry 2016The enzyme xanthine oxidoreductase (XOR) catalyzes the last two steps of purine catabolism in the highest uricotelic primates. XOR is an enzyme with dehydrogenase... (Review)
Review
The enzyme xanthine oxidoreductase (XOR) catalyzes the last two steps of purine catabolism in the highest uricotelic primates. XOR is an enzyme with dehydrogenase activity that, in mammals, may be converted into oxidase activity under a variety of pathophysiologic conditions. XOR activity is highly regulated at the transcriptional and post-translational levels and may generate reactive oxygen and nitrogen species, which trigger different consequences, ranging from cytotoxicity to inflammation. The low specificity for substrates allows XOR to metabolize a number of endogenous metabolites and a variety of exogenous compounds, including drugs. The present review focuses on the role of XOR as a drug-metabolizing enzyme, specifically for drugs with anticancer, antimicrobial, antiviral, immunosuppressive or vasodilator activities, as well as drugs acting on metabolism or inducing XOR expression. XOR has an activating role that is essential to the pharmacological action of quinone drugs, cyadox, antiviral nucleoside analogues, allopurinol, nitrate and nitrite. XOR activity has a degradation function toward thiopurine nucleotides, pyrazinoic acid, methylxanthines and tolbutamide, whose half-life may be prolonged by the use of XOR inhibitors. In conclusion, to avoid potential drug interaction risks, such as a toxic excess of drug bioavailability or a loss of drug efficacy, caution is suggested in the use of XOR inhibitors, as in the case of hyperuricemic patients affected by gout or tumor lysis syndrome, when it is necessary to simultaneously administer therapeutic substances that are activated or degraded by the drug-metabolizing activity of XOR.
Topics: Animals; Anti-Infective Agents; Antineoplastic Agents; Benzoquinones; Humans; Immunosuppressive Agents; Pharmaceutical Preparations; Purines; Vasodilator Agents; Xanthine Dehydrogenase
PubMed: 27458036
DOI: 10.2174/0929867323666160725091915 -
The Journal of Physical Chemistry. B Jan 2014The structure and properties of the electron donor-acceptor complexes formed between methyl viologen and purine nucleosides and nucleotides in water and the solid state...
The structure and properties of the electron donor-acceptor complexes formed between methyl viologen and purine nucleosides and nucleotides in water and the solid state have been investigated using a combination of experimental and theoretical methods. Solution studies were performed using UV-vis and (1)H NMR spectroscopy. Theoretical calculations were performed within the framework of density functional theory (DFT). Energy decomposition analysis indicates that dispersion and induction (charge-transfer) interactions dominate the total binding energy, whereas electrostatic interactions are largely repulsive. The appearance of charge transfer bands in the absorption spectra of the complexes are well-described by time-dependent DFT and are further explained in terms of the redox properties of purine monomers and solvation effects. Crystal structures are reported for complexes of methyl viologen with the purines 2'-deoxyguanosine 3'-monophosphate (DAD'DAD' type) and 7-deazaguanosine (DAD'ADAD' type). Comparison of the structures determined in the solid state and by theoretical methods in solution provides valuable insights into the nature of charge-transfer interactions involving purine bases as electron donors.
Topics: Crystallography, X-Ray; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; Paraquat; Protons; Purines; Quantum Theory; Spectrophotometry, Ultraviolet
PubMed: 24294996
DOI: 10.1021/jp410348b