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Purinergic Signalling Dec 2019Purines, among most influential molecules, are reported to have essential biological function by regulating various cell types. A large number of studies have led to the... (Review)
Review
Purines, among most influential molecules, are reported to have essential biological function by regulating various cell types. A large number of studies have led to the discovery of many biological functions of the purine nucleotides such as ATP, ADP, and adenosine, as signaling molecules that engage G protein-coupled or ligand-gated ion channel receptors. The role of purines in the regulation of cellular functions at the gene or protein level has been well documented. With the advances in multiomics, including those from metabolomic and bioinformatic analyses, metabolic reprogramming was identified as a key mechanism involved in the regulation of cellular function under physiological or pathological conditions. Recent studies suggest that purines or purine-derived products contribute to important regulatory functions in many fundamental biological and pathological processes related to metabolic reprogramming. Therefore, this review summarizes the role and potential mechanism of purines in the regulation of metabolic reprogramming. In particular, the molecular mechanisms of extracellular purine- and intracellular purine-mediated metabolic regulation in various cells during disease development are discussed. In summary, our review provides an extensive resource for studying the regulatory role of purines in metabolic reprogramming and sheds light on the utilization of the corresponding peptides or proteins for disease diagnosis and therapy.
Topics: Adenosine; Adenosine Triphosphate; Animals; Humans; Molecular Targeted Therapy; Purines; Signal Transduction
PubMed: 31493132
DOI: 10.1007/s11302-019-09676-z -
Progress in Neurobiology Sep 2021Despite continuous advances in understanding the underlying pathogenesis of hyperexcitable networks and lowered seizure thresholds, the treatment of epilepsy remains a... (Review)
Review
Despite continuous advances in understanding the underlying pathogenesis of hyperexcitable networks and lowered seizure thresholds, the treatment of epilepsy remains a clinical challenge. Over one third of patients remain resistant to current pharmacological interventions. Moreover, even when effective in suppressing seizures, current medications are merely symptomatic without significantly altering the course of the disease. Much effort is therefore invested in identifying new treatments with novel mechanisms of action, effective in drug-refractory epilepsy patients, and with the potential to modify disease progression. Compelling evidence has demonstrated that the purines, ATP and adenosine, are key mediators of the epileptogenic process. Extracellular ATP concentrations increase dramatically under pathological conditions, where it functions as a ligand at a host of purinergic receptors. ATP, however, also forms a substrate pool for the production of adenosine, via the action of an array of extracellular ATP degrading enzymes. ATP and adenosine have assumed largely opposite roles in coupling neuronal excitability to energy homeostasis in the brain. This review integrates and critically discusses novel findings regarding how ATP and adenosine control seizures and the development of epilepsy. This includes purine receptor P1 and P2-dependent mechanisms, release and reuptake mechanisms, extracellular and intracellular purine metabolism, and emerging receptor-independent effects of purines. Finally, possible purine-based therapeutic strategies for seizure suppression and disease modification are discussed.
Topics: Adenosine; Adenosine Triphosphate; Epilepsy; Humans; Purines; Seizures
PubMed: 34144123
DOI: 10.1016/j.pneurobio.2021.102105 -
Redox Biology Aug 2016It has long been recognized that energy metabolism is linked to the production of reactive oxygen species (ROS) and critical enzymes allied to metabolic pathways can be... (Review)
Review
It has long been recognized that energy metabolism is linked to the production of reactive oxygen species (ROS) and critical enzymes allied to metabolic pathways can be affected by redox reactions. This interplay between energy metabolism and ROS becomes most apparent during the aging process and in the onset and progression of many age-related diseases (i.e. diabetes, metabolic syndrome, atherosclerosis, neurodegenerative diseases). As such, the capacity to identify metabolic pathways involved in ROS formation, as well as specific targets and oxidative modifications is crucial to our understanding of the molecular basis of age-related diseases and for the design of novel therapeutic strategies. Herein we review oxidant formation associated with the cell's energetic metabolism, key antioxidants involved in ROS detoxification, and the principal targets of oxidant species in metabolic routes and discuss their relevance in cell signaling and age-related diseases.
Topics: Adenosine Triphosphate; Animals; Antioxidants; Citric Acid Cycle; Electron Transport Chain Complex Proteins; Energy Metabolism; Fatty Acids; Humans; Inactivation, Metabolic; Metabolic Networks and Pathways; Mitochondria; Oxidants; Oxidation-Reduction; Oxidative Stress; PPAR gamma; Purines; Reactive Oxygen Species
PubMed: 26741399
DOI: 10.1016/j.redox.2015.11.010 -
Neurochemistry International Oct 2020Parkinson's disease (PD) is a neurodegenerative disorder that primarily affects patients over the age of 65. PD is characterized by loss of neurons in the substantia... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disorder that primarily affects patients over the age of 65. PD is characterized by loss of neurons in the substantia nigra and dopamine deficiency in the striatum. Once PD is clinically diagnosed by the observation of motor dysfunction, the disease is already in its advance stages. Consequently, there is a major push to identify clinical biomarkers that are useful for the earlier detection of PD. Using untargeted metabolomics, several research groups have identified purine molecules, and specifically urate, as important biomarkers related to PD. This review will summarize recent findings in the field of purine metabolomics and biomarker identification for PD, including in the areas of PD pathophysiology, diagnosis, prognosis and treatment. In addition, this article will summarize and examine the primary research techniques that are employed to quantify purine molecules in both experimental systems and human subjects.
Topics: Animals; Biomarkers; Brain; Humans; Mass Spectrometry; Metabolomics; Parkinson Disease; Photoelectron Spectroscopy; Positron-Emission Tomography; Purines; Uric Acid
PubMed: 32650026
DOI: 10.1016/j.neuint.2020.104793 -
Nature Apr 2018Alterations in both cell metabolism and transcriptional programs are hallmarks of cancer that sustain rapid proliferation and metastasis . However, the mechanisms that...
Alterations in both cell metabolism and transcriptional programs are hallmarks of cancer that sustain rapid proliferation and metastasis . However, the mechanisms that control the interaction between metabolic reprogramming and transcriptional regulation remain unclear. Here we show that the metabolic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) regulates transcriptional reprogramming by activating the oncogenic steroid receptor coactivator-3 (SRC-3). We used a kinome-wide RNA interference-based screening method to identify potential kinases that modulate the intrinsic SRC-3 transcriptional response. PFKFB4, a regulatory enzyme that synthesizes a potent stimulator of glycolysis , is found to be a robust stimulator of SRC-3 that coregulates oestrogen receptor. PFKFB4 phosphorylates SRC-3 at serine 857 and enhances its transcriptional activity, whereas either suppression of PFKFB4 or ectopic expression of a phosphorylation-deficient Ser857Ala mutant SRC-3 abolishes the SRC-3-mediated transcriptional output. Functionally, PFKFB4-driven SRC-3 activation drives glucose flux towards the pentose phosphate pathway and enables purine synthesis by transcriptionally upregulating the expression of the enzyme transketolase. In addition, the two enzymes adenosine monophosphate deaminase-1 (AMPD1) and xanthine dehydrogenase (XDH), which are involved in purine metabolism, were identified as SRC-3 targets that may or may not be directly involved in purine synthesis. Mechanistically, phosphorylation of SRC-3 at Ser857 increases its interaction with the transcription factor ATF4 by stabilizing the recruitment of SRC-3 and ATF4 to target gene promoters. Ablation of SRC-3 or PFKFB4 suppresses breast tumour growth in mice and prevents metastasis to the lung from an orthotopic setting, as does Ser857Ala-mutant SRC-3. PFKFB4 and phosphorylated SRC-3 levels are increased and correlate in oestrogen receptor-positive tumours, whereas, in patients with the basal subtype, PFKFB4 and SRC-3 drive a common protein signature that correlates with the poor survival of patients with breast cancer. These findings suggest that the Warburg pathway enzyme PFKFB4 acts as a molecular fulcrum that couples sugar metabolism to transcriptional activation by stimulating SRC-3 to promote aggressive metastatic tumours.
Topics: Activating Transcription Factor 4; Animals; Breast Neoplasms; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Glucose; Glycolysis; Humans; Lung Neoplasms; Mice; Neoplasm Metastasis; Nuclear Receptor Coactivator 3; Pentose Phosphate Pathway; Phosphofructokinase-2; Phosphorylation; Phosphoserine; Prognosis; Purines; RNA Interference; Receptors, Estrogen; Transcriptional Activation; Transketolase; Xenograft Model Antitumor Assays
PubMed: 29615789
DOI: 10.1038/s41586-018-0018-1 -
The New England Journal of Medicine Oct 2015
Review
Topics: Anemia, Megaloblastic; DNA; Folic Acid; Gastrointestinal Absorption; Humans; Purines; Pyrimidines; Thymine Nucleotides; Vitamin B 12; Vitamin B 12 Deficiency
PubMed: 26488695
DOI: 10.1056/NEJMra1508861 -
Current Medicinal Chemistry 2023Purine, one of the nucleotides, is an important substance for the metabolism and regulation of the body. Purine plays a key role not only in the composition of coenzymes...
Purine, one of the nucleotides, is an important substance for the metabolism and regulation of the body. Purine plays a key role not only in the composition of coenzymes but also in the supply of energy. Since purine was artificially synthesized, it has always been an important scaffold for respiratory diseases, cardiovascular diseases, and anti- tumor and anti-viral drugs. In addition to being widely used as competitive antagonists in the treatment of diseases, purines can be used in combination with other drugs and as precursors to benefit human life. Unfortunately, few new discoveries have been made in recent years. In this article, purine drugs in the market have been classified according to their different targets. In addition, their mechanism of action and structure-activity relationship have also been introduced. This paper provides details of the signaling pathways through which purine drugs can bind to the respective receptors on the surface of cells and cause consequent reactions within the cell, which finally affect the targeted diseases. The various receptors and biological reactions involved in the signaling for respective disease targets within the cells are discussed in detail.
Topics: Humans; Purines
PubMed: 36201270
DOI: 10.2174/0929867329666221006112458 -
Journal of Structural Biology Mar 2017The recent discovery of several forms of higher order protein structures in cells has shifted the paradigm of how we think about protein organization and metabolic... (Review)
Review
The recent discovery of several forms of higher order protein structures in cells has shifted the paradigm of how we think about protein organization and metabolic regulation. These dynamic and controllable protein assemblies, which are composed of dozens or hundreds of copies of an enzyme or related enzymes, have emerged as important players in myriad cellular processes. We are only beginning to appreciate the breadth of function of these types of macromolecular assemblies. These higher order structures, which can be assembled in response to varied cellular stimuli including changing metabolite concentrations or signaling cascades, give the cell the capacity to modulate levels of biomolecules both temporally and spatially. This provides an added level of control with distinct kinetics and unique features that can be harnessed as a subtle, yet powerful regulatory mechanism. Due, in large part, to advances in structural methods, such as crystallography and cryo-electron microscopy, and the advent of super-resolution microscopy techniques, a rapidly increasing number of these higher order structures are being identified and characterized. In this review, we detail what is known about the structure, function and control mechanisms of these mesoscale protein assemblies, with a particular focus on those involved in purine and pyrimidine metabolism. These structures have important implications both for our understanding of fundamental cellular processes and as fertile ground for new targets for drug discovery and development.
Topics: Animals; Carbon-Nitrogen Ligases; Cryoelectron Microscopy; Humans; Macromolecular Substances; Purines; Pyrimidines
PubMed: 28115257
DOI: 10.1016/j.jsb.2017.01.003 -
Frontiers in Immunology 2022Limiting purine intake, inhibiting xanthine oxidoreductase (XOR) and inhibiting urate reabsorption in proximal tubule by uricosuric drugs, to reduce serum uric acid (UA)...
OBJECTIVE
Limiting purine intake, inhibiting xanthine oxidoreductase (XOR) and inhibiting urate reabsorption in proximal tubule by uricosuric drugs, to reduce serum uric acid (UA) levels, are recognized treatments for gout. However, the mechanism of increased how XOR expression and activity in hyperuricemia and gout remains unclear. This study aims to explore whether exogenous purines are responsible for increased XOR expression and activity.
METHODS
HepG2 and Bel-7402 human hepatoma cells were stimulated with exogenous purine, or were exposed to conditioned growth medium of purine-stimulated Jurkat cells, followed by measurement of XOR expression and UA production to determine the effect of lymphocyte-secreted cytokines on XOR expression in hepatocytes. The expression of STAT1, IRF1 and CBP and their binding on the promoter were detected by western blotting and ChIP-qPCR. The level of DNA methylation was determined by bisulfite sequencing PCR. Blood samples from 117 hyperuricemia patients and 119 healthy individuals were collected to analyze the correlation between purine, UA and IFN-γ concentrations.
RESULTS
Excess of purine was metabolized to UA in hepatocyte metabolism by XOR that was induced by IFN-γ secreted in the conditioned growth medium of Jurkat cells in response to exogenous purine, but it did not directly induce XOR expression. IFN-γ upregulated XOR expression due to the enhanced binding of STAT1 to IRF1 to further recruit CBP to the promoter. Clinical data showed positive correlation of serum IFN-γ with both purine and UA, and associated risk of hyperuricemia.
CONCLUSION
Purine not only acts as a metabolic substrate of XOR for UA production, but it induces inflammation through IFN-γ secretion that stimulates UA production through elevation of XOR expression.
Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Hepatocytes; Humans; Inflammation; Interferon-gamma; Jurkat Cells; Liver Neoplasms; Purines; Up-Regulation; Uric Acid; Xanthine Dehydrogenase
PubMed: 35154100
DOI: 10.3389/fimmu.2022.773001 -
Current Diabetes Reports Jun 2020This article reviews evidence linking cardiometabolic conditions with changes in purine metabolites, including increased serum uric acid (sUA), and discusses... (Review)
Review
PURPOSE OF REVIEW
This article reviews evidence linking cardiometabolic conditions with changes in purine metabolites, including increased serum uric acid (sUA), and discusses intervention studies that investigated the therapeutic relevance of these associations.
RECENT FINDINGS
Metabolic and epidemiological findings support a correlation between sUA and circulating levels of other purines with insulin resistance (IR) and risk factors for cardiovascular disease (CVD). In addition, increased activity of xanthine oxidoreductase (XOR), the rate-limiting enzyme for UA production, has been detected in tissues targeted by obesity. Yet, inhibition of XOR in pre-clinical and clinical studies generally failed to support a causal role for excess sUA in IR and CVD. The lack of efficacy of XOR inhibitors strongly suggests that UA is a marker of, rather than a direct contributory factor for, cardiometabolic diseases. Validation of the function of other purines will require a paradigm shift, from a "UA-centric" view to a more granular assessment of the entire purine network and its interaction with other pathways.
Topics: Diabetes Mellitus, Type 2; Humans; Purines; Uric Acid; Xanthine Dehydrogenase
PubMed: 32519009
DOI: 10.1007/s11892-020-01313-z