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Critical Reviews in Biochemistry and... Feb 2021The focus of this review is the human de novo purine biosynthetic pathway. The pathway enzymes are enumerated, as well as the reactions they catalyze and their physical... (Review)
Review
The focus of this review is the human de novo purine biosynthetic pathway. The pathway enzymes are enumerated, as well as the reactions they catalyze and their physical properties. Early literature evidence suggested that they might assemble into a multi-enzyme complex called a metabolon. The finding that fluorescently-tagged chimeras of the pathway enzymes form discrete puncta, now called purinosomes, is further elaborated in this review to include: a discussion of their assembly; the role of ancillary proteins; their locus at the microtubule/mitochondria interface; the elucidation that at endogenous levels, purinosomes function to channel intermediates from phosphoribosyl pyrophosphate to AMP and GMP; and the evidence for the purinosomes to exist as a protein condensate. The review concludes with a consideration of probable signaling pathways that might promote the assembly and disassembly of the purinosome, in particular the identification of candidate kinases given the extensive phosphorylation of the enzymes. These collective findings substantiate our current view of the de novo purine biosynthetic metabolon whose properties will be representative of how other metabolic pathways might be organized for their function.
Topics: Adenosine Monophosphate; Biosynthetic Pathways; Cyclic AMP; Cyclic GMP; Guanosine Monophosphate; Humans; Microtubules; Mitochondria; Multienzyme Complexes; Phosphoribosyl Pyrophosphate; Phosphorylation; Proteins; Purines; Signal Transduction
PubMed: 33179964
DOI: 10.1080/10409238.2020.1832438 -
Cell Host & Microbe Jun 2023The microbes and microbial pathways that influence host inflammatory disease progression remain largely undefined. Here, we show that variation in atherosclerosis burden...
The microbes and microbial pathways that influence host inflammatory disease progression remain largely undefined. Here, we show that variation in atherosclerosis burden is partially driven by gut microbiota and is associated with circulating levels of uric acid (UA) in mice and humans. We identify gut bacterial taxa spanning multiple phyla, including Bacillota, Fusobacteriota, and Pseudomonadota, that use multiple purines, including UA as carbon and energy sources anaerobically. We identify a gene cluster that encodes key steps of anaerobic purine degradation and that is widely distributed among gut-dwelling bacteria. Furthermore, we show that colonization of gnotobiotic mice with purine-degrading bacteria modulates levels of UA and other purines in the gut and systemically. Thus, gut microbes are important drivers of host global purine homeostasis and serum UA levels, and gut bacterial catabolism of purines may represent a mechanism by which gut bacteria influence health.
Topics: Humans; Animals; Mice; Gastrointestinal Microbiome; Homeostasis; Purines; Bacteria; Uric Acid
PubMed: 37279756
DOI: 10.1016/j.chom.2023.05.011 -
Cell Metabolism Jan 2022Still's disease, the paradigm of autoinflammation-cum-autoimmunity, predisposes for a cytokine storm with excessive T lymphocyte activation upon viral infection. Loss of...
Still's disease, the paradigm of autoinflammation-cum-autoimmunity, predisposes for a cytokine storm with excessive T lymphocyte activation upon viral infection. Loss of function of the purine nucleoside enzyme FAMIN is the sole known cause for monogenic Still's disease. Here we discovered that a FAMIN-enabled purine metabolon in dendritic cells (DCs) restrains CD4 and CD8 T cell priming. DCs with absent FAMIN activity prime for enhanced antigen-specific cytotoxicity, IFNγ secretion, and T cell expansion, resulting in excessive influenza A virus-specific responses. Enhanced priming is already manifest with hypomorphic FAMIN-I254V, for which ∼6% of mankind is homozygous. FAMIN controls membrane trafficking and restrains antigen presentation in an NADH/NAD-dependent manner by balancing flux through adenine-guanine nucleotide interconversion cycles. FAMIN additionally converts hypoxanthine into inosine, which DCs release to dampen T cell activation. Compromised FAMIN consequently enhances immunosurveillance of syngeneic tumors. FAMIN is a biochemical checkpoint that protects against excessive antiviral T cell responses, autoimmunity, and autoinflammation.
Topics: Autoimmunity; CD8-Positive T-Lymphocytes; Dendritic Cells; Lymphocyte Activation; Purines
PubMed: 34986329
DOI: 10.1016/j.cmet.2021.12.009 -
Molecules (Basel, Switzerland) Apr 2022The A adenosine receptor (AAR) is one of the four subtypes activated by nucleoside adenosine, and the molecules able to selectively counteract its action are attractive...
The A adenosine receptor (AAR) is one of the four subtypes activated by nucleoside adenosine, and the molecules able to selectively counteract its action are attractive tools for neurodegenerative disorders. In order to find novel AAR ligands, two series of compounds based on purine and triazolotriazine scaffolds were synthesized and tested at ARs. Compound was also tested in an in vitro model of neuroinflammation. Some compounds were found to possess high affinity for AAR, and it was observed that compound exerted anti-inflammatory properties in microglial cells. Molecular modeling studies results were in good agreement with the binding affinity data and underlined that triazolotriazine and purine scaffolds are interchangeable only when 5- and 2-positions of the triazolotriazine moiety (corresponding to the purine 2- and 8-positions) are substituted.
Topics: Adenosine A2 Receptor Antagonists; Purinergic P1 Receptor Antagonists; Purines; Receptor, Adenosine A2A; Structure-Activity Relationship
PubMed: 35458588
DOI: 10.3390/molecules27082386 -
Molecules (Basel, Switzerland) Oct 2021Beer corresponds to a fermented alcoholic beverage composed of several components, including purine compounds. These molecules, when ingested by humans, can be... (Review)
Review
Beer corresponds to a fermented alcoholic beverage composed of several components, including purine compounds. These molecules, when ingested by humans, can be catabolized into uric acid, contributing to uric acid's level increase in serum, which may lead to hyperuricemia and gout. To assure a proper management of this disease, physicians recommend restrictive dietary measures, particularly by avoiding the consumption of beer. Therefore, it is of relevance to develop efficient methods to remove purine compounds from alcoholic beverages such as beer. In this review, we provide an introduction on fermented alcoholic beverages, with emphasis on beer, as well as its purine compounds and their role in uric acid metabolism in the human body in relation to hyperuricemia and gout development. The several reported enzymatic, biological and adsorption methods envisaging purine compounds' removal are then reviewed. Some enzymatic and biological methods present drawbacks, which can be overcome by adsorption methods. Within adsorption methods, adsorbent materials, such as activated carbon or charcoal, have been reported and applied to beer or wort samples, showing an excellent capacity for adsorbing and removing purine compounds. Although the main topic of this review is on the removal of purine compounds from beer, other studies involving other matrices rather than beer or wort that are rich in purines are included, since they provide relevant clues on designing efficient removal processes. By ensuring the selective removal of purine compounds from this beverage, beer can be taken by hyperuricemic and gouty patients, avoiding restrictive dietary measures, while decreasing the related healthcare economic burden.
Topics: Adsorption; Beer; Molecular Structure; Particle Size; Purines; Surface Properties
PubMed: 34770869
DOI: 10.3390/molecules26216460 -
Purinergic Signalling Dec 2019Extracellular purines (ATP and adenosine) are ubiquitous intercellular messengers. During tissular damage, they function as damage-associated molecular patterns (DAMPs).... (Review)
Review
Extracellular purines (ATP and adenosine) are ubiquitous intercellular messengers. During tissular damage, they function as damage-associated molecular patterns (DAMPs). In this context, purines announce tissue alterations to initiate a reparative response that involve the formation of the inflammasome complex and the recruitment of specialized cells of the immune system. The present review focuses on the role of the purinergic system in liver damage, mainly during the onset and development of fibrosis. After hepatocellular injury, extracellular ATP promotes a signaling cascade that ameliorates tissue alterations to restore the hepatic function. However, if cellular damage becomes chronic, ATP orchestrates an aberrant reparative process that results in severe liver diseases such as fibrosis and cirrhosis. ATP and adenosine, their receptors, and extracellular ectonucleotidases are mediators of unique processes that will be reviewed in detail.
Topics: Adenosine; Adenosine Triphosphate; Animals; Humans; Liver; Liver Diseases; Purines; Receptors, Purinergic
PubMed: 31576486
DOI: 10.1007/s11302-019-09680-3 -
Molecular Cell Sep 2021With the elucidation of myriad anabolic and catabolic enzyme-catalyzed cellular pathways crisscrossing each other, an obvious question arose: how could these networks... (Review)
Review
With the elucidation of myriad anabolic and catabolic enzyme-catalyzed cellular pathways crisscrossing each other, an obvious question arose: how could these networks operate with maximal catalytic efficiency and minimal interference? A logical answer was the postulate of metabolic channeling, which in its simplest embodiment assumes that the product generated by one enzyme passes directly to a second without diffusion into the surrounding medium. This tight coupling of activities might increase a pathway's metabolic flux and/or serve to sequester unstable/toxic/reactive intermediates as well as prevent their access to other networks. Here, we present evidence for this concept, commencing with enzymes that feature a physical molecular tunnel, to multi-enzyme complexes that retain pathway substrates through electrostatics or enclosures, and finally to metabolons that feature collections of enzymes assembled into clusters with variable stoichiometric composition. Lastly, we discuss the advantages of reversibly assembled metabolons in the context of the purinosome, the purine biosynthesis metabolon.
Topics: Animals; Humans; Metabolic Networks and Pathways; Metabolism; Metabolome; Multienzyme Complexes; Protein Interaction Maps; Purines
PubMed: 34547238
DOI: 10.1016/j.molcel.2021.08.030 -
Cells Jan 2019Purine nucleotides are involved in a multitude of cellular processes, and the dysfunction of purine metabolism has drastic physiological and pathological consequences.... (Review)
Review
Purine nucleotides are involved in a multitude of cellular processes, and the dysfunction of purine metabolism has drastic physiological and pathological consequences. Accordingly, several genetic disorders associated with defective purine metabolism have been reported. The etiology of these diseases is poorly understood and simple model organisms, such as yeast, have proved valuable to provide a more comprehensive view of the metabolic consequences caused by the identified mutations. In this review, we present results obtained with the yeast to exemplify how a eukaryotic unicellular organism can offer highly relevant information for identifying the molecular basis of complex human diseases. Overall, purine metabolism illustrates a remarkable conservation of genes, functions and phenotypes between humans and yeast.
Topics: Humans; Metabolic Diseases; Models, Biological; Purines; Saccharomyces cerevisiae; Sequence Homology, Amino Acid
PubMed: 30658520
DOI: 10.3390/cells8010067 -
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 -
Purinergic Signalling Sep 2013The pancreas is an organ with a central role in nutrient breakdown, nutrient sensing and release of hormones regulating whole body nutrient homeostasis. In diabetes... (Review)
Review
The pancreas is an organ with a central role in nutrient breakdown, nutrient sensing and release of hormones regulating whole body nutrient homeostasis. In diabetes mellitus, the balance is broken-cells can be starving in the midst of plenty. There are indications that the incidence of diabetes type 1 and 2, and possibly pancreatogenic diabetes, is rising globally. Events leading to insulin secretion and action are complex, but there is emerging evidence that intracellular nucleotides and nucleotides are not only important as intracellular energy molecules but also as extracellular signalling molecules in purinergic signalling cascades. This signalling takes place at the level of the pancreas, where the close apposition of various cells-endocrine, exocrine, stromal and immune cells-contributes to the integrated function. Following an introduction to diabetes, the pancreas and purinergic signalling, we will focus on the role of purinergic signalling and its changes associated with diabetes in the pancreas and selected tissues/organ systems affected by hyperglycaemia and other stress molecules of diabetes. Since this is the first review of this kind, a comprehensive historical angle is taken, and common and divergent roles of receptors for nucleotides and nucleosides in different organ systems will be given. This integrated picture will aid our understanding of the challenges of the potential and currently used drugs targeted to specific organ/cells or disorders associated with diabetes.
Topics: Animals; Diabetes Mellitus; Humans; Purines; Receptors, Purinergic; Signal Transduction
PubMed: 23546842
DOI: 10.1007/s11302-013-9359-2