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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 -
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 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 -
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 -
Cellular and Molecular Life Sciences :... Jun 2007Adenosine 5'-triphosphate (ATP), in addition to its intracellular roles, acts as an extracellular signalling molecule via a rich array of receptors, which have been... (Review)
Review
Adenosine 5'-triphosphate (ATP), in addition to its intracellular roles, acts as an extracellular signalling molecule via a rich array of receptors, which have been cloned and characterised. P1 receptors are selective for adenosine, a breakdown product of ATP, produced after degradation by ectonucleotidases. Four subtypes have been identified, A(1), A(2A), A(2B) and A(3) receptors. P2 receptors are activated by purines and some subtypes also by pyrimidines. P2X receptors are ligand-gated ion channel receptors and seven subunits have been identified, which form both homomultimers and heteromultimers. P2Y receptors are G protein-coupled receptors, and eight subtypes have been cloned and characterised to date.
Topics: Adenosine Triphosphate; Animals; Dimerization; Gene Expression Regulation; Humans; Purinergic P1 Receptor Agonists; Purinergic P2 Receptor Agonists; Purines; Pyrimidines; Receptors, Purinergic P1; Receptors, Purinergic P2; Transcriptional Activation
PubMed: 17375261
DOI: 10.1007/s00018-007-6497-0 -
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 -
Molecular BioSystems Mar 2014Some metabolic pathway enzymes are known to organize into multi-enzyme complexes for reasons of catalytic efficiency, metabolite channeling, and other advantages of... (Review)
Review
Some metabolic pathway enzymes are known to organize into multi-enzyme complexes for reasons of catalytic efficiency, metabolite channeling, and other advantages of compartmentalization. It has long been an appealing prospect that de novo purine biosynthesis enzymes form such a complex, termed the "purinosome." Early work characterizing these enzymes garnered scarce but encouraging evidence for its existence. Recent investigations led to the discovery in human cell lines of purinosome bodies-cytoplasmic puncta containing transfected purine biosynthesis enzymes, which were argued to correspond to purinosomes. New discoveries challenge both the functional and physiological relevance of these bodies in favor of protein aggregation.
Topics: Cytoplasmic Granules; Humans; Multienzyme Complexes; Protein Binding; Protein Transport; Proteins; Purines
PubMed: 24413256
DOI: 10.1039/c3mb70397e -
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