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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 -
Cell Chemical Biology Sep 2023Uric acid, the end product of purine degradation, causes hyperuricemia and gout, afflicting hundreds of millions of people. The debilitating effects of gout are...
Uric acid, the end product of purine degradation, causes hyperuricemia and gout, afflicting hundreds of millions of people. The debilitating effects of gout are exacerbated by dietary purine intake, and thus a potential therapeutic strategy is to enhance purine degradation in the gut microbiome. Aerobic purine degradation involves oxidative dearomatization of uric acid catalyzed by the O-dependent uricase. The enzymes involved in purine degradation in strictly anaerobic bacteria remain unknown. Here we report the identification and characterization of these enzymes, which include four hydrolases belonging to different enzyme families, and a prenyl-flavin mononucleotide-dependent decarboxylase. Introduction of the first two hydrolases to Escherichia coli Nissle 1917 enabled its anaerobic growth on xanthine as the sole nitrogen source. Oral supplementation of these engineered probiotics ameliorated hyperuricemia in a Drosophila melanogaster model, including the formation of renal uric acid stones and a shortened lifespan, providing a route toward the development of purinolytic probiotics.
Topics: Humans; Animals; Hyperuricemia; Uric Acid; Anaerobiosis; Drosophila melanogaster; Gout; Purines; Escherichia coli; Hydrolases
PubMed: 37164019
DOI: 10.1016/j.chembiol.2023.04.008 -
ELife Feb 2022Adenylosuccinate lyase (ADSL) functions in de novo purine synthesis (DNPS) and the purine nucleotide cycle. ADSL deficiency (ADSLD) causes numerous neurodevelopmental...
Adenylosuccinate lyase (ADSL) functions in de novo purine synthesis (DNPS) and the purine nucleotide cycle. ADSL deficiency (ADSLD) causes numerous neurodevelopmental pathologies, including microcephaly and autism spectrum disorder. ADSLD patients have normal serum purine nucleotide levels but exhibit accumulation of dephosphorylated ADSL substrates, S-Ado, and SAICAr, the latter being implicated in neurotoxic effects through unknown mechanisms. We examined the phenotypic effects of ADSL depletion in human cells and their relation to phenotypic outcomes. Using specific interventions to compensate for reduced purine levels or modulate SAICAr accumulation, we found that diminished AMP levels resulted in increased DNA damage signaling and cell cycle delays, while primary ciliogenesis was impaired specifically by loss of ADSL or administration of SAICAr. ADSL-deficient chicken and zebrafish embryos displayed impaired neurogenesis and microcephaly. Neuroprogenitor attrition in zebrafish embryos was rescued by pharmacological inhibition of DNPS, but not increased nucleotide concentration. Zebrafish also displayed phenotypes commonly linked to ciliopathies. Our results suggest that both reduced purine levels and impaired DNPS contribute to neurodevelopmental pathology in ADSLD and that defective ciliogenesis may influence the ADSLD phenotypic spectrum.
Topics: Adenylosuccinate Lyase; Aminoimidazole Carboxamide; Animals; Autism Spectrum Disorder; Autistic Disorder; Cell Cycle; Cell Cycle Proteins; Cell Line; Chickens; Ciliopathies; DNA Damage; Humans; Microcephaly; Microtubule-Associated Proteins; Neurogenesis; Phenotype; Phosphoproteins; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Ribonucleotides; Zebrafish
PubMed: 35133277
DOI: 10.7554/eLife.70518 -
Hepatology (Baltimore, Md.) Nov 2023Purines are building blocks for the cellular genome, and excessive purine nucleotides are seen in tumors. However, how purine metabolism is dysregulated in tumors, and...
BACKGROUND AND AIMS
Purines are building blocks for the cellular genome, and excessive purine nucleotides are seen in tumors. However, how purine metabolism is dysregulated in tumors, and impacting tumorigenesis remains elusive.
APPROACH AND RESULTS
Transcriptomic and metabolomic analyses of purine biosynthesis and purine degradation pathways were performed in the tumor and associated nontumor liver tissues obtained from 62 patients with HCC, one of the most lethal cancers worldwide. We found that most genes in purine synthesis are upregulated, while genes in purine degradation are inhibited in HCC tumors. High purine anabolism is associated with unique somatic mutational signatures linked to patient prognosis. Mechanistically, we discover that increasing purine anabolism promotes epitranscriptomic dysregulation of DNA damage repairing (DDR) machinery through upregulating RNA N6-methyladenosine (m 6 A) modification. High purine anabolic HCC is sensitive to DDR-targeting agents but not to standard HCC treatments, correlating with the clinical outcomes in 5 independent HCC cohorts containing 724 patients. We further showed that high purine anabolism determines the sensitivity to DDR-targeting agents in 5 HCC cell lines in vitro and in vivo .
CONCLUSIONS
Our results reveal a central role of purine anabolism in regulating DDR, which could be therapeutically exploited in HCC.
Topics: Humans; Carcinoma, Hepatocellular; Cell Line, Tumor; DNA Damage; DNA Repair; Epigenesis, Genetic; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Liver Neoplasms; Purines
PubMed: 37094826
DOI: 10.1097/HEP.0000000000000420 -
Current Opinion in Clinical Nutrition... Jul 2021Purines have several important physiological functions as part of nucleic acids and as intracellular and extracellular signaling molecules. Purine metabolites,... (Review)
Review
PURPOSE OF REVIEW
Purines have several important physiological functions as part of nucleic acids and as intracellular and extracellular signaling molecules. Purine metabolites, particularly uric acid, have been implicated in congenital and complex diseases. However, their role in complex diseases is not clear and they have both beneficial and detrimental effects on disease pathogenesis. In addition, the relationship between purines and complex diseases is affected by genetic and nutritional factors. This review presents latest findings about the relationship between purines and complex diseases and the effect of genes and nutrients on this relationship.
RECENT FINDINGS
Evidence from recent studies show strong role of purines in complex diseases. Although they are causal in only few diseases, our knowledge about their role in other diseases is still evolving. Of all the purines, uric acid is the most studied. Uric acid acts as an antioxidant as well as a prooxidant under different conditions, thus, its role in disease also varies. Other purines, adenosine and inosine have been less studied, but they have neuroprotective properties which are valuable in neurodegenerative diseases.
SUMMARY
Purines are molecules with great potential in disease pathogenesis as either metabolic markers or therapeutic targets. More studies need to be conducted to understand their relevance for complex diseases.
Topics: Humans; Nutrients; Purines; Uric Acid
PubMed: 33928921
DOI: 10.1097/MCO.0000000000000764 -
Rheumatology (Oxford, England) Jul 2022SSc is a chronic autoimmune rheumatic disease that involves numerous organs and presents major management challenges. The histopathologic hallmarks of SSc include...
SSc is a chronic autoimmune rheumatic disease that involves numerous organs and presents major management challenges. The histopathologic hallmarks of SSc include vasculopathy, fibrosis and autoimmune phenomena involving both innate and adaptive immune systems. Purinergic signalling is a pathway that may be implicated in the pathophysiology of several of these disease manifestations. Extracellular purines are potent signalling mediators, which have been shown to be dysregulated in SSc. As examples, purines can exacerbate vasculopathy and provoke platelet dysfunction; as well as contributing to immune dysregulation. Elements of purinergic signalling further promote organ and tissue fibrosis in several disease models. Here, we provide an overview of extracellular purine metabolism in purinergic signalling and link disorders of these to the molecular pathology of SSc. We also discuss targeting the purinergic signalling and explore the translational applications for new therapeutic options in SSc.
Topics: Fibrosis; Humans; Purines; Scleroderma, Systemic; Signal Transduction; Vascular Diseases
PubMed: 34849624
DOI: 10.1093/rheumatology/keab859 -
Methods in Molecular Biology (Clifton,... 2020Purinergic signaling was proposed in 1972, after it was demonstrated that adenosine 5'-triphosphate (ATP) was a transmitter in nonadrenergic, noncholinergic inhibitory...
Purinergic signaling was proposed in 1972, after it was demonstrated that adenosine 5'-triphosphate (ATP) was a transmitter in nonadrenergic, noncholinergic inhibitory nerves supplying the guinea-pig taenia coli. Later, ATP was identified as an excitatory cotransmitter in sympathetic and parasympathetic nerves, and it is now apparent that ATP acts as a cotransmitter in most, if not all, nerves in both the peripheral nervous system and central nervous system (CNS). ATP acts as a short-term signaling molecule in neurotransmission, neuromodulation, and neurosecretion. It also has potent, long-term (trophic) roles in cell proliferation, differentiation, and death in development and regeneration. Receptors to purines and pyrimidines have been cloned and characterized: P1 adenosine receptors (with four subtypes), P2X ionotropic nucleotide receptors (seven subtypes) and P2Y metabotropic nucleotide receptors (eight subtypes). ATP is released from different cell types by mechanical deformation, and after release, it is rapidly broken down by ectonucleotidases. Purinergic receptors were expressed early in evolution and are widely distributed on many different nonneuronal cell types as well as neurons. Purinergic signaling is involved in embryonic development and in the activities of stem cells. There is a growing understanding about the pathophysiology of purinergic signaling and there are therapeutic developments for a variety of diseases, including stroke and thrombosis, osteoporosis, pain, chronic cough, kidney failure, bladder incontinence, cystic fibrosis, dry eye, cancer, and disorders of the CNS, including Alzheimer's, Parkinson's. and Huntington's disease, multiple sclerosis, epilepsy, migraine, and neuropsychiatric and mood disorders.
Topics: Adenosine Triphosphate; Animals; Central Nervous System Diseases; Humans; Nervous System Physiological Phenomena; Purines; Receptors, Purinergic; Signal Transduction; Synaptic Transmission
PubMed: 31646477
DOI: 10.1007/978-1-4939-9717-6_1 -
Cell Biochemistry and Biophysics Dec 2022Phosphoribosyl pyrophosphate synthetase-1 (PRPS-1; EC 2.7.6.1.) catalyzes the binding of phosphate-group to ribose 5-phosphate, forming the...
Phosphoribosyl pyrophosphate synthetase-1 (PRPS-1; EC 2.7.6.1.) catalyzes the binding of phosphate-group to ribose 5-phosphate, forming the 5-phosphoribosyl-1-pyrophosphate, which is necessary for the salvage pathways of purine and pyrimidine, pyridine nucleotide cofactors - NAD and NADP, the amino acids histidine and tryptophan biosynthesis. We aimed to investigate the impact of the different effectors on the activity of PRPS-1, to check the activity of the enzyme in vitro in a wide range of pHs and investigate some structural essentials of the enzyme, isolated from brain and liver. Molecular docking analyses were used to delineate the essentials of PRPS-1 structure, to find out the existence of enzyme effectors. Previously created by us kit was used for determination of the activity of PRPS-1 based on the formation of the inorganic phosphates (λ = 700 nm, Cary 60, Agilent, USA). Effectors impact on the activity of PRPS-1 was evaluated. In silico results of the effectors were later proven by in vitro experiments. For the first time biochemical essentials, including the existence of the multiple pockets, involvement of the amino acids into the processes of interactions with the effectors, evolutional of the sequence conservation, tissue depended V differences were identified.
Topics: Diphosphates; Histidine; Molecular Docking Simulation; NAD; NADP; Nucleotides; Phosphates; Phosphoribosyl Pyrophosphate; Purines; Pyridines; Pyrimidines; Ribose-Phosphate Pyrophosphokinase; Tryptophan
PubMed: 36201097
DOI: 10.1007/s12013-022-01104-1 -
Advances in Microbial Physiology 2023Purines are abundant among organic nitrogen sources and have high nitrogen content. Accordingly, microorganisms have evolved different pathways to catabolize purines and...
Purines are abundant among organic nitrogen sources and have high nitrogen content. Accordingly, microorganisms have evolved different pathways to catabolize purines and their metabolic products such as allantoin. Enterobacteria from the genera Escherichia, Klebsiella and Salmonella have three such pathways. First, the HPX pathway, found in the genus Klebsiella and very close relatives, catabolizes purines during aerobic growth, extracting all four nitrogen atoms in the process. This pathway includes several known or predicted enzymes not previously observed in other purine catabolic pathways. Second, the ALL pathway, found in strains from all three species, catabolizes allantoin during anaerobic growth in a branched pathway that also includes glyoxylate assimilation. This allantoin fermentation pathway originally was characterized in a gram-positive bacterium, and therefore is widespread. Third, the XDH pathway, found in strains from Escherichia and Klebsiella spp., at present is ill-defined but likely includes enzymes to catabolize purines during anaerobic growth. Critically, this pathway may include an enzyme system for anaerobic urate catabolism, a phenomenon not previously described. Documenting such a pathway would overturn the long-held assumption that urate catabolism requires oxygen. Overall, this broad capability for purine catabolism during either aerobic or anaerobic growth suggests that purines and their metabolites contribute to enterobacterial fitness in a variety of environments.
Topics: Allantoin; Uric Acid; Enterobacteriaceae; Purines; Nitrogen
PubMed: 36948655
DOI: 10.1016/bs.ampbs.2023.01.001 -
Expert Opinion on Biological Therapy Apr 2020: The management of patients with ulcerative colitis (UC) has evolved over the past few decades. While aminosalicylates remain the mainstay of induction and maintenance... (Review)
Review
: The management of patients with ulcerative colitis (UC) has evolved over the past few decades. While aminosalicylates remain the mainstay of induction and maintenance therapy in patients with mild-to-moderate UC, the advent of biologic agents and novel oral small molecules has substantively changed the treatment landscape for patients with moderate-to-severe disease and confounded the role of traditional immunomodulators (IMMs) such as thiopurines and methotrexate in the UC management algorithm.: We summarize the mechanism of action of thiopurines and methotrexate, identify clinical parameters for their use, and appraise the evidence supporting the efficacy and safety of IMMs in UC as both monotherapy and in combination with other therapies, emphasizing on prospective, controlled data.: With the advent of several classes of highly effective treatments for UC, emergence of data demonstrating no benefit of IMMs over placebo, and concerns about the relative safety profile of long-term IMM exposure, we propose that the role of thiopurines or methotrexate be restricted to patients with milder disease failing to maintain corticosteroid-free remission on aminosalicylates alone or in combination therapy with tumor necrosis factor antagonists in patients with moderate-to-severe UC.
Topics: Clinical Trials as Topic; Colitis, Ulcerative; Gastrointestinal Diseases; Humans; Immunologic Factors; Methotrexate; Purines; Severity of Illness Index; Treatment Outcome
PubMed: 31874578
DOI: 10.1080/14712598.2020.1708896