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International Journal of Cardiology Jun 2016Purines perform many important functions in the cell, being the formation of the monomeric precursors of nucleic acids DNA and RNA the most relevant one. Purines which... (Review)
Review
Purines perform many important functions in the cell, being the formation of the monomeric precursors of nucleic acids DNA and RNA the most relevant one. Purines which also contribute to modulate energy metabolism and signal transduction, are structural components of some coenzymes and have been shown to play important roles in the physiology of platelets, muscles and neurotransmission. All cells require a balanced quantity of purines for growth, proliferation and survival. Under physiological conditions the enzymes involved in the purine metabolism maintain in the cell a balanced ratio between their synthesis and degradation. In humans the final compound of purines catabolism is uric acid. All other mammals possess the enzyme uricase that converts uric acid to allantoin that is easily eliminated through urine. Overproduction of uric acid, generated from the metabolism of purines, has been proven to play emerging roles in human disease. In fact the increase of serum uric acid is inversely associated with disease severity and especially with cardiovascular disease states. This review describes the enzymatic pathways involved in the degradation of purines, getting into their structure and biochemistry until the uric acid formation.
Topics: 5'-Nucleotidase; Adenosine Deaminase; Cardiovascular Diseases; Humans; Metabolic Networks and Pathways; Purines; Uric Acid; Xanthine Dehydrogenase
PubMed: 26316329
DOI: 10.1016/j.ijcard.2015.08.109 -
Redox Biology May 2021Human xanthine oxidoreductase (XOR) is a multiple-level regulated enzyme, resulting from a complicated evolutionary process that assigned it many physiological roles.... (Review)
Review
Human xanthine oxidoreductase (XOR) is a multiple-level regulated enzyme, resulting from a complicated evolutionary process that assigned it many physiological roles. The main XOR activities are: (i) xanthine dehydrogenase (XDH) activity that performs the last two steps of purine catabolism, from hypoxanthine to uric acid; (ii) xanthine oxidase (XO) activity that, besides purine catabolism, produces reactive oxygen species (ROS); (iii) nitrite reductase activity that generates nitric oxide, contributing to vasodilation and regulation of blood pressure; (iv) NADH oxidase activity that produces ROS. All these XOR activities contribute also to metabolize various endogenous and exogenous compounds, including some drugs. About XOR products, it should be considered that (i) uric acid is not only a proinflammatory agent, but also a fundamental antioxidant molecule in serum and (ii) XOR-derived ROS are essential to the inflammatory defensive response. Although XOR has been the object of a large number of studies, most of them were focused on the pathological consequences of its activity and there is not a clear and schematic picture of XOR physiological roles. In this review, we try to fill this gap, reporting and graphically schematizing the main roles of XOR and its products.
Topics: Humans; Nitric Oxide; Oxidation-Reduction; Reactive Oxygen Species; Uric Acid; Xanthine Dehydrogenase; Xanthine Oxidase
PubMed: 33578127
DOI: 10.1016/j.redox.2021.101882 -
New insights into purine metabolism in metabolic diseases: role of xanthine oxidoreductase activity.American Journal of Physiology.... Nov 2020Xanthine oxidoreductase (XOR) consists of two different forms, xanthine dehydrogenase and xanthine oxidase (XO), and is a rate-limiting enzyme of uric acid production... (Review)
Review
Xanthine oxidoreductase (XOR) consists of two different forms, xanthine dehydrogenase and xanthine oxidase (XO), and is a rate-limiting enzyme of uric acid production from hypoxanthine and xanthine. Uric acid is the end product of purine metabolism in humans and has a powerful antioxidant effect. The lack of ascorbic acid, known as vitamin C, in hominoids has been thought to cause a compensatory increase in uric acid as an antioxidant by unfunctional gene mutation of uricase to a pseudogene. Because XO is involved in an increase in reactive oxygen species (ROS) by generating superoxide and hydrogen peroxide, inadequate activation of XOR promotes oxidative stress-related tissue injury. Plasma XOR activity is associated with obesity, smoking, liver dysfunction, hyperuricemia, dyslipidemia, insulin resistance, and adipokines, indicating a novel biomarker of metabolic disorders. However, XOR activity in adipose tissue is low in humans unlike in rodents, and hypoxanthine is secreted from human adipose tissue. The concentration of hypoxanthine, but not xanthine, is independently associated with obesity in a general population, indicating differential regulation of hypoxanthine and xanthine. Treatment with an XOR inhibitor can decrease uric acid for preventing gout, reduce production of XO-related ROS, and promote reutilization of hypoxanthine and ATP production through the salvage pathway. It has recently been suggested that discontinuation of an XOR inhibitor causes adverse cardiovascular outcomes as XOR inhibitor withdrawal syndrome, possibly due to cardiac disturbance of conduction and contraction by reduced ATP production. New insights into purine metabolism, including the role of XOR activity in the past 5 yr, are mainly discussed in this review.
Topics: Biomarkers; Humans; Metabolic Diseases; Purines; Reactive Oxygen Species; Uric Acid; Xanthine Dehydrogenase
PubMed: 32893671
DOI: 10.1152/ajpendo.00378.2020 -
Molecules (Basel, Switzerland) Feb 2023A personal perspective is provided regarding the work in several laboratories, including the author's, that has established the reaction mechanism of xanthine oxidase... (Review)
Review
A personal perspective is provided regarding the work in several laboratories, including the author's, that has established the reaction mechanism of xanthine oxidase and related enzymes.
Topics: Xanthine Oxidase; Electron Spin Resonance Spectroscopy; Molybdenum; Xanthine Dehydrogenase
PubMed: 36838909
DOI: 10.3390/molecules28041921 -
International Journal of Cardiology Jun 2016Hyperuricemia has long been established as the major etiologic factor in gout. Alongside with an inflammatory state triggered by urate crystal deposition in the joints,... (Review)
Review
Hyperuricemia has long been established as the major etiologic factor in gout. Alongside with an inflammatory state triggered by urate crystal deposition in the joints, hyperuricemia displayed additional pathophysiological consequences leading to tissue inflammation mainly in the vascular wall. Thus, therapeutic strategies used to treat hyperuricemia in the past decades have often been focused on limiting acute episodes. Recently, evidence has been accumulated suggesting that chronic urate deposition requires a correct treatment not limited to acute episodes based on the modulation of the activity of key enzymes involved in metabolism and excretion of urate including xanthine oxidoreductase (XO) and URAT1. The present review article will try to summarize the most recent evidences on the efficacy of XO inhibitors and uricosuric compounds in lowering uric acid levels in both the bloodstream and peripheral tissues. In particular, we will focus on the effect of novel XO inhibitors in counteracting uric acid overproduction. On the other hand, the effect of lowering uric acid levels via XO inhibition will be correlated with attenuation oxidative stress which leads to endothelial dysfunction thereby contributing to the pathophysiology of diabetes, hypertension, arteriosclerosis, and chronic heart failure. Hence, scavenging and prevention of the XO generated oxygen radical accumulation emerge as an intriguing novel treatment option to counteract uric acid-induced tissue damages.
Topics: Enzyme Inhibitors; Gout Suppressants; Humans; Hyperuricemia; Oxidative Stress; Uric Acid; Xanthine Dehydrogenase
PubMed: 26320372
DOI: 10.1016/j.ijcard.2015.08.087 -
Pharmacological Research Oct 2022The present review explores the role of xanthine oxidoreductase (XOR) in the development and progression of chronic kidney disease (CKD). Human XOR is a multi-level... (Review)
Review
The present review explores the role of xanthine oxidoreductase (XOR) in the development and progression of chronic kidney disease (CKD). Human XOR is a multi-level regulated enzyme, which has many physiological functions, but that is also implicated in several pathological processes. The main XOR activities are the purine catabolism, which generates uric acid, and the regulation of cell redox state and cell signaling, through the production of reactive oxygen species. XOR dysregulation may lead to hyperuricemia and oxidative stress, which could have a pathogenic role in the initial phases of CKD, by promoting cell injury, hypertension, chronic inflammation and metabolic derangements. Hypertension is common in CKD patients and many mechanisms inducing it (upregulation of renin-angiotensin-aldosterone system, endothelial dysfunction and atherosclerosis) may be influenced by XOR products. High XOR activity and hyperuricemia are also risk factors for obesity, insulin resistance, type 2 diabetes and metabolic syndrome that are frequent CKD causes. Moreover, CKD is common in patients with gout, which is characterized by hyperuricemia, and in patients with cardiovascular diseases, which are associated with hypertension, endothelial dysfunction and atherosclerosis. Although hyperuricemia is undoubtedly related to CKD, controversial findings have been hitherto reported in patients treated with urate-lowering therapies.
Topics: Atherosclerosis; Diabetes Mellitus, Type 2; Humans; Hypertension; Hyperuricemia; Purines; Reactive Oxygen Species; Renal Insufficiency, Chronic; Uric Acid; Xanthine Dehydrogenase
PubMed: 35995347
DOI: 10.1016/j.phrs.2022.106407 -
Age Jul 1997Xanthine dehydrogenase (XDH) and xanthine oxidase (XOD) are single-gene products that exist in separate but interconvertible forms. XOD utilizes hypoxanthine or xanthine...
Xanthine dehydrogenase (XDH) and xanthine oxidase (XOD) are single-gene products that exist in separate but interconvertible forms. XOD utilizes hypoxanthine or xanthine as a substrate and O2 as a cofactor to produce superoxide (·O2 (-)) and uric acid. XDH acts on these same substrates but utilizes NAD as a cofactor to produce NADH instead of ·O2 (-) and uric acid. XOD has been proposed as a source of oxygen radicals in polymorphonuclear, endothelial, epithelial, and connective tissue cells. However, several questions remain about the physiological significance and functions of XOD on aging and oxidative stress. XOD is reported to play an important role in cellular oxidative status, detoxification of aldehydes, oxidative injury in ischemia-reperfusion, and neutrophil mediation. For example, XOD may serve as a messenger or mediator in the activation of neutrophil, T cell, cytokines, or transcription in defense mechanisms rather than as a free radical generator of tissue damage. Emerging evidence on the synergistic interactions of ·O2 (-), a toxic product of XOD and nitric oxide, may be another illustration of XOD involvement in tissue injury and cytotoxicity in an emergent condition such as ischemia or inflammation.
PubMed: 23604305
DOI: 10.1007/s11357-997-0012-2 -
Oxidative Medicine and Cellular... 2016Xanthine oxidoreductase (XOR) is the enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid and is widely distributed among species.... (Review)
Review
Xanthine oxidoreductase (XOR) is the enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid and is widely distributed among species. In addition to this housekeeping function, mammalian XOR is a physiological source of superoxide ion, hydrogen peroxide, and nitric oxide, which can function as second messengers in the activation of various pathways. This review intends to address the physiological and pathological roles of XOR-derived oxidant molecules. The cytocidal action of XOR products has been claimed in relation to tissue damage, in particular damage induced by hypoxia and ischemia. Attempts to exploit this activity to eliminate unwanted cells via the construction of conjugates have also been reported. Moreover, different aspects of XOR activity related to phlogosis, endothelial activation, leukocyte activation, and vascular tone regulation, have been taken into consideration. Finally, the positive and negative outcomes concerning cancer pathology have been analyzed because XOR products may induce mutagenesis, cell proliferation, and tumor progression, but they are also associated with apoptosis and cell differentiation. In conclusion, XOR activity generates free radicals and other oxidant reactive species that may result in either harmful or beneficial outcomes.
Topics: Antioxidants; Apoptosis; Cell Adhesion; Endothelial Cells; Enzyme Inhibitors; Focal Adhesion Protein-Tyrosine Kinases; Free Radicals; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Nitric Oxide; Phosphorylation; Protein Tyrosine Phosphatases; Reactive Oxygen Species; Vanadates; Xanthine Dehydrogenase; Xanthine Oxidase
PubMed: 26823950
DOI: 10.1155/2016/3527579 -
Pathology Oncology Research : POR Jan 2014Free radical mediated pathologies occupy a special place in medical semiology and in mechanistic interpretation of diseases. Free radicals, or better reactive oxygen... (Review)
Review
Free radical mediated pathologies occupy a special place in medical semiology and in mechanistic interpretation of diseases. Free radicals, or better reactive oxygen species (ROS) or reactive nitrogen species (RNS) play also an important role in cell signaling. This is the basis of the ambivalent (Jekyll-Hyde) situation of ROS in biology and pathology. Aging itself is attributed by a popular theory to free radicals. A number of ROS-scavenging substances and procedures were described without however reaching credibility for their therapeutic value. An interesting exception is the xanthine oxido-reductase produced ROS and their role in cardiovascular disease. Allopurinol inhibition of xanthine oxido-reductase was shown to be efficient in some cases of cardiovascular diseases. Another important aspect of xanthine oxido-reductase produced ROS is their antibacterial capacity considered to be of importance with newborns fed on milk rich in this enzyme as well as at the gastrointestinal barrier. This ambivalent role of xanthine oxido-reductase justifies this review on the basic enzymatic mechanisms involved, derived ROS production, their role in the above mentioned biological processes and especially the interest of the inhibition of this enzyme as a preventive or curative measure in some cardiovascular pathologies.
Topics: Animals; Cardiovascular Diseases; Free Radicals; Humans; Reactive Oxygen Species; Xanthine Dehydrogenase
PubMed: 24127160
DOI: 10.1007/s12253-013-9698-x -
Metal Ions in Life Sciences 2013The transition element molybdenum is of essential importance for (nearly) all biological systems. It needs to be complexed by a special cofactor in order to gain...
The transition element molybdenum is of essential importance for (nearly) all biological systems. It needs to be complexed by a special cofactor in order to gain catalytic activity. With the exception of bacterial Mo-nitrogenase, where Mo is a constituent of the FeMo-cofactor, Mo is bound to a pterin, thus forming the molybdenum cofactor Moco, which in different versions is the active compound at the catalytic site of all other Mo-containing enzymes. In eukaryotes, the most prominent Mo enzymes are nitrate reductase, sulfite oxidase, xanthine dehydrogenase, aldehyde oxidase, and the mitochondrial amidoxime reductase. The biosynthesis of Moco involves the complex interaction of six proteins and is a process of four steps, which also requires iron, ATP, and copper. After its synthesis, Moco is distributed to the apoproteins of Mo enzymes by Moco-carrier/binding proteins. A deficiency in the biosynthesis of Moco has lethal consequences for the respective organisms. In humans, Moco deficiency is a severe inherited inborn error in metabolism resulting in severe neurodegeneration in newborns and causing early childhood death. Eubacteria possess different versions of the pteridin cofactor as reflected by a large number of enzymes such as nitrate reductase, formate dehydrogenase, and dimethyl sulfoxide reductase, while in archaea a tungsten atom replaced molybdenum as catalytic metal in the active center.
Topics: Aldehyde Oxidase; Humans; Molybdenum; Nitrate Reductase; Sulfite Oxidase; Xanthine Dehydrogenase
PubMed: 23595682
DOI: 10.1007/978-94-007-5561-1_15