scholarly journals Effect of NADH on hypoxanthine hydroxylation by native NAD+-dependent xanthine oxidoreductase of rat liver, and the possible biological role of this effect

1981 ◽  
Vol 200 (3) ◽  
pp. 597-603 ◽  
Author(s):  
Z W Kamiński ◽  
M M Jezewska
Keyword(s):  
Uric Acid ◽  
Rat Liver ◽  
Time Course ◽  
De Novo ◽  
Xanthine Oxidoreductase ◽  
Reaction Sequence ◽  
Oxidoreductase Activity ◽  
Dependent Activity ◽  
Sepharose 4B

The course of the reaction sequence hypoxanthine leads to xanthine leads to uric acid, catalysed by the NAD+-dependent activity of xanthine oxidoreductase, was investigated under conditions either of immediate oxidation of the NADH formed or of NADH accumulation. The enzymic preparation was obtained from rat liver, and purified 75-fold (as compared with the 25000 g supernatant) on a 5′-AMP-Sepharose 4B column; in this preparation the NAD+-dependent activity accounted for 100% of total xanthine oxidoreductase activity. A spectrophotometric method was developed for continuous measurements of changes in the concentrations of the three purines involved. The time course as well as the effects of the concentrations of enzyme and of hypoxanthine were examined. NADH produced by the enzyme lowered its activity by 50%, resulting in xanthine accumulation and in decreases of uric acid formation and of hypoxanthine utilization. The inhibition of the Xanthine oxidoreductase NAD+-dependent activity by NADH is discussed as a possible factor in the regulation of IMP biosynthesis by the ‘de novo’ pathway or (from unchanged hypoxanthine) by ther salvage pathway.

New insights into purine metabolism in metabolic diseases: role of xanthine oxidoreductase activity

2020 ◽  
Vol 319 (5) ◽  
pp. E827-E834 ◽  
Author(s):  
Masato Furuhashi
Keyword(s):  
Adipose Tissue ◽  
Uric Acid ◽  
Metabolic Diseases ◽  
Tissue Injury ◽  
Human Adipose Tissue ◽  
Purine Metabolism ◽  
Xanthine Oxidoreductase ◽  
Oxidoreductase Activity ◽  
Atp Production

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.

scholarly journals Xanthine oxidoreductase activity is associated with serum uric acid and glycemic control in hemodialysis patients

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Ayumi Nakatani ◽  
Shinya Nakatani ◽  
Eiji Ishimura ◽  
Takayo Murase ◽  
Takashi Nakamura ◽  
...  
Keyword(s):  
Uric Acid ◽  
Glycemic Control ◽  
Serum Uric Acid ◽  
Hemodialysis Patients ◽  
Xanthine Oxidoreductase ◽  
Oxidoreductase Activity

scholarly journals The effects of allopurinol, uric acid, and inosine administration on xanthine oxidoreductase activity and uric acid concentrations in broilers

2012 ◽  
Vol 91 (11) ◽  
pp. 2895-2903 ◽  
Author(s):  
T. Settle ◽  
M.D. Carro ◽  
E. Falkenstein ◽  
W. Radke ◽  
H. Klandorf
Keyword(s):  
Uric Acid ◽  
Xanthine Oxidoreductase ◽  
Oxidoreductase Activity

scholarly journals BIOCHEMICAL ROLE OF XANTHINE OXIDOREDUCTASE AND ITS NATURAL INHIBITORS: AN OVERVIEW

2016 ◽  
Vol 8 (10) ◽  
pp. 57
Author(s):  
Kiranmai Mandava ◽  
Uma Rajeswari Batchu
Keyword(s):  
Uric Acid ◽  
Milk Fat ◽  
Major Constituent ◽  
Xanthine Oxidoreductase ◽  
Purine Catabolism ◽  
Biochemical Processes ◽  
Fat Globules ◽  
Milk Fat Globule ◽  
Natural Inhibitors

<p>Xanthine oxidoreductase (XOR) is a widely distributed housekeeping enzyme in mammals that catalyzes the last two steps in human purine catabolism to produce uric acid. The enzyme exists as a homodimer with independent electron transfer in each monomer. This has been studied extensively as a major constituent of the milk fat globule membrane (MFGM) which surrounds fat globules in cow's milk even though purine catabolism is the most accepted function of XOR. A huge number of literature highlights on the different catalytic forms of XOR and their importance in the generation of reactive oxygen species/reactive nitrogen species (ROS/RNS) and synthesis of uric acid which are involved in many physiological and pathological processes. However, a slight ambiguity resides in their biochemical functions. The aim of this article was to review the literature published on the structural, catalytical, physiological and pathological role of XOR and to resolve the ambiguity in biochemical processes and to firm up various natural inhibitors of XOR collectively. Uric acid, the product of purine catabolism shows antioxidant activity, and XOR-derived ROS and RNS play a role in innate immunity, milk secretion and also be involved in signaling and metabolism of xenobiotics. Furthermore, XOR is likely to be engaged in pathology because of excessive production of uric acid and ROS/RNS. This review also reports natural XOR inhibitors in plants which inhibit the enzyme to treat XOR associated pathology.</p>

Time-course of cadmium-induced acute hepatotoxicity in the rat liver: the role of apoptosis

2003 ◽  
Vol 77 (12) ◽  
pp. 694-701 ◽  
Author(s):  
Konstantinos N. Tzirogiannis ◽  
Georgios I. Panoutsopoulos ◽  
Maria D. Demonakou ◽  
Rosa I. Hereti ◽  
Katerina N. Alexandropoulou ◽  
...  
Keyword(s):  
Rat Liver ◽  
Time Course

scholarly journals Involvement of a single thiol group in the conversion of the NAD+-dependent activity of rat liver xanthine oxidoreductase to the O2-dependent activity

1982 ◽  
Vol 207 (2) ◽  
pp. 341-346 ◽  
Author(s):  
Z W Kamiński ◽  
M M Jezewska
Keyword(s):  
Rat Liver ◽  
Thiol Group ◽  
Enzymic Activity ◽  
Xanthine Oxidoreductase ◽  
Complete Protection ◽  
First Order ◽  
Nitrobenzoic Acid ◽  
Modification Process ◽  
Dependent Activity ◽  
Iodosobenzoic Acid

The effects of 2-iodosobenzoic acid, 4-chloromercuribenzoate, 5,5′-dithiobis-(2-nitrobenzoic acid) and tetraethylthioperoxydicarbonic diamide (disulphiram) on the NAD+-dependent activity of xanthine oxidoreductase from rat liver were investigated. Only disulphiram converted the NAD+-dependent activity into the O2-dependent activity quantitatively, without changing the xanthine hydroxylation rate. The modification process was a first-order reaction with respect to time (min) and disulphiram concentration (microM). The kinetic data showed that modification of single thiol group is sufficient for loss of the enzymic activity towards NAD+ as electron acceptor. The complete protection afforded by NAD+ against the action of disulphiram suggests that the essential thiol group may be involved in binding of NAD+ to the xanthine oxidoreductase molecule.

scholarly journals Plasma Xanthine Oxidoreductase Activity Associated with Glycemic Control in Patients with Pre-Dialysis Chronic Kidney Disease

2021 ◽  
pp. 1-9
Author(s):  
Shinya Nakatani ◽  
Eiji Ishimura ◽  
Takayo Murase ◽  
Takashi Nakamura ◽  
Ayumi Nakatani ◽  
...  
Keyword(s):  
Uric Acid ◽  
Glycemic Control ◽  
Multiple Regression ◽  
Plasma Glucose ◽  
Hemoglobin A1c ◽  
Cross Sectional Study ◽  
Xanthine Oxidoreductase ◽  
Oxidoreductase Activity ◽  
Cross Sectional ◽  
Increased Risk

<b><i>Introduction:</i></b> Xanthine oxidoreductase (XOR) activity plays an important role as a pivotal source of reactive oxygen species, which is associated with cardiovascular disease (CVD) events. Patients with CKD have increased risk of CVD events. In the present study, factors associated with plasma XOR activity in pre-dialysis CKD patients were investigated. <b><i>Methods:</i></b> In this cross-sectional study, plasma XOR activity in 118 pre-dialysis CKD patients (age 68 [57–75] years; 64 males, 26 with diabetes mellitus [DM]) was determined using a newly established highly sensitive assay based on (<sup>13</sup>C<sub>2</sub>,<sup>15</sup>N<sub>2</sub>) xanthine and liquid chromatography/triple quadrupole mass spectrometry. <b><i>Results:</i></b> Plasma glucose, hemoglobin A1c, and estimated glomerular filtration (eGFR) were significantly and positively correlated with plasma logarithmically transformed XOR (ln-XOR) activity. In multiple regression analyses, eGFR and hemoglobin A1c or plasma glucose were significantly, independently, and positively associated with plasma ln-XOR activity after adjusting for several confounders. Plasma XOR activity was significantly higher in CKD patients with (<i>n</i> = 26) than in those without (<i>n</i> = 92) DM (62.7 [32.3–122] vs. 25.7 [13.4–45.8] pmol/h/mL, <i>p</i> &#x3c; 0.001). A total of 38 patients were taking uric acid-lowering drugs. Multiple regression analysis of CKD patients not administered uric acid-lowering drugs (<i>n</i> = 80) showed no significant association between eGFR and plasma ln-XOR activity. In contrast, association between glycemic control and plasma ln-XOR activity was significant even in CKD patients without uric acid-lowering drug treatment. <b><i>Conclusions:</i></b> These results indicate the importance of glycemic control in CKD patients in regard to decreased XOR, possibly leading to a decrease in CVD events.

scholarly journals NMDA receptor channel gating control by the pre-M1 helix

2020 ◽  
Vol 152 (4) ◽  
Author(s):  
Miranda J. McDaniel ◽  
Kevin K. Ogden ◽  
Steven A. Kell ◽  
Pieter B. Burger ◽  
Dennis C. Liotta ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Conformational Changes ◽  
Time Course ◽  
Transmembrane Domain ◽  
Single Channel ◽  
De Novo ◽  
Channel Gating ◽  
Open Probability ◽  
Single Channel Currents

The NMDA receptor (NMDAR) is an ionotropic glutamate receptor formed from the tetrameric assembly of GluN1 and GluN2 subunits. Within the flexible linker between the agonist binding domain (ABD) and the M1 helix of the pore-forming transmembrane helical bundle lies a two-turn, extracellular pre-M1 helix positioned parallel to the plasma membrane and in van der Waals contact with the M3 helix thought to constitute the channel gate. The pre-M1 helix is tethered to the bilobed ABD, where agonist-induced conformational changes initiate activation. Additionally, it is a locus for de novo mutations associated with neurological disorders, is near other disease-associated de novo sites within the transmembrane domain, and is a structural determinant of subunit-selective modulators. To investigate the role of the pre-M1 helix in channel gating, we performed scanning mutagenesis across the GluN2A pre-M1 helix and recorded whole-cell macroscopic and single channel currents from HEK293 cell-attached patches. We identified two residues at which mutations perturb channel open probability, the mean open time, and the glutamate deactivation time course. We identified a subunit-specific network of aromatic amino acids located in and around the GluN2A pre-M1 helix to be important for gating. Based on these results, we are able to hypothesize about the role of the pre-M1 helix in other NMDAR subunits based on sequence and structure homology. Our results emphasize the role of the pre-M1 helix in channel gating, implicate the surrounding amino acid environment in this mechanism, and suggest unique subunit-specific contributions of pre-M1 helices to GluN1 and GluN2 gating.

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