Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018099 (gout)
 5,192 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Uricase is an important medical enzyme which can be used to determine urate in clinical analysis, to therapy gout, hyperuricemia, and tumor lysis syndrome. Uricase of Candida utilis was successfully expressed in Hansenula polymorpha under the control of methanol oxidase promoter using Saccharomyces cerevisiae alpha-factor signal peptide as the secretory sequence. Recombinant H. polymorpha MU200 with the highest extracellular uricase production was characterized with three copies of expression cassette and selected for process optimization for the production of recombinant enzyme. Among the parameters investigated in shaking flask cultures, the pH value of medium and inoculum size had great influence on the recombinant uricase production. The maximum extracellular uricase yield of 2.6 U/ml was obtained in shaking flask culture. The yield of recombinant uricase was significantly improved by the combined use of a high cell-density cultivation technique and a pH control strategy of switching culture pH from 5.5 to 6.5 in the induction phase. After induction for 58 h, the production of recombinant uricase reached 52.3 U/ml (about 2.1 g/l of protein) extracellularly and 60.3 U/ml (about 2.4 g/l) intracellularly in fed-batch fermentation, which are much higher than those expressed in other expression systems. To our knowledge, this is the first report about the heterologous expression of uricase in H. polymorpha.
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PMID:Uricase production by a recombinant Hansenula polymorpha strain harboring Candida utilis uricase gene. 1843 74

Urate oxidase catalyzes the oxidation of uric acid with poor solubility to produce 5-hydroxyisourate and allantoin. Since allantoin is excreted in vivo, urate oxidase has the potential to be a therapeutic target for the treatment of gout. However, its severe immunogenicity limits its clinical application. Furthermore, studies on the structure-function relationships of urate oxidase have proven difficult. We developed a method for genetically incorporating p-azido-L-phenylalanine into target protein in Escherichia coli in a site-specific manner utilizing a tyrosyl suppressor tRNA/aminoacyl-tRNA synthetase system. We substituted p-azido-L-phenylalanine for Phe(170) or Phe(281) in urate oxidase. The products were purified and their enzyme activities were analyzed. In addition, we optimized the system by adding a "Shine-Dalgarno (SD) sequence" and tandem suppressor tRNA. This method has the benefit of site-specifically modifying urate oxidase with homogeneous glycosyl and PEG derivates, which can provide new insights into structure-function relationships and improve pharmacological properties of urate oxidase.
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PMID:Site-specific incorporation of unnatural amino acids into urate oxidase in Escherichia coli. 1859 2

Uric acid has historically been viewed as a purine metabolic waste product excreted by the kidney and gut that is relatively unimportant other than its penchant to crystallize in joints to cause the disease gout. In recent years, however, there has been the realization that uric acid is not biologically inert but may have a wide range of actions, including being both a pro- and anti-oxidant, a neurostimulant, and an inducer of inflammation and activator of the innate immune response. In this paper, we present the hypothesis that uric acid has a key role in the foraging response associated with starvation and fasting. We further suggest that there is a complex interplay between fructose, uric acid and vitamin C, with fructose and uric acid stimulating the foraging response and vitamin C countering this response. Finally, we suggest that the mutations in ascorbate synthesis and uricase that characterized early primate evolution were likely in response to the need to stimulate the foraging "survival" response and might have inadvertently had a role in accelerating the development of bipedal locomotion and intellectual development. Unfortunately, due to marked changes in the diet, resulting in dramatic increases in fructose- and purine-rich foods, these identical genotypic changes may be largely responsible for the epidemic of obesity, diabetes and cardiovascular disease in today's society.
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PMID:Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society? 1864 82

Hyperuricemia contributes to the pathomechanism of diseases such as renal failure, gout, tumor lysis syndrome and metabolic syndrome. Tumor lysis syndrome is a complication of malignancies caused by massive tumor cell lysis due to either spontaneous tumor cell lysis or to different therapies and it may cause hyperuricemia. Recently, for treatment of hyperuricemia the recombinant urate oxidase (rasburicase) therapy has been used. This enzyme converts uric acid with high affinity into soluble allantoin which is eliminated by the kidneys. In this reaction high concentration of hydrogen peroxide is generated. This hydrogen peroxide could cause hemolysis and especially methemoglobin formation, in case of glucose-6-phosphate-dehydrogenase and catalase deficiencies. Therefore it is recommended that these enzymes are determined before therapy. For monitoring of rasburicase therapy the determination of serum uric acid concentration is used. More than 95 per cent of Hungarian clinical laboratories are using the uricate oxidase/peroxidase reactions and hydrogen peroxide measurements in the uric acid assays. These assays may be interfered by ascorbic acid and hydrogen peroxide which is generated by rasburicase either in vivo or in vitro.
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PMID:[Rasburicase therapy may cause hydrogen peroxide shock]. 1870 12

Gout is the most common form of inflammatory arthritis in the elderly. In the last two decades, both hyperuricemia and gout have increased markedly and similar trends in the epidemiology of the metabolic syndrome have been observed. Recent studies provide new insights into the transporters that handle uric acid in the kidney as well as possible links between these transporters, hyperuricemia, and hypertension. The treatment of established hyperuricemia has also seen new developments. Febuxostat and PEG-uricase are two novel treatments that have been evaluated and shown to be highly effective in the management of hyperuricemia, thus enlarging the therapeutic options available to lower uric acid levels. Monosodium urate (MSU) crystals are potent inducers of inflammation. Within the joint, they trigger a local inflammatory reaction, neutrophil recruitment, and the production of pro-inflammatory cytokines as well as other inflammatory mediators. Experimentally, the uptake of MSU crystals by monocytes involves interactions with components of the innate immune system, namely Toll-like receptor (TLR)-2, TLR-4, and CD14. Intracellularly, MSU crystals activate multiple processes that lead to the formation of the NALP-3 (NACHT, LRR, and pyrin domain-containing-3) inflammasome complex that in turn processes pro-interleukin (IL)-1 to yield mature IL-1 beta, which is then secreted. The inflammatory effects of MSU are IL-1-dependent and can be blocked by IL-1 inhibitors. These advances in the understanding of hyperuricemia and gout provide new therapeutic targets for the future.
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PMID:Developments in the scientific and clinical understanding of gout. 1894 74

Allopurinol, the first-line drug for serum urate-lowering therapy in gout, is approved by the US Food and Drug Administration for a dose up to 800 mg/d and is available as a low-cost generic drug. However, the vast majority of allopurinol prescriptions are for doses < or = 300 mg/d, which often fails to adequately treat hyperuricemia in gout. This situation has been promoted by longstanding, non-evidence-based guidelines for allopurinol use calibrated to renal function (and oxypurinol levels) and designed, without proof of efficacy, to avoid allopurinol hypersensitivity syndrome. Severe allopurinol hypersensitivity reactions are not necessarily dose-dependent and do not always correlate with serum oxypurinol levels. Limiting allopurinol dosing to < or = 300 mg/d suboptimally controls hyperuricemia and fails to adequately prevent hypersensitivity reactions. However, the long-term safety of elevating allopurinol dosages in chronic kidney disease requires further study. The emergence of novel urate-lowering therapeutic options, such as febuxostat and uricase, makes timely this review of current allopurinol dosing guidelines, safety, and efficacy in gout hyperuricemia therapy, including patients with chronic kidney disease.
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PMID:A critical reappraisal of allopurinol dosing, safety, and efficacy for hyperuricemia in gout. 1929 86

Gout is a common rheumatic disease in humans which is characterized by elevation in serum uric acid levels, and deposition of uric acid crystals in the joint. Hyperuricaemia is the primary risk factor for the development of gout and primates have uniquely high levels of serum uric acid due to missense mutations in the uricase gene. Levels of serum uric acid are known to be highly heritable, and mutations in genes which encode enzymes in the purine salvage pathway have long been recognized as rare causes of gout. Until recently, however, little has been known about the genetic determinants of urate metabolism and susceptibility to gout in the general population. Over recent months, a series of large scale genome wide association studies have been performed which have shed new light on the genes which regulate serum uric acid levels and susceptibility to gout. Most of these genes seem to be involved in regulating the renal excretion of uric acid which underscores the importance of reduced urate excretion as opposed to increased endogenous production as a cause of gout. Further work will now be required to investigate the mechanisms by which these genetic variants regulate urate excretion and serum urate levels. However, it seems likely that the genes so far identified will represent new molecular targets for the design of drugs to enhance urate excretion and the genetic variants that predispose to gout might be of value as genetic markers of susceptibility to gout.
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PMID:Recent insights into the pathogenesis of hyperuricaemia and gout. 1980 94

Gout, a disease recognized since antiquity, has increased in prevalence in recent years and the clinical profile of this disease has become increasingly complex, owing to large numbers of cases with iatrogenic factors, multiple comorbidities, advanced age, and hyperuricemia and arthritis refractory to treatment. In this Review, key advances in gout research made during the past decade are summarized. Revised strategies for safe and effective employment of dietary measures and pharmacologic treatments for active gouty arthritis, prevention of gout flares and urate lowering are also reviewed, with an emphasis on dosing of colchicine and allopurinol, and the evidence-based approach to systemic glucocorticosteroid treatment of acute gout. Also discussed are new and emerging treatments for gout and hyperuricemia, and the potential influence of dual energy CT imaging on treatment. In this context, the therapeutic role of febuxostat, and clinical development of pegylated uricase urate-lowering therapy and interleukin 1 antagonism for gouty inflammation are reviewed. Collectively, novel approaches will hopefully lead to improved management of hyperuricemia and gout, and also to improvements in patient-centered outcomes, even for those who have previously failed to respond to treatment.
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PMID:Update on gout: new therapeutic strategies and options. 2004 4

Urate oxidase (EC 1.7.3.3) is an enzyme involved in purine metabolism which is used in the treatment of gout and as diagnostic reagent for detection of uric acid. In order to produce this enzyme in large quantities for biotechnological purposes, the gene coding for the Bacillus subtilis urate oxidase was cloned and heterologously expressed in Escherichia coli. Time course induction in E. coli showed an induced protein with an apparent molecular mass of approximately 60 kDa. Soluble recombinant enzyme was purified in a single-step procedure using Ni-NTA column. The enzyme was purified 2.1-fold with a yield of 56% compared to the crude extract. MALDI-TOF analysis revealed an ion with a mass of 58675 Da which is in agreement with the expected mass of the recombinant protein. The purified enzyme showed an optimal pH and temperature of 8.0 and 37 degrees C, respectively, and retained 90% of its activity after 72 hours of incubation at -20 degrees C and 4 degrees C.
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PMID:Cloning, purification, and partial characterization of Bacillus subtilis urate oxidase expressed in Escherichia coli. 2016 77

Uric acid (UA) results from xanthine oxidase (XO) catabolism of xanthine and is the final product of purine catabolism in humans. In this species, hyperuricemia is associated with gout, nephropathy, and increased cardiovascular disease risk. Although the effects of hyperuricemia in vascular biology are overall controversial, UA has been described as an antioxidant and as potentially improving endothelial function. Hypertension is associated with endothelial dysfunction. We hypothesized that UA improves the endothelial function of aorta from deoxycorticosterone acetate (DOCA)-salt hypertensive rats. UA (100 microM) in the presence of the uricase inhibitor oxonic acid (10 microM) did not modify relaxation to acetylcholine (ACh) (1 nM-10 microM) in the aorta from nontreated, sham normotensive, and DOCA-salt hypertensive rats [response to 10 microM ACh for UA versus vehicle, respectively: nontreated = 37 +/- 7 versus 48 +/- 7%, sham = 53 +/- 15 versus 57 +/- 20%, DOCA = 81 +/- 4 versus 85 +/- 2% from 20 microM prostaglandin 2alpha (PGF(2alpha))-induced contraction]. Allopurinol (100 microM), a XO inhibitor, did not significantly alter the ACh-induced relaxation of sham and DOCA aortic rings (response to 10 microM ACh for allopurinol versus vehicle, respectively: sham = 61 +/- 5 versus 68 +/- 9%, DOCA = 87 +/- 6 versus 88 +/- 3% from 20 microM PGF(2alpha)-induced contraction). Uricemia, ranging from unmeasurable to 547 microM in sham and to 506 microM in DOCA rats, was not significantly different between these two groups. The expression and activity of XO, as well as the expression of uricase, were not different between sham and DOCA rat aorta. We conclude that, at least in vitro, UA does not affect the ACh-induced relaxation of normotensive and DOCA-salt hypertensive rats.
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PMID:Uric acid does not affect the acetylcholine-induced relaxation of aorta from normotensive and deoxycorticosterone acetate-salt hypertensive rats. 2021 10


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