Disease relevance of UOX

• Efficacy and safety of rasburicase (recombinant urate oxidase) for the prevention and treatment of hyperuricemia during induction chemotherapy of aggressive non-Hodgkin's lymphoma: results of the GRAAL1 (Groupe d'Etude des Lymphomes de l'Adulte Trial on Rasburicase Activity in Adult Lymphoma) study [1].
• Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients With leukemia or lymphoma [2].
• Furthermore, rational approaches to treat complications of tumor lysis syndrome by administration of the recombinant urate oxidase protein, also known as rasburicase, which corrects the biochemical defect present in humans, were discussed [3].
• Clinical responses to urate oxidase were also determined in eight patients with newly diagnosed B cell ALL or advanced-stage non-Hodgkin lymphoma [4].
• Thus, non-recombinant urate oxidase is a more effective uricolytic agent than allopurinol but is associated with acute hypersensitivity reactions, even in patients without a history of allergy [4].

High impact information on UOX

• Moreover, when mice treated with the urate oxidase inhibitor potassium oxonate were fed inosine or inosinic acid, serum UA levels were elevated markedly for a period of hours, whereas only a minor, transient increase in serum inosine was detected [5].
• The gene coding for urate oxidase, an enzyme that catalyzes the oxidation of uric acid to allantoin, is inactivated in humans [6].
• The structure of the active site of urate oxidase around the 8-azaxanthine inhibitor reveals an original mechanism of oxidation that does not require any ions or prosthetic groups [6].
• Urate oxidase may be the archetype of an expanding new family of tunnel-shaped proteins that now has three members; tetrahydropterin synthase, GTP cyclohydrolase I and urate oxidase [6].
• PURPOSE: To improve the control of hyperuricemia in patients with leukemia or lymphoma, we tested a newly developed uricolytic agent, recombinant urate oxidase (SR29142; Rasburicase; Sanofi-Synthelabo, Inc, Paris, France), which catalyzes the oxidation of uric acid to allantoin, a highly water-soluble metabolite readily excreted by the kidneys [2].

Chemical compound and disease context of UOX

• Between February 1994 and December 1996, we administered non-recombinant urate oxidase (Uricozyme) to 126 children with newly diagnosed non-B cell acute lymphoblastic leukemia (ALL) during the first 5 days of chemotherapy with methotrexate, 6-mercaptopurine or both [4].
• Polyethylene glycol-modified urate oxidase (PEG-uricase) holds promise as a hypouricemic agent for treating gout and as an adjunct to cytolytic therapy of hematologic malignancies [7].
• Rasburicase is a new recombinant urate oxidase developed to prevent and treat hyperuricaemia in patients with cancer or renal failure; it degrades uric acid to allantoin, a less toxic and more soluble product [8].

Biological context of UOX

• It is known that murine Uox is expressed only in the liver, whereas human UOX has been inactivated as a pseudogene [9].
• We suggest that although the inactivation of the hominoid Uox gene was caused by independent nonsense or frameshift mutations, the gene has taken a two-step deterioration process, first in the promoter and second in the coding region during primate evolution [10].
• Nevertheless, we demonstrate rather strong selective constraint against nonsynonymous sites of the functional Uox gene and argue that this observation is consistent with the fact that the Uox gene is unique in the genome and evolutionarily conserved not only among animals but also among eukaryotes [10].
• None of the three mutations was present in the gibbon; in contrast, a 13-bp deletion was identified that disrupted the gibbon urate oxidase reading frame [11].
• The human urate oxidase (E.C.1.7.3.3) gene, UOX, is assigned to chromosome 1 by Southern analysis of human x hamster cell hybrids [12].

Anatomical context of UOX

• These results demonstrate that, unlike rat kidney peroxisomes which lack urate oxidase, peroxisomes of frog kidney contain this enzyme [13].
• Uric acid degrading enzymes, urate oxidase and allantoinase, are associated with different subcellular organelles in frog liver and kidney [13].
• Peroxisomes in frog liver parenchymal cells and kidney proximal tubular epithelium contained a semi-dense subcrystalloid core, which was found to be the exclusive site of urate oxidase localization [13].
• Using specific antibodies against frog urate oxidase and allantoinase, we have undertaken an immunocytochemical study of the localization of these two proteins in frog liver and kidney, and demonstrate that whereas urate oxidase is present in peroxisomes, allantoinase is localized in mitochondria [13].
• In contrast, urate oxidase activity increased in carcinoma as compared with normal mucosa [14].

Associations of UOX with chemical compounds

• Urinary glycolate (a metabolic precursor of Ox) always remained below the upper limit of the normal range and did not change between different diets, indicating that changes in UOX x V reflect respective variations in intestinal absorption of Ox [15].
• Consequently, urate oxidase is used as a protein drug to overcome severe disorders induced by uric acid accumulation [6].
• We report the identification and purification of a novel enzyme from soybean root nodules that catalyzes the hydrolysis of 5-hydroxyisourate, which is the true product of the urate oxidase reaction [16].
• A protein drp90 encoded on the leftwards strand of soybean nodule urate oxidase cDNA binds to a regulatory sequence in leghemoglobin C3 gene [17].
• Cisplatin was administered to normouricemic and hyperuricemic rats (the latter generated by administering the urate oxidase inhibitor, oxonic acid) [18].

Other interactions of UOX

• The head-to-head organization of DLAD and UOX is conserved in the human genomic sequence [9].
• We also find that compared with other organisms, the primate functional Uox gene is exceptional in terms of usage of CGA codons which are prone to TGA nonsense mutations [10].
• The mutant cells exhibited a temperature-sensitive (TS) phenotype on the peroxisomal localizations of the recombinant GFP and urate oxidase appending a genuine peroxisome targeting signal 1 (PTS1), a tripeptide of Ser-Lys-Leu (SKL) at the C-terminus, but did not on that of catalase harboring a divergent PTS1, Lys-Ala-Asn-Leu (KANL) sequence [19].
• Hemolytic anemia due to G6PD deficiency and urate oxidase in a kidney-transplant patient [20].
• Catalase, D-amino acid oxidase, and urate oxidase were found to be expressed in mammary carcinoma and in surrounding non-malignant tissue when the postnuclear supernatant fractions prepared from homogenates were assessed by Western blot techniques [21].

Analytical, diagnostic and therapeutic context of UOX

• Interestingly, sequence analysis of Dlad showed that the 1st exon of the urate oxidase gene, Uox, is located on the opposite strand in its 5'-flanking region [9].
• UOX increased up to 10(4) micromol/24 h after transplantation and declined to normal values thereafter [22].
• This study was designed to evaluate the efficacy and the safety of rasburicase (recombinant urate oxidase) in adult patients with aggressive NHL during their first cycle of chemotherapy [1].
• On the basis of differential and density gradient centrifugation studies, the site of the uric acid degrading enzymes, urate oxidase and allantoinase, in amphibia was previously assigned to the hepatic peroxisomes [13].
• CONCLUSIONS: Only 1.7% of patients in our study receiving urate-oxidase during their induction chemotherapy needed renal dialysis [23].

References