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Rasburicase G6Pd Nejm Resident 360 Nejm Full Suite OfNote: To access the full suite of resources, you must create a personal account while on campus or through our NEJM subscription from off-campus. Access: NEJM Resident 360 Help: Ask a Librarian Database Type: Other Access Method: login with NetID. Additionally, the fact that UA structurally resembles neuro-stimulants such as caffeine and theobromine has led to the speculation that increased UA levels may have led to an intellectualcognitive jump however, this is controversial 9, 10. As a consequence of this enzyme deficiency, humans have high serum uric acid levels. In some people, uric acid levels rise above the solubility limit resulting in crystallization in joints, acute inflammation in response to those crystals causes severe pain; a condition known as gout. Treatment for severe gout includes injection of non-human uricase to reduce serum uric acid levels. Krystexxa is a hyper-PEGylated pig-baboon chimeric uricase indicated for chronic refractory gout that induces an immunogenic response in 91 of treated patients, including infusion reactions (26) and anaphylaxis (6.5). These properties limit its use and effectiveness. An innovative approach has been used to develop a therapeutic uricase with improved properties such as: soluble expression, neutral pH solubility, high E. More than 200 diverse uricase sequences were aligned to guide protein engineering and reduce putative sequence liabilities. A single uricase lead candidate was identified, which showed low potential for immunogenicity in 200 human donor samples selected to represent diverse HLA haplotypes. Cysteines were engineered into the lead sequence for site specific PEGylation and studies demonstrated 95 PEGylation efficiency. PEGylated uricase retains enzymatic activity in vitro at neutral pH, in human serum and in vivo (rats and canines) and has an extended half-life. In canines, an 85 reduction in serum uric acid levels was observed with a single subcutaneous injection. This PEGylated, non-immunogenic uricase has the potential to provide meaningful benefits to patients with gout. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The specific roles of these authors are articulated in the author contributions section. Competing interests: Aside from being employed by the company supporting the work, we have no significant competing financial, professional or personal interests that might have influenced the performance or presentation of the work described in this manuscript. The commercial affiliates do not alter our adherence to PLOS ONE policies on sharing data and materials. Rasburicase G6Pd Nejm Resident 360 Nejm Series Of ReactionsThis enzyme initiates a series of reactions that convert uric acid (UA) to a more soluble and easily excreted product, allantoin. In short, uricase catalyzes the reaction of UA with O 2 and H 2 O to form 5-hydroxy-isourate (HIU) and the release of H 2 O 2 2. HIU is an unstable product that undergoes non-enzymatic hydrolysis to 2-oxo-4-hydroxy-4-carboxy- 5 -ureidoimidazoline (OHCU) which then decarboxylates spontaneously to form racemic allantoin 2, 3. Living species that contain a functional uricase also express two additional enzymes (HIU hydrolase and OHCU decarboxylase) which catalyze these reactions more quickly to generate (S)-allantoin 2. A functional uricase can be found in a wide range of organisms, such as: archaea, bacteria, and eukaryotes. However, in humans and some primates a functional uricase enzyme is not expressed 4, 5. The lack of functional uricase expression in humans is due to three mutations that result in complete silencing of the gene 4. A number of hypotheses have been proposed to explain the evolutionary elimination of uricase activity and commensurate increase in UA levels 6. These include the idea that an increase in UA levels (powerful antioxidant and scavenger of oxygen radical) led to a decrease in oxygen free radical associated disease (cancer) and an increase in lifespan 7, 8.
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