New developments in clinically relevant mechanisms and treatment of hyperuricemia

Lee, Susan J.; Terkeltaub, Robert

doi:10.1007/s11926-996-0029-z

Cited by 22 publications

(12 citation statements)

References 39 publications

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“…Nonsteroidal anti-inflammatory drugs were not considered, because they were mostly prescribed as needed and taken irregularly. We also noted uricosuric drugs, mainly fenofibrate and losartan (25). Although other medications enhance or reduce Ua excretion, they were not used in this cohort.…”

Section: Study Design and Participantsmentioning

confidence: 82%

“…We excluded three with a known history of renal disease. The remaining 943 were 5469 years old, with 51% women and a body mass index (BMI) of 26 (23)(24)(25)(26)(27)(28)(29)(30) (Table 1); 83% were white, 5% had a parent from Africa, 1% had a parent from Latin America, 4% had a parent from the Middle East, 2% were Asian, and 5% were from another descent. Cardiovascular risk factors and history were prevalent: 28% reported hyperlipidemia, 17% reported hypertension, 11% reported diabetes, and 6.7% had a history of coronary artery disease or stroke.…”

Section: Cohort Characteristicsmentioning

confidence: 99%

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Clinical, Genetic, and Urinary Factors Associated with Uromodulin Excretion

Troyanov

Delmas-Frenette

Bollée

et al. 2016

Clinical Journal of the American Society of Nephrology

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Background and objectives The urinary excretion of uromodulin is influenced by common variants in the UMOD gene, and it may be related to NaCl retention and hypertension. Levels of uromodulin are also dependent of the renal function, but other determinants remain unknown.Design, setting, participants, & measurements We tested associations between the urinary excretion of uromodulin; medical history and medication; serum and urinary levels of electrolytes, glucose, and uric acid; and the genotype at the UMOD/Protein Disulfide Isomerase-Like, Testis Expressed locus (rs4293393 and rs12446492); 943 participants from the CARTaGENE Cohort, a random sample from the Canadian population of 20,004 individuals, were analyzed. Participants with available genotyping were obtained from a substudy addressing associations between common variants and cardiovascular disease in paired participants with high and low Framingham risk scores and vascular rigidity indexes.Results The population studied was 5469 years old, with 51% women and eGFR of 9614 ml/min per 1.73 m 2 . Uromodulin excretion was 25 (11-42) mg/g creatinine. Using linear regression, it was independently higher among patients with higher eGFR, the TT genotype of rs4293393, and the TT genotype of rs12446492. The fractional excretions of urate and sodium showed a strong positive correlation with uromodulin, likely linked to the extracellular volume status. The presence of glycosuria and the use of uricosuric drugs, which both increased the fraction excretion of urate, were independently associated with a lower uromodulin excretion, suggesting novel interactions between uric acid and uromodulin excretion. ConclusionsIn this large cohort, the excretion of uromodulin correlates with clinical, genetic, and urinary factors. The strongest associations were between uric acid, sodium, and uromodulin excretions and are likely linked to the extracellular volume status.

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Section: Study Design and Participantsmentioning

confidence: 82%

Section: Cohort Characteristicsmentioning

confidence: 99%

Clinical, Genetic, and Urinary Factors Associated with Uromodulin Excretion

Troyanov

Delmas-Frenette

Bollée

et al. 2016

Clinical Journal of the American Society of Nephrology

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“…Inactivation by pseudogenization of all three genes of the pathway occurred during hominoid evolution (6), resulting in high concentration of urate in the blood and susceptibility to gout. Urate oxidase is currently being employed therapeutically for refractory hyperuricemia (8). Addition of OHCU decarboxylase to this therapeutic regimen in humans could speed the conversion of urate oxidation products and thus make urate oxidase therapy better tolerated and safer.…”

mentioning

confidence: 99%

The Structure of 2-Oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline Decarboxylase Provides Insights into the Mechanism of Uric Acid Degradation

Cendron

Berni

Folli

et al. 2007

Journal of Biological Chemistry

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The complete degradation of uric acid to (S)-allantoin, as recently elucidated, involves three enzymatic reactions. Inactivation by pseudogenization of the genes of the pathway occurred during hominoid evolution, resulting in a high concentration of urate in the blood and susceptibility to gout. Here, we describe the 1.8 Å resolution crystal structure of the homodimeric 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline decarboxylase, which catalyzes the last step in the urate degradation pathway, for both ligand-free enzyme and enzyme in complex with the substrate analogs (R)-allantoin and guanine. Each monomer comprises ten ␣-helices, grouped into two domains and assembled in a novel fold. The structure and the mutational analysis of the active site have allowed us to identify some residues that are essential for catalysis, among which His-67 and Glu-87 appear to play a particularly significant role. Glu-87 may facilitate the exit of the carboxylate group because of electrostatic repulsion that destabilizes the ground state of the substrate, whereas His-67 is likely to be involved in a protonation step leading to the stereoselective formation of the (S)-allantoin enantiomer as reaction product. The structural and functional characterization of 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline decarboxylase can provide useful information in view of the potential use of this enzyme in the enzymatic therapy of gout.Uric acid, a key compound in the degradation pathway of purines (1), is degraded in many organisms to (S)-allantoin. It had long been thought that allantoin was formed directly from urate by the action of urate oxidase. However, a refined analysis of the urate oxidation reaction (2, 3) has led to the identification of other enzymatic activities associated with urate degradation (4, 5) and to the elucidation of the complete urate degradation pathway (6), involving three enzymatic reactions: oxidation of urate, catalyzed by urate oxidase, yields 5-hydroxyisourate (HIU), 3 which is then acted upon HIU hydrolase to yield 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline (OHCU); in turn, OHCU undergoes stereoselective decarboxylation by the action of OHCU decarboxylase to give CO 2 and (S)-allantoin (Scheme 1). In contrast, the slow non-enzymatic OHCU decarboxylation generates the racemic mixture of (S)-and (R)-allantoin (7).Genes encoding for OHCU decarboxylase are present in a variety of organisms, including bacteria, fungi, plants, and metazoa and are tightly associated with urate oxidase and HIU hydrolase; in general, a species either has all three genes involved in urate degradation or none of them (6). Inactivation by pseudogenization of all three genes of the pathway occurred during hominoid evolution (6), resulting in high concentration of urate in the blood and susceptibility to gout. Urate oxidase is currently being employed therapeutically for refractory hyperuricemia (8). Addition of OHCU decarboxylase to this therapeutic regimen in humans could speed the conversion of urate oxidation products and thus make ...

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“…Die Identifizierung des hURAT1Gens als erstes Kandidatengen der Hypourikos urie bei Patienten mit primärer Hyper urikämie bildet die Grundlage zur Ent wicklung von Pharmaka, die mit diesem Harnsäuretransportprotein interagieren und die gestörte renale Ausscheidung der schwer löslichen Substanz beeinflussen [8,9,12,14,20,21,23]. Neue Medikamente könnten so die nebenwirkungsreichen Urikosurika Benzbromaron und Probenecid [2,14,23], die die Uratreabsorption durch Interaktion mit hURAT1 vom tu bulären Lumen hemmen (CisInhibition; [10,13]), in der Therapie der Hyperurikä mie und Gicht ablösen [12,14,23].…”

Section: Pharmakologische Relevanz Des Hurat1unclassified

“…Neue Medikamente könnten so die nebenwirkungsreichen Urikosurika Benzbromaron und Probenecid [2,14,23], die die Uratreabsorption durch Interaktion mit hURAT1 vom tu bulären Lumen hemmen (CisInhibition; [10,13]), in der Therapie der Hyperurikä mie und Gicht ablösen [12,14,23].…”

Section: Pharmakologische Relevanz Des Hurat1unclassified

Molekulare Grundlagen der primär-renalen Hyperurikämie

et al. 2007

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In highly industrialized countries hyperuricemia is one of the most common metabolic disorders. High uric acid blood levels may lead to the manifestation of gout owing to the precipitation of urate crystals in connective tissue, the skeletal system and kidneys. A primary reduction of renal uric acid excretion can be detected in more than 90% of all cases of hyperuricemia. Despite the identification of several uric acid transporting proteins their pathogenetic role for the induction of primary reduced renal uric acid excretion has not yet been verified. As a result of a case-control study on individuals with normal and reduced renal uric acid excretion, an association of polymorphisms in the human urate transporter 1 gene (hURAT1) with primary reduced urate excretion has been demonstrated for the first time. The hURAT1 gene is an organic anion transporter (SLC22A12), which is preferentially expressed in the apical membrane of proximal renal tubule cells. Functioning as an antiporter, hURAT1 mediates the uptake of urate from the lumen into proximal tubule cells in exchange for organic and inorganic anions. Loss-of-function mutations in the hURAT1 gene are a cause of hereditary renal hypouricemia. The precisely regulated hURAT1 is a candidate gene for hyperuricemia and an important target for the development and optimization of new diagnostic approaches and pharmacological interventions of primary reduced renal uric acid excretion.

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New developments in clinically relevant mechanisms and treatment of hyperuricemia

Cited by 22 publications

References 39 publications

Clinical, Genetic, and Urinary Factors Associated with Uromodulin Excretion

Clinical, Genetic, and Urinary Factors Associated with Uromodulin Excretion

The Structure of 2-Oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline Decarboxylase Provides Insights into the Mechanism of Uric Acid Degradation

Molekulare Grundlagen der primär-renalen Hyperurikämie

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