X-ray crystal structure of a xanthine oxidase complex with the flavonoid inhibitor quercetin.

Journal of natural products (2014-07-26)
Hongnan Cao, James M Pauff, Russ Hille
RESUMO

Xanthine oxidase catalyzes the sequential hydroxylation of hypoxanthine to uric acid via xanthine as intermediate. Deposition of crystals of the catalytic product uric acid or its monosodium salt in human joints with accompanying joint inflammation is the major cause of gout. Natural flavonoids are attractive leads for rational design of preventive and therapeutic xanthine oxidase inhibitors due to their beneficial antioxidant, anti-inflammatory, and antiproliferative activities in addition to their micromolar inhibitory activities toward xanthine oxidase. We determined the first complex X-ray structure of mammalian xanthine oxidase with the natural flavonoid inhibitor quercetin at 2.0 Å resolution. The inhibitor adopts a single orientation with its benzopyran moiety sandwiched between Phe 914 and Phe 1009 and ring B pointing toward the solvent channel leading to the molybdenum active center. The favorable steric complementarity of the conjugated three-ring structure of quercetin with the active site and specific hydrogen-bonding interactions of exocyclic hydroxy groups with catalytically relevant residues Arg 880 and Glu 802 correlate well with a previously reported structure-activity relationship of flavonoid inhibitors of xanthine oxidase. The current complex provides a structural basis for the rational design of flavonoid-type inhibitors against xanthine oxidase useful for the treatment of hyperuricemia, gout, and inflammatory disease states.

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Sigma-Aldrich
Quercetin, ≥95% (HPLC), solid
Sigma-Aldrich
Uric acid, ≥99%, crystalline
Sigma-Aldrich
L-Phenylalanine, reagent grade, ≥98%
Sigma-Aldrich
L-Phenylalanine, from non-animal source, meets EP, JP, USP testing specifications, suitable for cell culture, 98.5-101.0%
Sigma-Aldrich
Xanthine, ≥99%
Sigma-Aldrich
Xanthine, ≥99.5% (HPLC), purified by recrystallization
Supelco
L-Phenylalanine, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
L-Phenylalanine, BioUltra, ≥99.0% (NT)
Sigma-Aldrich
Uric acid, BioXtra, ≥99% (HPLC)
Sigma-Aldrich
Molybdenum, powder, <150 μm, 99.9% trace metals basis
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Molybdenum, foil, thickness 0.1 mm, ≥99.9% trace metals basis
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Molybdenum, powder, <150 μm, 99.99% trace metals basis
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Molybdenum, powder, 1-5 μm, ≥99.9% trace metals basis
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L-Phenylalanine, 99%
SAFC
L-Phenylalanine
Sigma-Aldrich
Xanthine, BioUltra, ≥99%
Supelco
L-Phenylalanine, certified reference material, TraceCERT®
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L-Phenylalanine, 99%, FCC
Supelco
L-Phenylalanine, analytical standard, for Nitrogen Determination According to Kjeldahl Method
Sigma-Aldrich
Molybdenum, wire, diam. 1.0 mm, 99.95% trace metals basis
Sigma-Aldrich
Molybdenum, foil, thickness 1.0 mm, ≥99.9% trace metals basis
Sigma-Aldrich
Molybdenum, foil, thickness 0.025 mm, ≥99.9% trace metals basis
Molybdenum, wire reel, 100m, diameter 0.5mm, annealed, 99.95%
Molybdenum, foil, 6mm disks, thickness 0.5mm, annealed, 99.9%
Molybdenum, foil, 6mm disks, thickness 0.75mm, annealed, 99.9%
Molybdenum, foil, 8mm disks, thickness 0.005mm, 99.9%
Molybdenum, foil, 8mm disks, thickness 0.006mm, 99.9%
Molybdenum, foil, 8mm disks, thickness 0.007mm, 99.9%
Molybdenum, foil, 8mm disks, thickness 0.008mm, 99.9%
Molybdenum, foil, 8mm disks, thickness 0.009mm, 99.9%

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