The complete catalytic mechanism of xanthine oxidase: a computational study

Ribeiro, Pedro M. G.; Fernandes, Henrique S.; Maia, Luísa B.; Sousa, Sérgio F.; Moura, José J. G.; Cerqueira, Nuno M. F. S. A.

doi:10.1039/d0qi01029d

Cited by 20 publications

(27 citation statements)

References 77 publications

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“…Proton transfer from the molybdopterin residue’s hydroxyl group to Glu1261 is an initial step required for the conversion of xanthine to uric acid by XO. Glu802, Arg880, and Thr1010 have also been reported to be essential in the catalytic transformation of xanthine to uric acid [ 37 , 38 ]. Therefore, interactions observed between 2 and 4 and these residues provide a reasonable mechanistic background to the compounds’ XO inhibitory activity.…”

Section: Resultsmentioning

confidence: 99%

Oxidized Resveratrol Metabolites as Potent Antioxidants and Xanthine Oxidase Inhibitors

et al. 2022

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Resveratrol is a well-known natural polyphenol with a plethora of pharmacological activities. As a potent antioxidant, resveratrol is highly oxidizable and readily reacts with reactive oxygen species (ROS). Such a reaction not only leads to a decrease in ROS levels in a biological environment but may also generate a wide range of metabolites with altered bioactivities. Inspired by this notion, in the current study, our aim was to take a diversity-oriented chemical approach to study the chemical space of oxidized resveratrol metabolites. Chemical oxidation of resveratrol and a bioactivity-guided isolation strategy using xanthine oxidase (XO) and radical scavenging activities led to the isolation of a diverse group of compounds, including a chlorine-substituted compound (2), two iodine-substituted compounds (3 and 4), two viniferins (5 and 6), an ethoxy-substituted compound (7), and two ethoxy-substitute,0d dimers (8 and 9). Compounds 4, 7, 8, and 9 are reported here for the first time. All compounds without ethoxy substitution exerted stronger XO inhibition than their parent compound, resveratrol. By enzyme kinetic and in silico docking studies, compounds 2 and 4 were identified as potent competitive inhibitors of the enzyme, while compound 2 and the viniferins acted as mixed-type inhibitors. Further, compounds 2 and 9 had better DPPH scavenging activity and oxygen radical absorbing capacity than resveratrol. Our results suggest that the antioxidant activity of resveratrol is modulated by the effect of a cascade of chemically stable oxidized metabolites, several of which have significantly altered target specificity as compared to their parent compound.

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Section: Resultsmentioning

confidence: 99%

Oxidized Resveratrol Metabolites as Potent Antioxidants and Xanthine Oxidase Inhibitors

et al. 2022

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“…Xanthine oxidase is a homodimer containing one flavin adenine dinucleotide (FAD), one molybdenum cofactor (Moco), and two iron–sulfur centers in each of its two subunits. , Although aspects of the mechanism by which XO catalyzes XA oxidation remain uncertain, most proposed reaction schemes share some common features. The reaction requires XA binding to Moco and donation of its two electrons to the enzyme, thereby reducing Mo 6+ to Mo 4+ .…”

Section: Resultsmentioning

confidence: 99%

“…The reaction requires XA binding to Moco and donation of its two electrons to the enzyme, thereby reducing Mo 6+ to Mo 4+ . The two electrons are then shuttled from the Moco to the FAD cofactor through the iron–sulfur centers, reducing FAD to FADH 2 . , This reductive half reaction is summarized in reaction . Electrons are then transferred from the enzyme to NiOOH sites on the GLAD electrode surface according to reaction , yielding Ni(OH) 2 and reoxidizing XO(FADH 2 ) to its original XO(FAD) form.…”

Section: Resultsmentioning

confidence: 99%

Amperometric Determination of Xanthine Using Nanostructured NiO Electrodes Loaded with Xanthine Oxidase

Tripathi

Elias

Jemere

et al. 2022

ACS Food Sci. Technol.

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Nickel oxide (NiO) thin films prepared by glancing angle deposition (GLAD) were investigated as electrodes for enzymatic electrochemical quantification of xanthine, a noted indicator of meat freshness. The large surface area of the macroporous GLAD NiO electrodes provided a suitable scaffold to successfully immobilize the enzyme xanthine oxidase (XO), and this XO immobilization was characterized by cyclic voltammetry, electrochemical impedance spectroscopy, and X-ray photoelectron spectroscopy. The XO-modified GLAD NiO electrodes electrochemically oxidize xanthine, with electron transfer from this adsorbed XO to the (Ni2+/Ni3+) redox species resulting in a strong amperometric response to xanthine in a reagent-free alkaline medium. Under optimal conditions, the fabricated xanthine biosensor exhibited a rapid response (∼7 s), wide dynamic range (0.1–650 μM), good reproducibility (relative standard deviation of ∼4%, n = 18), superior limit of detection (37 nM), and very high sensitivity (1.1 μA·μM–1·cm–2 in the low concentration range from 0.1–5 μM and 0.3 μA·μM–1·cm–2 in the higher concentration range from 5–650 μM). The biosensor was also evaluated against a selection of potential interferents commonly found in fish samples (hypoxanthine, uric acid, glucose, and sodium benzoate), demonstrating good selectivity toward xanthine. A low Michaelis–Menten constant (K m) of 0.4 mM for xanthine signifies the high affinity of the enzymatic sensor toward the target analyte. Measurements in real fish samples were also successfully performed, revealing strongly increased xanthine sensitivity in the presence of fish matrices (from 0.085 μA μM–1 without fish extract to as much as 0.27 μA μM–1).

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“…This general approach has been used with success in the detailed atomic-level study of the catalytic mechanism of several enzymes. 64–69…”

Section: Methodsmentioning

confidence: 99%

The critical role of Asp206 stabilizing residues on the catalytic mechanism of the Ideonella sakaiensis PETase

Magalhães

Fernandes

Sousa

2022

Catal. Sci. Technol.

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The complete catalytic mechanism of xanthine oxidase: a computational study

Abstract: In this article, Quantum mechanical/molecular mechanical (QM/MM) methods were used to study the full catalytic mechanism of xanthine oxidase (XO). The XO catalyzes the conversion of xanthine (XAN) to uric...

Cited by 20 publications

References 77 publications

Oxidized Resveratrol Metabolites as Potent Antioxidants and Xanthine Oxidase Inhibitors

Oxidized Resveratrol Metabolites as Potent Antioxidants and Xanthine Oxidase Inhibitors

Amperometric Determination of Xanthine Using Nanostructured NiO Electrodes Loaded with Xanthine Oxidase

The critical role of Asp206 stabilizing residues on the catalytic mechanism of the Ideonella sakaiensis PETase

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