Chemical Nature and Reaction Mechanisms of the Molybdenum Cofactor of Xanthine Oxidoreductase

Okamoto, Ken; Kusano, Tyuzi; Nishino, Tokuzo

doi:10.2174/1381612811319140010

Cited by 79 publications

(107 citation statements)

References 68 publications

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“…Both contain a molybdenum cofactor (molybdopterin), two Fe-S clusters of the [2Fe-2S] type and FAD [148]. All of these redox centres are positioned linearly, and close enough to allow sequential transfer of electrons through them.…”

Section: Ec 1161: Oxidoreductases Of Metal Ionsmentioning

confidence: 99%

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Review of NAD(P)H-dependent oxidoreductases: Properties, engineering and application

Vidal

Kelly

Mordaka

et al. 2018

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

233

147

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A B S T R A C T NAD(P)H-dependent oxidoreductases catalyze the reduction or oxidation of a substrate coupled to the oxidation or reduction, respectively, of a nicotinamide adenine dinucleotide cofactor NAD(P)H or NAD(P) + . NAD(P)Hdependent oxidoreductases catalyze a large variety of reactions and play a pivotal role in many central metabolic pathways. Due to the high activity, regiospecificity and stereospecificity with which they catalyze redox reactions, they have been used as key components in a wide range of applications, including substrate utilization, the synthesis of chemicals, biodegradation and detoxification. There is great interest in tailoring NAD(P)H-dependent oxidoreductases to make them more suitable for particular applications. Here, we review the main properties and classes of NAD(P)H-dependent oxidoreductases, the types of reactions they catalyze, some of the main protein engineering techniques used to modify their properties and some interesting examples of their modification and application.

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Section: Ec 1161: Oxidoreductases Of Metal Ionsmentioning

confidence: 99%

“…Then, the bond between the Mo cofactor and the substrate is hydrolysed, releasing the free hydroxylated product. Finally, the hydride groups are transferred first to the Fe-S centers, then to FAD and eventually to NAD(P) + to yield NAD(P)H [148] (Fig. 13).…”

Section: Ec 1161: Oxidoreductases Of Metal Ionsmentioning

confidence: 99%

Review of NAD(P)H-dependent oxidoreductases: Properties, engineering and application

Vidal

Kelly

Mordaka

et al. 2018

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

233

147

View full text Add to dashboard Cite

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“…1). 41 In mammalian tissues, XOR is found in various organs including the heart, lung, kidney, and brain as well as in the plasma, with the elevated levels being found in liver and intestine. 42 XOR is a cytosolic enzyme, 43 but it also discharges into the circulation under certain pathological conditions.…”

Section: Structure Overview and Functionsmentioning

confidence: 99%

Toward an Understanding of Structural Insights of Xanthine and Aldehyde Oxidases: An Overview of their Inhibitors and Role in Various Diseases

Kumar

Joshi

Kler

et al. 2017

Medicinal Research Reviews

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Almost all drug molecules become the substrates for oxidoreductase enzymes, get metabolized into more hydrophilic products and eliminated from the body. These metabolites sometime may be more potent, active, inactive, or toxic in nature compared to parent molecule. Xanthine oxidoreductase and aldehyde oxidase belong to molybdenum containing family and are well characterized for their structures and functions, in particular to their ability to oxidize/hydroxylate the xenobiotics. Their upregulated clinical levels causing oxidative stress are associated with pathways either directly involved in the progression of diseases, gout, or indirectly with the succession of other diseases such as diabetes, cancer, etc. Herein, we have put forth a comprehensive review on the xanthine and aldehyde oxidases pertaining to their structures, functions, pathophysiological role, and a comparative analysis of structural insights of xanthine and aldehyde oxidases' binding domains with endogenous ligands or inhibitors. Though both the enzymes are molybdenum containing and are likely to share some common pathways and interact with inhibitors in a similar manner but we have focused on structural prerequisites for inhibitor specificity to both the enzymes keeping in view of the existing X-ray structures. This review also provides futuristic implications in the design of inhibitors derived from inorganic complexes or small organic molecules considering the spatial features and structural insights of both the enzymes.

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“…Xanthine oxidase (XO) is a form of Xanthine oxidoreductase (XOR) enzyme which is a kind of molybdoflavoenzyme that catalyzes the oxidation of hypoxanthine to xanthine or xanthine to uric acid [Okamoto, Kusano and Nishino, (2013), Danijela, Kostić, Danica S. Dimitrijević, Gordana S. Stojanović, Ivan R. Palić, Aleksandra S. Đorđević, and Jovana D. Ickovski, (2015) and, Zhang, Cheng, Xu, Lu, (2016)]. Xanthine oxidoreductase (XOR) exists in a great variety of organisms from bacteria to higher plants and humans (Okamoto et al, (2013)].…”

Section: Introductionmentioning

confidence: 99%

Probing the mechanism of xanthine oxidase and 2-amino xanthine: an implication of energy, charge bond order and wave function.

Bitew

2018

IJAC

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Xanthine oxidase (XO) is an important molybdenum-containing enzyme catalyzing the hydroxylation of hypoxanthine to xanthine and xanthine to uricacid. The mechanistic action by which xanthine oxidase oxidizes purine derivatives is not well understood. A better understanding of the overall mechanism is supposed to enhance our ability to control the metabolic properties of potential drug molecules metabolized by this enzyme. In this work a model substrate, 2-Amino Xanthine has been used to study the mechanistic action of the enzyme. For this reason, the present theoretical work was intended to probe a unified mechanism for the oxidation of 2-Amino Xanthine by xanthine oxidase. Parameters like total electronic energy, Mulliken atomic charges, wave functions, and percent contribution of chemical fragments were generated using a DFT method employing B3LYP level of theory with 6-31G(d',p') basis set for nonmetals and LanL2DZ basis set for molybdenum. AOmix software package that employs single point energy output as an input file was employed for wave function and percent fragment analysis. From these result new reaction intermediates and plausible reaction mechanism root has been reported for reductive and oxidative half reaction using 2-Amino Xanthine as model substrate. In this work it can be concluded that a stepwise mechanistic route with hydrogen bonding reaction complex and active site resemble very rapid Mo (V) intermediate is most plausible.

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Chemical Nature and Reaction Mechanisms of the Molybdenum Cofactor of Xanthine Oxidoreductase

Cited by 79 publications

References 68 publications

Review of NAD(P)H-dependent oxidoreductases: Properties, engineering and application

Review of NAD(P)H-dependent oxidoreductases: Properties, engineering and application

Toward an Understanding of Structural Insights of Xanthine and Aldehyde Oxidases: An Overview of their Inhibitors and Role in Various Diseases

Probing the mechanism of xanthine oxidase and 2-amino xanthine: an implication of energy, charge bond order and wave function.

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