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Review
. 2015 Mar;20(2):195-207.
doi: 10.1007/s00775-014-1210-x. Epub 2014 Dec 12.

Mechanistic insights into xanthine oxidoreductase from development studies of candidate drugs to treat hyperuricemia and gout

Takeshi Nishino  1 , Ken Okamoto
Affiliations
Review

Mechanistic insights into xanthine oxidoreductase from development studies of candidate drugs to treat hyperuricemia and gout

Takeshi Nishino et al. J Biol Inorg Chem. 2015 Mar.

Abstract

Xanthine oxidoreductase (XOR), which is widely distributed from humans to bacteria, has a key role in purine catabolism, catalyzing two steps of sequential hydroxylation from hypoxanthine to xanthine and from xanthine to urate at its molybdenum cofactor (Moco). Human XOR is considered to be a target of drugs not only for therapy of hyperuricemia and gout, but also potentially for a wide variety of other diseases. In this review, we focus on studies of XOR inhibitors and their implications for understanding the chemical nature and reaction mechanism of the Moco active site of XOR. We also discuss further experimental or clinical studies that would be helpful to clarify remaining issues.

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Figures

Fig. 1
Fig. 1
Schematic illustration of purine metabolism in primates. Hypoxanthine formed from inosine is hydroxylated to afford xanthine. Xanthine is also formed from guanine by deamination. Xanthine is further hydroxylated to uric acid (the final product in primates) in cytosol. Uric acid is converted to allantoin in peroxisomes of other mammalian species
Fig. 2
Fig. 2
Structure of bovine XOR. Top Primary structure of bovine XOR subunit illustrated as three domains connected with two linker peptides. The N-terminal (red), the C-terminal (blue) and the intermediate (yellow) domains contain the iron–sulfur centers, the Moco center and the FAD center, respectively. Middle left Homodimer structure of bovine XOR illustrated with one subunit as a ribbon model and the other as a space-filling model. Right Cofactor arrangement. Figures were generated from PDB ID 1F4Q. Bottom Hydroxylation reactions of hypoxanthine to xanthine and xanthine to uric acid. Two electrons are transferred to the Mo atom of Moco
Fig. 3
Fig. 3
Inhibitors of XOR. A Mechanism of inhibition of XOR by allopurinol. Allopurinol is a good substrate of XOR and is converted to oxipurinol with concomitant reduction of Mo (VI) to Mo(IV). Mo(IV) is mainly re-oxidized via electron transfer to the other cofactors in XOR. During turnover, Mo(IV) reacts with oxipurinol to form a tightly bound complex; its crystal structure is shown as an electron-density map. B Representative potent inhibitors reported after the clinical application of allopurinol. (a) from ICN Pharma: IC50, 25 nM; (b) from C. Silipo: IC50, 10 nM; (c) from E. Merck: IC50, 40 nM; (d) from Eli Lilly: IC50, 13 nM. In box inhibitors that have been examined in detail, including crystal structure of the XOR-bound form. (e) BOF-4272; (f) febuxostat, TEI-6720; (g) pyranoxostat, Y-700; (h) topiroxostat, FYX-051
Fig. 4
Fig. 4
Crystal structures of potent inhibitors bound to the XOR Moco center. A Inhibitors and amino acid residues are illustrated by stick models with atom colors reproduced from PDB. Salicylate, PDB:1FO4; oxipurinol, PDB:3BDJ; BOF-4272: data deposition in process; Febuxostat, PDB:1N5X. B Schematic model of interaction of febuxostat with the active site cavity. Interaction of febustostat with the open cavity affords a weakly bound complex with the K i values determined by steady-state kinetics using initial velocity, and this is subsequently converted to a tightly bound complex, of which the K d value is too low to be determined accurately (see text)
Fig. 5
Fig. 5
Crystal structure of topiroxostat (FYX-051) bound to XOR and binding modes of substrates. A Electron-density map around the Mo atom in the complex of fully active XOR with topiroxostat. B Interaction of amino acid residues in the protein cavity. Two protonated glutamate residues, E802 and E1261, are at hydrogen-bonding distances from N atoms of topiroxostat. C Electron density around the Mo atom in the complex of fully active XOR with topiroxostat, showing electron density between Mo and a carbon atom of topiroxostat. See similar electron densities of two sulfur atoms connected to pterin moiety. D Electron density around the Mo atom in the case of inactive desulfo-XOR, showing no electron density between Mo and a carbon atom. Lower electron density is observed, similar to that another oxygen atom coordinated to the equatorial position. Both are viewed from the apical position. Differences in electron density are indicated by arrows
Fig. 6
Fig. 6
Crystal structure of XOR with oxipurines. A Two binding models have been proposed. (a) Binding mode proposed by the authors of this paper. (b) Binding mode proposed by Hille et al. and Kisker et al. B Binding mode for the complex of desulfo-XOR with hypoxanthine obtained by the authors of this paper. C Crystal structures urate bound to demolybdo-XOR. D Urate bound to reduced Mo of fully active XOR
Fig. 7
Fig. 7
Schematic presentation of possible metabolic and pathological roles of XOR. ROS reactive oxygen species, NOS nitric oxide synthetase. ·OH can be produced under special conditions
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