Xanthinuria Type I With a Novel Mutation of Xanthine Dehydrogenase

Tanaka, Kenichiro; Kanazawa, Ippei; Yamasaki, Haruka; Hasegawa, Hiroshi; Ichida, Kimiyoshi; Sugimoto, Toshitsugu

doi:10.1097/maj.0000000000000498

Cited by 11 publications

(10 citation statements)

References 8 publications

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“…In addition, several clinical studies have been performed on the mutagenesis of XO, in which either the mutations led to xanthinuria (XOR deficiency leading to hypouricemia) or hyperuricemia (higher activity of XOR). Some of these trials on human cases with xanthinuria have reported XO mutants corresponding to R149C, R228T, K721X, R824X, R880X, T909M, R912W, and R1282X …”

Section: Resultsmentioning

confidence: 99%

Computational Characterization of the Inhibition Mechanism of Xanthine Oxidoreductase by Topiroxostat

2023

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Xanthine oxidase (XO) is a member of the molybdopterin-containing enzyme family. It interconverts xanthine to uric acid as the last step of purine catabolism in the human body. The high uric acid concentration in the blood directly leads to human diseases like gout and hyperuricemia. Therefore, drugs that inhibit the biosynthesis of uric acid by human XO have been clinically used for many years to decrease the concentration of uric acid in the blood. In this study, the inhibition mechanism of XO and a new promising drug, topiroxostat (code: FYX-051), is investigated by employing molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) calculations. This drug has been reported to act as both a noncovalent and covalent inhibitor and undergoes a stepwise inhibition by all its hydroxylated metabolites, which include 2-hydroxy-FYX-051, dihydroxy-FYX-051, and trihydroxy-FYX-051. However, the detailed mechanism of inhibition of each metabolite remains elusive and can be useful for designing more effective drugs with similar inhibition functions. Hence, herein we present the computational investigation of the structural and dynamical effects of FYX-051 and the calculated reaction mechanism for all of the oxidation steps catalyzed by the molybdopterin center in the active site. Calculated results for the proposed reaction mechanisms for each metabolite's inhibition reaction in the enzyme's active site, binding affinities, and the noncovalent interactions with the surrounding amino acid residues are consistent with previously reported experimental findings. Analysis of the noncovalent interactions via energy decomposition analysis (EDA) and noncovalent interaction (NCI) techniques suggests that residues L648, K771, E802, R839, L873, R880, R912, F914, F1009, L1014, and A1079 can be used as key interacting residues for further hybrid-type inhibitor development.

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Section: Resultsmentioning

confidence: 99%

Computational Characterization of the Inhibition Mechanism of Xanthine Oxidoreductase by Topiroxostat

2023

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“…Some of these trials on human cases with xanthinuria have reported XO mutants corresponding to R149C, 191 R228T, 192 K721X, 193 R824X, 194 R880X, 194 T909M, 195 R912W, 196 and R1282X. 197 Investigating the effects of the mutations on xanthine and allopurinol and comparing the results with our non-bonded contributions can provide a good insight into the residues with significant effects on the XO inhibition. This can be used in future studies on designing more efficient drugs with better covalent inhibitory effects and better non-covalent inhibition of the XO by interacting with the candidate residues.…”

Section: Non-covalent Interactions Between the Xo And Studied Inhibitorsmentioning

confidence: 98%

Computational Characterization of the Inhibition Mechanism of Xanthine Oxidoreductase by Topiroxostat

Maghsoud

Dong

Cisneros

2022

Preprint

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Xanthine oxidase (XO) is a member of the molybdopterin-containing enzyme family. It interconverts xanthine to uric acid as the last step of purine catabolism in the human body. The high uric acid concentration in the blood directly leads to human diseases like gout and hyperuricemia. Therefore, drugs that inhibit the biosynthesis of uric acid by human XO have been clinically used for many years to decrease the concentration of uric acid in the blood. In this study, the inhibition mechanism of XO and a new promising drug, Topiroxostat (code: FYX-051), is investigated by employing molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) calculations. This drug has been reported to act as both a non-covalent and covalent inhibitor and undergoes a stepwise inhibition by all its hydroxylated metabolites, which include 2-hydroxy-FYX-051, dihydroxy-FYX-051, and trihydroxy-FYX-051. However, the detailed mechanism of inhibition of each metabolite remains elusive and can be useful for designing more effective drugs with similar inhibition functions. Hence, herein we present the computational investigation of the structural and dynamical effects of FYX-051 and the calculated reaction mechanism for all the oxidation steps catalyzed by the molybdopterin center in the active site. Calculated results for the proposed reaction mechanisms for each metabolite’s inhibition reaction in the enzyme’s active site, binding affinities, and the non-covalent interactions with surrounding amino acid residues are consistent with previously reported experimental findings. Analysis of the non-covalent interactions via EDA and NCI suggests residues L648, K771, E802, R839, L873, R880, R912, F914, F1009, L1014, and A1079 can be used as key interacting residues for further hybrid-type inhibitor development.

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“…We showed that higher uric acid/xanthine and xanthine/hypoxanthine ratios were associated with higher DBP z-scores. Our hypothesis is based on studies examining the effect of a deficiency in XO on purine metabolite concentrations [33][34][35]; however, whether an opposite effect in purine metabolite concentrations occurs by an increased XO activity is unknown. Further investigation is required to examine whether increased XO activity leads to a relative increase in the more downstream metabolites and that this will not be compensated by alterations in urinary excretion of uric acid or xanthine, or the degradation of hypoxanthine to inosine monophosphate by hypoxanthine-guanine phosphoribosyltransferase [35].…”

Section: Discussionmentioning

confidence: 99%

“…As is known that XO is a rate-limiting enzyme, an increased XO activity may lead to a relative decrease in the more upstream metabolites, thus, lower hypoxanthine compared with xanthine and lower xanthine compared with uric acid concentration, resulting in higher ratios of xanthine/hypoxanthine, uric acid/ xanthine, and uric acid/hypoxanthine. The latter is based on animal studies and studies examining patients with xanthine oxidoreductase deficiency, a genetic disorder called xanthinuria, who have decreased concentrations of the more upstream metabolites [32][33][34][35].…”

mentioning

confidence: 99%

Associations of plasma uric acid and purine metabolites with blood pressure in children

Scheepers

Boonen

Pijnenburg

et al. 2017

Journal of Hypertension

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Xanthinuria Type I With a Novel Mutation of Xanthine Dehydrogenase

Cited by 11 publications

References 8 publications

Computational Characterization of the Inhibition Mechanism of Xanthine Oxidoreductase by Topiroxostat

Computational Characterization of the Inhibition Mechanism of Xanthine Oxidoreductase by Topiroxostat

Computational Characterization of the Inhibition Mechanism of Xanthine Oxidoreductase by Topiroxostat

Associations of plasma uric acid and purine metabolites with blood pressure in children

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